WO2017077528A2

WO2017077528A2 - Methods and pharmaceutical compositions for treatment of lung inflammation

Info

Publication number: WO2017077528A2
Application number: PCT/IL2016/051174
Authority: WO
Inventors: Edward George BARRETT; Andrew Lurie Salzman
Original assignee: Salzman Lovelace Investments, Ltd.
Priority date: 2015-11-02
Filing date: 2016-10-31
Publication date: 2017-05-11
Also published as: WO2017077528A3

Abstract

The present invention relates to use of resolvin molecules selected from mono- or poly-hydroxylated eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or n-3 docosapentanoic acid (n-3 DPA), e.g., Rv E1, or pharmaceutically acceptable salts, esters, or amides thereof, for preventing or treating lung inflammation due to pseudomonal infection or a viral infection.

Description

METHODS AND PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF

LUNG INFLAMMATION

TECHNICAL FIELD

[0001] The present invention provides methods and pharmaceutical compositions for treatment of lung inflammation, more particularly lung inflammation due to pseudomonal infection or a viral infection.

BACKGROUND ART

[0002] Resolvins are endogenous picomolar-potent small molecules derived from cellular metabolism of dietary omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA; C20:5) and docosahexaenoic acid (DHA; C22:6), that activate a complex intracellular mechanism by which tissue inflammation is modulated and ultimately resolved. These compounds are, in fact, multi-focal-acting mediators acting via limiting polymorphonuclear (PMN) cell/neutrophil transendothelial migration in vitro and infiltration in vivo (Pluess et al., 2007; Rittirsch et al., 2009), as well as enhancing proinflammatory chemokine scavenging (Buras et al., 2005), non-phlogistic recruitment on monocytes and phagocytosis, and phagocyte clearance via the lymphatics (Spite et al., 2009).

[0003] A particular such compound, resolvin El (RvEl), is an enzymatically-oxygenated lipid mediator that functions as a specialized pro-resolution mediator and actively "turns off" the inflammatory response (Farolan et al., 1996). RvEl acts via its binding to the two discrete G-protein coupled receptors (GPCRs) ChemR23 and BLT-1 (Levy, et al. 2012; Seki et al 2010), which transduce the resolution of inflammation via the removal ("efferocytosis") of neutrophils (PMNs) and the reduction of a broad array of proinflammatory cytokines and chemokines. The relevance of these receptors is demonstrated in genetic deletion models in mice. For instance, ChemR23(-/-) mice challenged with pneumonia virus of mice display higher mortality/morbidity, alteration of lung function, delayed viral clearance, and increased neutrophil infiltration (Bondue, et al. 2011).

[0004] RvEl has been shown to be effective in various rodent models of inflammatory disease, e.g., asthma, colitis, pneumonia, acute lung injury (ALI), peritonitis, periodontitis, and renal fibrosis (Haworth et al., 2008; Gilroy et al., 2004; Flierl et al., 2008; Serhan et al., 2008; Kurihara et al., 2013; Schwartz et al., 1994; Schwab et al., 2007; Busse et al., 2007; Bettelli et al, 2007; Langrish et al, 2005), at doses as low as 4 μg/kg. As shown in models of inflammation such as allergic asthma, RvEl reduces IL-6, IL-17 and IL-23, and increases IFN-y and LXA4 in lungs to dampen allergic airway inflammation (Gilroy et al., 2004); and decreases eosinophil and lymphocyte recruitment in a murine model of asthma (Flierl et al., 2008; Serhan et al., 2008). These effects on inflammation were associated with a reduction in airway hyperresponsiveness (Buras et al., 2005; Spite et al., 2009; Seki et al., 2010). With respect to more neutrophilic disease models, RvEl administered prior to a murine model of aspiration pneumonia (hydrochloric acid with subsequent Escherichia coli challenge) is associated with a reduction in pro-inflammatory cytokines, decreased pulmonary PMN accumulation, enhanced bacterial clearance, and improved survival (Seki et al., 2010). Administration of RvEl stimulates murine dermal healing, reducing neutrophilic infiltration and stimulating re-epithelialization (Allard et al., 2011; Fredman et al, 2011; Gao et al, 2013; Hasturk et al, 2007; Herrera et al, 2008). A further study has shown that RvEl is also protective in periodontal disease, a chronic inflammatory disease in which infection leads to PMN-mediated tissue injury around the tooth, as demonstrated by its effect on stimulation of bone regeneration in lapine models of periodontitis (Amin et al., 2013).

[0005] In mammals, alpha-linolenic acid is converted via elongation and desaturation to EPA and subsequently to DHA. An intermediate in the conversion of EPA to DHA is n-3 docosapentaenoic acid (n-3 DP A), which carries 22 carbons and contains five double bonds, with the first double bond being found on carbon 7 (Dalli et al., 2013).

Pseudomonal pneumonia

[0006] Pseudomonal pneumonia is a common hospital acquired pneumonia caused by the Gram-negative bacterium Pseudomonas aeruginosa (P. aeruginosa), and one of the more clinically difficult-to-treat hospital-acquired infections. A primary infection normally develops in debilitated individuals with pre-existing lung disease, such as bronchiectasis, chronic bronchitis or cystic fibrosis, or following an aspiration pneumonia induced by sedation or endotracheal intubation; and a secondary infection usually develops after the eradication of more sensitive flora with antibiotics and in patients with neutropaenia due to cytotoxic chemotherapy. Pseudomonal pneumonia is of considerable clinical significance in patients with cystic fibrosis since it correlates with worsening clinical condition and increased mortality. Previous work on treating a model bacterial (E. coli) pneumonia with RvEl was reported by Seki et ah, 2010. Although RvEl was shown effective for resolving an E. coli infection, there are no reports describing its efficacy of therapies for treating pseudomonal or non-enterobacterial infections, which form biofilms in the lungs that significantly impair their clearance and limit the efficacy of active therapy for cystic fibrosis, in which infections become entrenched, chronic, and nearly impossible to eradicate. The consequences of such chronic pseudomonal infections are inflammation and progressive respiratory insufficiency, as well as alterations in the architecture of the lung. Despite the success of RvEl therapy for the experimental E. coli infection of the lung, it is unknown whether resolvin therapy can favorably impact the course of pulmonary pseudomonal disease.

Viral pneumonia

[0007] Despite immunization programs, viruses are a major cause of morbidity and mortality throughout the world, especially among individuals with high risk factors such as diabetes, asthma, or pregnancy. Further, pneumonia impacts young children and older adults disproportionately (older adults are more susceptible to more severe infection due to developing and aging immune responses) with viral pneumonia/pneumonitis accounting for about 200 million cases globally. In persons requiring hospitalization, mortality may be as high as 10%, and in those requiring intensive care it may reach 30-50%. The development of new treatments for viral pneumonitis would thus represent a major public health advance.

[0008] Vaccine strategies dominate the approaches for prevention of seasonal influenza and respiratory syncytial virus (RSV) (passive antibody protection); however, their effectiveness is suboptimal for a variety of reasons (seasonal-matching, compliance, age, health, cost, etc.). Treatment of viral pneumonia may include antiviral approaches for influenza A virus (IAV) although their effectiveness is dependent on time of delivery after onset of symptoms and severity of disease. There is no known specific efficacious treatment for pneumonia caused by RSV, severe acute respiratory syndrome (SARS) coronavirus, adenovirus, hantavirus, parainfluenza; where treatment is largely supportive, although ribavirin may be recommend with varying effects.

[0009] As schematically shown in Fig. 1, severe viral pneumonitis is characterized by acute inflammation and epithelial lung damage requiring hospitalization. Endogenous lipid mediators such as the RvEl play a pivotal role in the vascular response and leukocyte trafficking during inflammation, from the phase of initiation to ultimate resolution. Resolvins stimulate the recruitment of non-phlogistic monocytes. These cells are transformed into resolving macrophages that are then able clear apoptotic PMNs in a process entitled "efferocytosis". Additional signs of resolution include the sequestration of pro-inflammatory cytokines, the clearance of PMNs from epithelial surfaces, the phagocytosis of apoptotic PMNs, and the removal of inflammatory debris and microbial invaders. After this has taken place, normal structure and homeostasis can be restored. Conversely, failed resolution can lead to aberrant repair-fibrosis, and death in severe cases.

[0010] Understanding virally-mediated induction of lung inflammation also provides an important opportunity to evaluate the impact of the broad immuneregulation by RvEl on host defense. By definition, pro-resolving mediators or therapeutics should enhance host defense rather than immunocompromise the host by immunosuppression. Use of existing anti-inflammatory approaches such as corticosteroids in the context of virally mediated inflammation is controversial due to their potential to suppress protective immune responses (Arita et ah, 2005).

[0011] While other proresolution mediators such as RvDl, RvD2, lipoxin A4 and protectin Dl have been evaluated in the context of viral challenge, RvEl has not (Morita et al., 2013). RvDl, RvD2 and lipoxin were shown to have only a limited to no effect on viral load, viral induced inflammation and cytokines (IL-6, IP- 10, CXCL2), following H1N1 infection in mice.

SUMMARY OF INVENTION

[0012] It has now been found, in accordance with the present invention, that a resolvin molecule such as a tri-hydroxylated EPA, more particularly RvEl, is highly effective in reducing both P. aeruginosa- and influenza A virus-induced inflammation in the lung and ameliorating associated inflammatory sequelae, and may thus be used for prevention and/or treatment of lung inflammation caused by pseudomonal infection or a viral infection.

[0013] In one aspect, the present invention thus relates to a method for prevention or treatment of lung inflammation by administration of a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof. More specifically, the present invention relates to a method for preventing or treating lung inflammation due to pseudomonal infection or a viral infection in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a resolvin molecule selected from a mono- or poly- hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0014] In another aspect, the present invention provides a pharmaceutical composition for prevention or treatment of lung inflammation due to pseudomonal infection or a viral infection, said composition comprising a resolvin molecule selected from a mono- or poly- hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof, and a pharmaceutically acceptable carrier.

[0015] In yet another aspect, the present invention relates to use of a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof, for the preparation of a pharmaceutical composition for prevention or treatment of lung inflammation due to pseudomonal infection or a viral infection.

[0016] The method of the present invention, when used for preventing or treating lung inflammation due to pseudomonal infection, may further comprise administration of at least one antibiotic agent; and when used for preventing or treating lung inflammation due to a viral infection, may further comprise administration of at least one antiviral agent.

[0017] In a further aspect, the present invention thus provides a kit for preventing or treating lung inflammation due to pseudomonal infection or a viral infection, wherein: said kit for preventing or treating lung inflammation due to pseudomonal infection comprises: (i) a pharmaceutical composition comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof; (ii) at least one antibiotic agent; and (iii) instructions for administration of said resolvin molecule and said at least one antibiotic agent sequentially in any order, or simultaneously, and

said kit for preventing or treating lung inflammation due to a viral infection comprises: (i) a pharmaceutical composition comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof; (ii) at least one antiviral agent; and (iii) instructions for administration of said resolvin molecule and said at least one antiviral agent sequentially in any order, or simultaneously. BRIEF DESCRIPTION OF DRAWINGS

[0018] Fig. 1 shows a schematic of lung injury following infectious challenge and the role of RvEl in restoring homeostasis. Severe viral pneumonitis is characterized by acute inflammation and epithelial lung damage requiring hospitalization (1). Endogenous lipid mediators, such as the RvEl, play a pivotal role in the vascular response and leukocyte trafficking during inflammation, from the phase of initiation to ultimate resolution. Resolvins (2) stimulate the recruitment of non-phlogistic monocytes. These cells are transformed into resolving macrophages that then are able to clear apoptotic PMNs in a process entitled "efferocytosis". Additional signs of resolution include the sequestration of pro -inflammatory cytokines, the clearance of PMNs from epithelial surfaces, the phagocytosis of apoptotic PMNs, and the removal of inflammatory debris and microbial invaders. After this has taken place, normal structure and homeostasis can be restored (3). Conversely, failed resolution can lead to aberrant repair-fibrosis, and death in severe cases.

[0019] Fig. 2 shows high levels of infection in mouse lungs infected with P. aeruginosa, and RvEl -induced reduction of the infection that is dose-dependent.

[0020] Fig. 3 shows high levels of the neutrophil marker MPO in P. aeruginosa-infected lungs, and RvEl-induced reduction of MPO that is dose-dependent.

[0021] Fig. 4 shows high levels of the inflammatory cytokine TNFa in P. aeruginosa- infected lungs, and RvEl-induced reduction of TNFa that is dose-dependent.

[0022] Figs. 5A-5F show lung histology indicating high levels of damage in mouse lungs infected with P. aeruginosa, and RvEl-induced reduction of the damage that is dose- dependent (5A, Sham; 5B, P. aeruginosa; 5C, RvEl 100 μg/kg; 5D, RvEl 30 μg/kg; 5E, RvEl 10 μg/kg; 5F, histological injury score. Panels a, b and c in 5A-5E represent xlO, x20, x40, respectively).

[0023] Fig. 6 shows that, while P. aeruginosa infection causes severe damage to the lungs that is accompanied by prominent MPO elevation, RvEl treatment (1 mg/kg, IP) significantly attenuates MPO levels in CFTR knockout mice infected with P. aeruginosa.

[0024] Figs. 7A-7B show lung histology (13A) and histological score (13B) indicating high levels of damage in CFTR mouse lungs infected with P. aeruginosa, and RvEl- induced reduction of the damage.

[0025] Fig. 8 shows that RvEl treatment (1 mg/kg, IP) 4 hours post induction of pneumonia with P. aeruginosa causes 100-order of magnitude reduction in bacterial load. [0026] Fig. 9 shows survival post lethal influenza A virus (IAV) infection (5.0x10 PFU/mouse; HK/2/68 mouse-adapted H3N2). Treatment started on day 2 post viral challenge, for 5 days (days 2-6), and included oral administration of RvEl (TID; 3.3 mg/kg based on initial pre-infection body weight), oseltamivir (2 mg/kg; twice a day [BID]), or both. *p<0.05, **p<0.001; determined by Log-rank (Mantel-Cox) Test.

[0027] Fig. 10 shows bronchoalveolar lavage (BAL) cells (neutrophils, macrophages, and lymphocytes) on day 5 post IAV infection (5.0x10 PFU/mouse; HK/2/68 mouse-adapted H3N2). RvEl was orally administered (TID; 3.3 mg/kg based on initial pre-infection body weight) starting on day 2 post infectious challenge. *p<0.05; determined by one-way Anova with Dunnet's post-test.

[0028] Fig. 11 shows IAV viral M gene expression in lung tissue on day 5 post infection (5.0xl0³ PFU/mouse; HK/2/68 mouse adapted H3N2). RvEl orally administered (TID; 3.3 mg/kg based on initial pre-infection body weight) starting on day 2 post infectious challenge. GAPDH - glyceraldehyde 3-phosphate dehydrogenase.

[0029] Fig. 12 shows BAL cells (neutrophils, macrophages, and lymphocytes) on day 5 post IAV infection (Hkx31; H3N2 influenza A; 5xl0² PFU). RvEl was delivered by the intranasal route (BID; 25 μg/kg based on initial pre-infection body weight) starting either 1 day prior to infectious challenge (prophylactic; P), or 2 days post infectious challenge (therapeutic; T). *p<0.05; **p<0.01; ***/?<0.001; determined by unpaired T-test.

[0030] Fig. 13 shows airway hyperresponsiveness (methacholine challenge day 5 post IAV infectious challenge). RvEl was delivered by the intranasal route (BID; 25 μg/kg based on initial pre-infection body weight] starting either 1 day prior to infectious challenge (prophylactic, P; left panel), or 2 days post infectious challenge (therapeutic, T; right panel). *p<0.0001 determined by Two-way ANOVA with Bonferroni post-test.

[0031] Fig. 14 shows IAV viral M gene expression in lung tissue on day 5 post IAV infection. RvEl was delivered by the intranasal route (BID; 25 μg/kg based on initial pre- infection body weight) starting either 1 day prior to infectious challenge (prophylactic; P), or 2 days post infectious challenge (therapeutic; T). GAPDH - glyceraldehyde 3-phosphate dehydrogenase.

DETAILED DESCRIPTION OF THE INVENTION

[0032] In one aspect, the present invention relates to a method for preventing or treating lung inflammation due to pseudomonal infection or a viral infection in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0033] The term "subject" as used herein refers to any mammal including, but not limited to, a human, non-human primate, horse, ferret dog, cat, cow, and goat. In a preferred embodiment, the term "subject" refers to a human, i.e., to an individual.

[0034] The term "therapeutically effective amount" as used herein refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result, i.e., to treat or prevent lung inflammation due to either pseudomonal infection or a viral infection. A therapeutically effective amount of a resolvin molecule as defined herein, or a pharmaceutically acceptable salt, ester, or amide thereof, may vary according to factors including the disease or injury state, age, sex, and weight of the individual, and the ability of the therapeutic compound to elicit a desired response in the subject treated. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of a disease, the effective amount used for prevention of said lung inflammation will be less than the effective amount used for treatment of said inflammation.

[0035] In certain embodiments, the resolvin molecule administered according to the method of the present invention, so as to prevent or treat said lung inflammation, is a mono-hydroxylated or poly-hydroxylated, e.g., di- or tri-hydroxylated, EPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0036] In other embodiments, the resolvin molecule administered according to the method of the present invention, so as to prevent or treat said lung inflammation, is a mono-hydroxylated or poly-hydroxylated, e.g., di- or tri-hydroxylated, DHA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0037] In further embodiments, the resolvin molecule administered according to the method of the present invention, so as to prevent or treat said lung inflammation, is a mono-hydroxylated or poly-hydroxylated, e.g., di- or tri-hydroxylated, n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0038] The resolvin molecule administered according to the method of the present invention has one or more asymmetric centers at each one of the hydroxyl groups thereof, and may accordingly exist both as enantiomers, i.e., optical isomers (R, S, or racemate, wherein a certain enantiomer may have an optical purity of about 90%, about 95%, about 99% or more) and as diastereoisomers. Accordingly, each one of the hydroxyl groups of the resolvin molecule or pharmaceutically acceptable salt, ester, or amide thereof independently has either an R or S configuration, or is a racemic mixture.

[0039] Optically active forms of the resolvin molecules used may be prepared using any method known in the art, e.g., by resolution of the racemic form by recrystallization techniques; by chiral synthesis; by extraction with chiral solvents; or by chromatographic separation using a chiral stationary phase. A non-limiting example of a method for obtaining optically active materials is transport across chiral membranes, i.e., a technique whereby a racemate is placed in contact with a thin membrane barrier, the concentration or pressure differential causes preferential transport across the membrane barrier, and separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including simulated moving bed chromatography, can also be used. A wide variety of chiral stationary phases are commercially available.

[0040] In certain embodiments, the method of the invention comprises administering a therapeutically effective amount of a resolvin molecule selected from a mono- or poly- hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt or ester thereof. In particular embodiments, the resolvin molecule administered is a compound having a carboxyl group of the formula -COOR, wherein R is H, (Ci-C₈)alkyl, (C₃- Cio)cycloalkyl, -CH₂-CHOH-CH₂OH, or -CH-(CH₂OH)₂; and one or more hydroxyl groups each independently of the formula -OP, wherein P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof.

[0041] The term "alkyl" as used herein typically means a linear or branched saturated hydrocarbon radical having 1-8 carbon atoms and includes, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, ie/t-butyl, n-pentyl, isoamyl, 2,2-dimethylpropyl, n- hexyl, n-heptyl, n-octyl, and the like. In certain embodiments, the term "alkyl" refers to (Ci-C6)alkyl groups, e.g., (Ci-C₄)alkyl groups such as methyl, ethyl and isopropyl.

[0042] The term "cycloalkyl" as used herein means a cyclic or bicyclic hydrocarbyl group having 3-10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, and the like. Particular such cycloalkyls are (C5-Cio)cycloalkyls, e.g., (Cs-C7)cycloalkyls. [0043] The term "hydroxyl protecting group" as used herein refers to any hydroxyl protecting group known in the art. An artisan skilled in the art can readily determine which protecting group(s) may be useful for the protection of the hydroxyl group(s), and standard methods are known in the art and are described in the literature. For example, suitable protecting groups are described in Green and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Chapters 5 and 7, 1991. Preferred protecting groups include methyl and ethyl ethers, silyl ethers such as trimethylsilyl ether (TMS), triisopropylsilyl ether (TIPPS), ie/t-butyldimethylsilyl ether (TBDMS), and tert- butyldiphenylsilyl ether (TBDPS) groups, acetate or proprionate groups, and glycol ethers such as ethylene glycol and propylene glycol derivatives.

[0044] The mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or pharmaceutically acceptable salt or ester thereof, used according to the method of the invention, may be protected in one or more of the hydroxyl groups thereof, wherein this can be accomplished by the stoichiometric choice of reagents used to protect the hydroxyl groups. In order to separate the various protected compounds, e.g., the mono, di- or tri-protected hydroxylated EPA or DHA, methods known in the art such as HPLC, LC, flash chromatography, gel permeation chromatography, crystallization, and distillation, can be utilized.

[0045] In more particular such embodiments, the resolvin molecule administered is a mono-, di- or tri-hydroxylated EPA selected from the formulae (l)-(5), a mono- or tri- hydroxylated DHA selected from the formulae (6)-(13), or a mono- or di-hydroxylated n-3 DPA selected from the formulae (14)-(24), wherein R and P each independently is as defined above, or a pharmaceutically acceptable salt thereof:

[0046] According to the present invention, (i) in the mono -hydroxylated EPA of the formula (1), the hydroxyl linked to the carbon atom at position 15 has either R or S configuration, or is an R/S racemic mixture; (ii) in the mono-hydroxylated EPA of the formula (2), the hydroxyl linked to the carbon atom at position 18 has either R or S configuration, or is an R/S racemic mixture; (iii) in the tri-hydroxylated EPA of the formula (3), the hydroxyl linked to the carbon atom at position 5 has S configuration, the hydroxyl linked to the carbon atom at position 12 has R configuration, and the hydroxyl linked to the carbon atom at position 18 has R configuration; or each one of the hydroxyls linked to the carbon atoms at positions 5, 12 and 18 independently has R/S configuration; (iv) in the di-hydroxylated EPA of the formula (4), the hydroxyl linked to the carbon atom at position 5 has S configuration, and the hydroxyl linked to the carbon atom at position 18 has R configuration; or each one of the hydroxyls linked to the carbon atoms at positions 5 and 18 independently has R/S configuration; (v) in the tri-hydroxylated EPA of the formula (5), the hydroxyl linked to the carbon atom at position 5 has S configuration, the hydroxyl linked to the carbon atom at position 6 has R configuration, and the hydroxyl linked to the carbon atom at position 15 has R configuration; or each one of the hydroxyls linked to the carbon atoms at positions 5, 6 and 15 independently has R/S configuration; (vi) in the mono-hydroxylated DHA of the formula (6), the hydroxyl linked to the carbon atom at position 13 has either R or S configuration, or is an R/S racemic mixture; (vii) in the mono-hydroxylated DHA of the formula (7), the hydroxyl linked to the carbon atom at position 14 has either R or S configuration, or is an R/S racemic mixture; (viii) in the mono-hydroxylated DHA of the formula (8), the hydroxyl linked to the carbon atom at position 16 has either R or S configuration, or is an R/S racemic mixture; (ix) in the mono- hydroxylated DHA of the formula (9), the hydroxyl linked to the carbon atom at position 17 has either R or S configuration, or is an R/S racemic mixture; (x) in the mono- hydroxylated DHA of the formula (10), the hydroxyl linked to the carbon atom at position

19 has either R or S configuration, or is an R/S racemic mixture; (xi) in the mono- hydroxylated DHA of the formula (11), the hydroxyl linked to the carbon atom at position

20 has either R or S configuration, or is an R/S racemic mixture; (xii) in the tri- hydroxylated DHA of the formula (12), the hydroxyl linked to the carbon atom at position 7 has S configuration, the hydroxyl linked to the carbon atom at position 8 has R configuration, and the hydroxyl linked to the carbon atom at position 17 has S configuration; or each one of the hydroxyls linked to the carbon atoms at positions 7, 8 and 17 independently has R/S configuration; (xiii) in the tri-hydroxylated DHA of the formula (13), the hydroxyl linked to the carbon atom at position 7 has S configuration, the hydroxyl linked to the carbon atom at position 16 has R configuration, and the hydroxyl linked to the carbon atom at position 17 has S configuration; or each one of the hydroxyls linked to the carbon atoms at positions 7, 16 and 17 independently has R/S configuration; (xiv) in the mono-hydroxylated n-3 DPA of the formula (14), the hydroxyl linked to the carbon atom at position 17 has either R or S configuration, or is an R/S racemic mixture; (xv) in the mono-hydroxylated n-3 DPA of the formula (15), the hydroxyl linked to the carbon atom at position 14 has either R or S configuration, or is an R/S racemic mixture; (xvi) in the mono-hydroxylated n-3 DPA of the formula (16), the hydroxyl linked to the carbon atom at position 7 has either R or S configuration, or is an R/S racemic mixture; (xvii) in the di- hydroxylated n-3 DPA of the formula (17), each one of the hydroxyls linked to the carbon atoms at positions 7 and 8 independently has either R or S configuration, or is an R/S racemic mixture; (xviii) in the tri-hydroxylated n-3 DPA of the formula (18), each one of the hydroxyls linked to the carbon atoms at positions 7, 16 and 17 independently has either R or S configuration, or is an R/S racemic mixture; (xix) in the di-hydroxylated n-3 DPA of the formula (19), each one of the hydroxyls linked to the carbon atoms at positions 7 and 17 independently has either R or S configuration, or is an R/S racemic mixture; (xx) in the di-hydroxylated n-3 DPA of the formula (20), each one of the hydroxyls linked to the carbon atoms at positions 10 and 17 independently has either R or S configuration, or is an R/S racemic mixture; (xxi) in the di-hydroxylated n-3 DPA of the formula (21), each one of the hydroxyls linked to the carbon atoms at positions 16 and 17 independently has either R or S configuration, or is an R/S racemic mixture; (xxii) in the di-hydroxylated n-3 DPA of the formula (22), each one of the hydroxyls linked to the carbon atoms at positions 7 and 14 independently has either R or S configuration, or is an R/S racemic mixture; (xxiii) in the mono-hydroxylated n-3 DPA of the formula (23), the hydroxyl linked to the carbon atom at position 14 has either R or S configuration, or is an R/S racemic mixture; and (xxiv) in the di-hydroxylated n-3 DPA of the formula (24), each one of the hydroxyls linked to the carbon atoms at positions 14 and 21 independently has either R or S configuration, or is an R/S racemic mixture.

[0047] More specific such resolvin molecules for use according to the method of the invention are tri-hydroxylated EPAs of the formula (3), wherein R is H, or (Ci-Cg)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof, e.g., a tri-hydroxylated EPA of the formula (3), wherein R is H; and P is H, such as 5S,12R,18R-trihydroxy EPA (RvEl) or a pharmaceutically acceptable salt thereof.

[0048] In certain embodiments, the resolvin molecule used according to the method of the present invention, is administered intravenously, intraarterially, intramuscularly, intraperitoneally, intrathecally, intrapleurally, intratracheally, subcutaneously, transdermally, intranasally, inhalationally, orally, sublingually, or rectally.

[0049] In certain embodiments, the present invention relates to a method for preventing or treating lung inflammation due to pseudomonal infection, by administration of a resolvin molecule as defined in any one of the embodiments above.

[0050] In particular such embodiments, said method further comprises administering to said individual a therapeutically effective amount of at least one antibiotic agent such as ceftazidime, ciprofloxacin, imipenem, gentamicin, tobramycin, mezlocillin or piperacillin. According to the method of the invention, the resolvin molecule and said at least one antibiotic agent may be administered either sequentially in any order, or simultaneously. It should be understood that said resolvin molecule and said at least one antibiotic agent may also be administered by different administration routes, provided that the cell, tissue, or both are exposed to both said resolvin molecule and said at least one antibiotic agent taking into consideration the formulation of both and their administration route(s).

[0051] In certain embodiments, the method of the present invention comprises administration of a resolvin molecule as defined in any one of the embodiments above, for prevention or treatment of primary pseudomonal pneumonia. In certain particular such embodiments, the individual treated according to this method is an individual having preexisting lung disease such as bronchiectasis, chronic bronchitis, chronic obstructive pulmonary disease, or cystic fibrosis. In other particular such embodiments, said individual is an individual who has experienced an aspiration pneumonia induced by sedation or endotracheal intubation. In one specific such embodiment, the individual treated according to the method of the invention is an individual having cystic fibrosis, and said method further comprises colistin administration, e.g., by inhalation.

[0052] In other embodiments, the method of the present invention comprises administration of a resolvin molecule as defined in any one of the embodiments above, for prevention or treatment of secondary pseudomonal pneumonia. In certain particular such embodiments, the individual treated according to this method is an individual currently receiving or having completed a course of antibiotic treatment. In other particular such embodiments, said individual is an individual having neutropaenia, e.g., due to cytotoxic chemotherapy.

[0053] In certain embodiments, the present invention relates to a method for preventing or treating lung inflammation due to a viral infection, i.e., viral pneumonia, caused, e.g., by influenza virus A (IAV) or B, respiratory syncytial virus (RSV), rhinovirus, coronavirus, a human parainfluenza virus, an adenovirus, a metapneumovirus, severe acute respiratory syndrome virus (SARS-coronovirus), Epstein-Barr virus, cytomegalovirus, measles, hantaviruses, bocavirus, or middle east respiratory syndrome virus (MERS), by administration of a resolvin molecule as defined in any one of the embodiments above.

[0054] In particular such embodiments, said method further comprises administering to said individual a therapeutically effective amount of at least one antiviral agent such as oseltamivir, paramavir, zanamivir, rimantadine, aspirin, palivizumab or ribavirin. According to the method of the invention, the resolvin molecule and said at least one antiviral agent may be administered either sequentially in any order, or simultaneously. Said resolvin molecule and said at least one antiviral agent may also be administered by different administration routes, provided that the cell, tissue, or both are exposed to both said resolvin molecule and said at least one antiviral agent taking into consideration the formulation of both and their administration route(s).

[0055] In particular embodiments, the present invention relates to a method for prevention or treatment of lung inflammation due to a viral infection caused by influenza virus A or B, wherein the resolvin molecule administered is a tri-hydroxylated EPA of the formula (3), wherein R is H, or (Ci-Cs)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof, e.g., a tri- hydroxylated EPA of the formula (3), wherein R is H; and P is H, such as RvEl or a pharmaceutically acceptable salt thereof. In certain such embodiments, the method of the invention further comprises administering to said individual a therapeutically effective amount of an antiviral agent, e.g., oseltamivir.

[0056] The method of the present invention as defined in any one of the embodiments above, including when further comprising administration of either at least one antibiotic agents (for prevention or treatment of lung inflammation due to pseudomonal infection) or at least one antiviral agents (for prevention or treatment of lung inflammation due to a viral infection), may further comprise administering to said individual a therapeutically effective amount of at least one anti-inflammatory agent such as a non-steroidal anti-inflammatory drug (NSAID) and/or at least one antioxidant agent. The administration of said NSAID(s) and/or antioxidant agent(s) can be done sequentially in any order, or simultaneously, with said resolvin molecule and optionally said at least one antibiotic or antiviral agent, and by any administration route(s).

[0057] The term "non-steroidal anti-inflammatory drug" (NSAID) as used herein refers to any non-steroidal anti-inflammatory drug/agent/analgesic/medicine, and relates to both cyclooxygenase (COX)-2 selective and non-selective inhibitors. Non-limiting examples of NSAIDs include celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, acetaminophen (paracetamol, considered to be an NSAID for the purposes of the present invention), firocoxib, meloxicam, etodolac, aspirin, naproxen, ibuprofen, indomethacin, piroxicam, nabumetone, flurbiprofen, ketoprofen, ketorolac, lornoxicam, droxicam, tenoxicam, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, and phenylbutazone, oxaprozin, CS-502, JTE-522, L-745,337, and NS398.

[0058] Examples of antioxidant agents that can be used according to the present invention include, without being limited to, ascorbic acid or a salt thereof such as sodium ascorbate, potassium ascorbate, calcium ascorbate, ascorbyl stearate, and ascorbyl palmitate; L-cysteine (L-Cys) or a salt thereof such as cysteine hydrochloride; a cysteine derivative such as N-acetylcysteine (NAC), glutathione, diacetylcystine, S-methyl-N- acetylcysteine amide, acetyl derivatives of S-methyl-N-acetylcysteine methylhydrazide, S- methylcysteine morpholineamide, and S-methyl-N-acetylcysteine morpholineamide, or a salt thereof; a bisulfite such as sodium bisulfite, sodium hydrogen sulfite, or sodium metabisulfite; a tocopherol, and a superoxide dismutase (SOD) mimetic, i.e., a synthetic compound that mimic the native SOD enzyme, e.g., manganese(III)meso-tetrakis(N,N'- diethyl-l,3-imidazolium-2-yl)porphyrin, 3-nitratomethyl-proxyl, l-0-[4-(di-sodium- phosphonoxy)phenyl]acetyl-(2,2,5,5-tetramethyl pyrrolidin-3-yl)methyl nitrate, and 2,2,5, 5-tetramethyl-3-(nitrooxymethyl)pyrrolidin- 1-yl acetate.

[0059] The mono- or poly-hydroxylated EPA or DHA described herein can be prepared by any method or technique known in the art, e.g., as described in detail in US 6,670,396. Mono- or poly-hydroxylated n-3 DPA as described herein can be prepared by any method or technique known in the art, e.g., as described with respect to some of the compounds described above in Dalli et ah, 2013. [0060] The resolvin molecule administered according to the method of the present invention can be provided in a variety of formulations, e.g., in a pharmaceutically acceptable form and/or in a salt form, as well as in a variety of dosages.

[0061] In one embodiment, the resolvin molecule administered according to the method of the present invention is in the form of a relatively non-toxic pharmaceutically acceptable salt of a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable ester or amide thereof. Suitable pharmaceutically acceptable salts include acid addition salts such as, without being limited to, the mesylate salt; the maleate salt, the fumarate salt, the tartrate salt, the hydrochloride salt, the hydrobromide salt, the esylate salt; the p-toluenesulfonate salt, the benzoate salt, the acetate salt, the phosphate salt, the sulfate salt, the citrate salt, the carbonate salt, and the succinate salt. Additional pharmaceutically acceptable salts include salts of ammonium (NH₄ ⁺) or an organic cation derived from an amine of the formula R₄N⁺, wherein each one of the Rs independently is selected from H, C1-C22, e-g-, CrC₆ alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, n-hexyl, and the like, phenyl, or heteroaryl such as pyridyl, imidazolyl, pyrimidinyl, and the like, or two of the Rs together with the nitrogen atom to which they are attached form a 3-7 membered ring optionally containing a further heteroatom selected from N, S and O, such as pyrrolydine, piperidine and morpholine. Furthermore, where the resolvin molecule of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g., lithium, sodium or potassium salts, and alkaline earth metal salts, e.g., calcium or magnesium salts.

[0062] Further pharmaceutically acceptable salts include salts of a cationic lipid or a mixture of cationic lipids. Cationic lipids are often mixed with neutral lipids prior to use as delivery agents. Neutral lipids include, but are not limited to, lecithins; phosphatidylethanolamine; diacyl phosphatidylethanolamines such as dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, palmitoyloleoyl phosphatidylethanolamine and distearoyl phosphatidylethanolamine; phosphatidylcholine; diacyl phosphatidylcholines such as dioleoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, palmitoyloleoyl phosphatidylcholine and distearoyl phosphatidylcholine; phosphatidylglycerol; diacyl phosphatidylglycerols such as dioleoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol and distearoyl phosphatidylglycerol; phosphatidylserine; diacyl phosphatidylserines such as dioleoyl- or dipalmitoyl phosphatidylserine; and diphosphatidylglycerols; fatty acid esters; glycerol esters; sphingolipids; cardiolipin; cerebrosides; ceramides; and mixtures thereof. Neutral lipids also include cholesterol and other 3β hydroxy- sterols.

[0063] Examples of cationic lipid compounds include, without being limited to, Lipofectin^® (Life Technologies, Burlington, Ontario) (1 : 1 (w/w) formulation of the cationic lipid N-[l-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride and dioleoylphosphatidyl-ethanolamine); Lipofectamine™ (Life Technologies, Burlington, Ontario) (3: 1 (w/w) formulation of polycationic lipid 2,3-dioleyloxy-N-[2(spermine- carboxamido)ethyl] -Ν,Ν-dimethyl- 1 -propanamin-iumtrifluoroacetate and dioleoylphosphatidyl-ethanolamine), Lipofectamine Plus (Life Technologies, Burlington, Ontario) (Lipofectamine and Plus reagent), Lipofectamine 2000 (Life Technologies, Burlington, Ontario) (Cationic lipid), Effectene (Qiagen, Mississauga, Ontario) (Non liposomal lipid formulation), Metafectene (Biontex, Munich, Germany) (Polycationic lipid), Eu-fectins (Promega Biosciences, San Luis Obispo, Calif.) (ethanolic cationic lipids numbers 1 through 12: C5₂H₁₀₆N₆O₄4CF₃CO₂H, C₈₈H₁₇₈N₈0₄S₂-4CF₃C0₂H, C₄₀H₈₄NO₃P CF₃CO₂H, C₅oH₁₀₃N₇0₃-4CF₃C0₂H, C₅₅H₁₁₆N₈0₂-6CF₃C0₂H,

C₄9H₁₀₂N₆O₃4CF₃CO₂H, C₄₄H₈₉N₅0₃-2CF₃C0₂H, CiooH₂o₆Ni₂0₄S₂ 8CF₃C0₂H, C ι₆₂Η₃₃₀Ν₂₂Ο₉· 13CF₃C0₂H, C₄₃H₈₈N₄0₂2CF₃C0₂H, C₄₃H₈₈N₄0₃-2CF₃C0₂H,

C₄iH₇₈N0₈P); Cytofectene (Bio-Rad, Hercules, Calif.) (mixture of a cationic lipid and a neutral lipid), GenePORTER^® (Gene Therapy Systems, San Diego, Calif.) (formulation of a neutral lipid (Dope) and a cationic lipid) and FuGENE 6 (Roche Molecular Biochemicals, Indianapolis, Ind.) (Multi-component lipid based non-liposomal reagent).

[0064] Pharmaceutically acceptable salts of the resolvin molecules used according to the method of the present invention may be formed by conventional means, e.g., by reacting the free base form of the resolvin molecule with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying, or by exchanging the anion/cation on a suitable ion exchange resin.

[0065] The resolvin molecule or pharmaceutically acceptable salt, ester, or amide thereof administered according to the method of the present invention can be given per se or as a pharmaceutical composition containing, e.g., about 0.1 to about 99%, or about 0.5 to about 90%, of the active ingredient, in combination with a pharmaceutically acceptable carrier. [0066] In another aspect, the present invention provides a pharmaceutical composition for prevention or treatment of lung inflammation due to pseudomonal infection or a viral infection caused, e.g., by influenza virus A or B, RSV, rhinovirus, coronavirus, a human parainfluenza virus, an adenovirus, a metapneumovirus, severe acute respiratory syndrome virus (SARS-coronovirus), Epstein-Barr virus, cytomegalovirus, measles, hantaviruses, bocavirus, or MERS, said composition comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof as defined in any one of the embodiments above, herein also interchangeably referred to as "the active agent/compound/ingredient" or "the therapeutic agent/compound/ingredient" , and a pharmaceutically acceptable carrier.

[0067] In certain embodiments, the resolvin molecule comprised within the pharmaceutical composition of the present invention is a mono- or poly-hydroxylated, e.g., di- or tri-hydroxylated, EPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0068] In other embodiments, the resolvin molecule comprised within the pharmaceutical composition of the present invention is a mono- or poly-hydroxylated, e.g., di- or tri- hydroxylated, DHA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0069] In further embodiments, the resolvin molecule comprised within the pharmaceutical composition of the present invention is a mono- or poly-hydroxylated, e.g., di- or tri-hydroxylated, n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

[0070] According to the present invention, each one of the hydroxyl groups of the resolvin molecule or pharmaceutically acceptable salt, ester, or amide thereof independently has either R or S configuration, or is a racemic mixture.

[0071] In certain embodiments, the active agent comprised within the pharmaceutical composition of the invention is a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt or ester thereof. In particular such embodiments, said active agent is a mono- or poly-hydroxylated EPA, DHA or n-3 DPA having a carboxyl group of the formula -COOR, wherein R is H, (Ci-C₈)alkyl, (C3-Cio)cycloalkyl, -CH₂- CHOH-CH₂OH, or -CH-(CH₂OH)2; and one or more hydroxyl groups each independently of the formula -OP, wherein P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof.

[0072] In more particular such embodiments, the active agent comprised within the pharmaceutical composition of the invention is a mono-, di- or tri-hydroxylated EPA selected from the formulae (l)-(5), or a mono- or tri-hydroxylated DHA selected from the formulae (6)-(13), or a mono- or di-hydroxylated n-3 DPA selected from the formulae (14)-(24), wherein R and P each independently is as defined above, or a pharmaceutically acceptable salt thereof. In certain such embodiments, the active agent comprised within the pharmaceutical composition is a tri-hydroxylated EPA of the formula (3), wherein R is H, or (Ci-Cs)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof, e.g., a tri-hydroxylated EPA of the formula (3), wherein R is H; and P is H, such as RvEl or a pharmaceutically acceptable salt thereof.

[0073] The pharmaceutical composition of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19^th Ed., 1995. The compositions can be prepared, e.g., by uniformly and intimately bringing the active agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. The compositions may be in solid, semisolid or liquid form and may further include pharmaceutically acceptable fillers, carriers, diluents or adjuvants, and other inert ingredients and excipients. The compositions can be formulated for any suitable route of administration, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, transdermal, intranasal, inhalational, oral, sublingual, or rectal administration.

[0074] The actual dosage of the active ingredient in the pharmaceutical composition of the present invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired prophylactic/therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject. The selected dosage level will depend upon a variety of factors including the activity of the active agent employed, the route of administration, the time of administration, the rate of excretion of the particular active agent being employed, the duration of the treatment, other drugs used in combination with the particular active agent employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0075] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the therapeutic agent employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0076] The pharmaceutical composition of the present invention may be in a form suitable for oral use, e.g., as tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs, or oral semi-solids such as gels (see, e.g., D. Bar-Shalom, K. Rose (Eds.) Pediatric Formulations: A Roadmap. Advances in the Pharmaceutical Sciences Series 11. Springer, New York, NY; 2014). Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and may further comprise one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, e.g., corn starch or alginic acid; binding agents, e.g., starch, gelatin or acacia; and lubricating agents, e.g., magnesium stearate, stearic acid, or talc. The tablets may be either uncoated or coated utilizing known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated using the techniques described in the US Patent Nos. 4,256,108, 4, 166,452 and 4,265,874 to form osmotic therapeutic tablets for control release. The pharmaceutical composition of the invention may also be in the form of oil-in-water emulsion.

[0077] Oral pharmaceutical compositions according to the invention may be formulated such that the release of a soluble active agent is controlled by having the active diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid (in vitro) or gastro-intestinal fluid (in vivo). Many polymers have been described as capable of forming such gel, e.g., derivatives of cellulose, in particular the cellulose ethers such as hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose or methyl hydroxypropyl cellulose, and among the different commercial grades of these ethers are those showing fairly high viscosity. [0078] The pharmaceutical composition of the invention may be in the form of a sterile injectable aqueous or oleaginous suspension, which may be formulated according to the known art using suitable dispersing, wetting or suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed include, e.g., water, Ringer's solution and isotonic sodium chloride solution.

[0079] The pharmaceutical compositions of the present invention may comprise the active agent formulated for controlled release in microencapsulated dosage form, in which small droplets of the active agent are surrounded by a coating or a membrane to form particles in the range of a few micrometers to a few millimeters, or in controlled-release matrix.

[0080] Another contemplated formulation is depot systems, based on biodegradable polymers, wherein as the polymer degrades, the active agent is slowly released. The most common class of biodegradable polymers is the hydrolytically labile polyesters prepared from lactic acid, glycolic acid, or combinations of these two molecules. Polymers prepared from these individual monomers include poly (D,L-lactide) (PLA), poly (glycolide) (PGA), and the copolymer poly (D,L-lactide-co-glycolide) (PLG).

[0081] Pharmaceutical compositions according to the present invention, when formulated for inhalation, may be administered utilizing any suitable device known in the art, such as metered dose inhalers, liquid nebulizers, dry powder inhalers, sprayers, thermal vaporizers, electrohydrodynamic aerosolizers, and the like.

[0082] In certain embodiments, the pharmaceutical composition of the present invention as defined in any one of the embodiments above is for preventing or treating lung inflammation due to pseudomonal infection. In certain particular such embodiments, the pharmaceutical composition of the invention is for prevention or treatment of primary pseudomonal pneumonia; and in other particular such embodiments, the composition is for prevention or treatment of secondary pseudomonal pneumonia.

[0083] In certain embodiments, the pharmaceutical composition of the present invention as defined in any one of the embodiments above is for preventing or treating lung inflammation due to a viral infection. In particular such embodiments, the invention provides a pharmaceutical composition for prevention or treatment of lung inflammation due to a viral infection caused by influenza virus A or B, wherein the active agent comprised within said pharmaceutical composition is a tri-hydroxylated EPA of the formula (3), wherein R is H, or (Ci-Cs)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof. More particular such embodiments are those wherein the active agent is such a tri-hydroxylated EPA wherein R is H; and P is H, such as RvEl or a pharmaceutically acceptable salt thereof.

[0084] In yet another aspect, the present invention relates to use of a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof, for the preparation of a pharmaceutical composition for prevention or treatment of lung inflammation due to pseudomonal infection or a viral infection.

[0085] As stated above, in certain embodiments, the method of the present invention comprises co-administration of a resolvin molecule as defined above together with either at least one antibiotic agent or an antiviral agent, depending whether said lung inflammation results from pseudomonal infection or a viral infection.

[0086] In a further aspect, the present invention thus provides a kit for preventing or treating lung inflammation due to pseudomonal infection or a viral infection, wherein: said kit for preventing or treating lung inflammation due to pseudomonal infection comprises: (i) a pharmaceutical composition comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof; (ii) at least one antibiotic agent; and (iii) instructions to administer said resolvin molecule and said at least one antibiotic agent sequentially in any order, or simultaneously, and

said kit for preventing or treating lung inflammation due to a viral infection comprises: (i) a pharmaceutical composition comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof; (ii) at least one antiviral agent; and (iii) instructions to administer said resolvin molecule and said at least one antiviral agent sequentially in any order, or simultaneously.

[0087] The kit of the present invention may further comprise one or more antiinflammatory agents such as NSAIDs and/or one or more antioxidant agents, for administration together, i.e., sequentially in any order or simultaneously, with said resolvin molecule and said at least one antibiotic or antiviral agent, in accordance with the instructions provided therein. [0001] Unless otherwise indicated, all numbers expressing quantities of ingredients, optical purities, and so forth used in the specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

EXAMPLES

Experimental

[0088] Measurement of Pseudomonal infection. Lungs were removed, dissected, and immediately put into ice-cold PBS (1 ml). Then, the lungs were homogenized by mincing in a sterile Petri dish with scissors followed by 1 min at high setting with a Polytron tissue homogenizer. The homogenate was serially diluted in PBS and plated on appropriate solid medium (Pseudomonas Selective Agar, Oxoid, UK) for colony counting. Counting was performed in duplicate.

[0089] Determination of myeloperoxidase (MPO) activity. MPO activity was evaluated according to Bradley et ah, 1982. Frozen samples of lung tissue weighing approximately 100 mg were homogenized in 1.5 ml of 50 mmol L^"1 potassium phosphate buffer, pH 6. One milliliter of the homogenate was centrifuged at 10,000xg for 10 minutes, and the pellet was suspended in 1 ml of potassium phosphate buffer (50 mmol L^"1), pH 6, containing 0.5% hexadecyl-trimethylammonium bromide (Sigma) to negate peroxidase activity of hemoglobin and myoglobin, and to solubilize membrane-bound MPO. The suspensions were treated with three cycles of freezing-thawing, sonicated on ice for 10 seconds, and centrifuged at 12,000xg for 10 minutes. MPO activity was determined in the supematants. An aliquot of the supernatant was then allowed to react with a solution of tetramethylbenzidine (1.6 mM) and 0.1 mM H₂O₂. The rate of change in absorbance was measured spectrophotometrically at 650 nm. MPO activity was defined as the quantity of enzyme degrading 1 μιηοΐ of peroxide/min^"1 at 37°C and was expressed in milliunits per 100 mg weight of wet tissue. Five independent measurements were taken for each animal.

[0090] TNFa-specific ELISA. TNF-a levels were measured in the collected lung tissues. Briefly, portions of lung were homogenized in PBS containing phenyl-methyl sulfonyl fluoride (PMSF, 2 mmol Γ¹). The assay was carried out using a colorimetric, commercial kit (Calbiochem-Novabiochem Corporation, USA) according to the manufacturer's instructions. All determinations were performed in duplicate serial dilutions.

[0091] Tissue histology. All organs were harvested under anaesthesia. The biopsies were fixed for 1 week in buffered formaldehyde solution (10% in phosphate buffered saline) at room temperature, dehydrated by graded ethanol and embedded in Paraplast (Sherwood Medical, Mahwah, NJ). Tissue sections (thickness 7 μιη) were deparaffinised with xylene stained with haematoxylin/eosin and studied using light microscopy (Dialux 22 Leitz). The following morphological criteria were used for scoring: 0, no damage; 1 (mild), focal swelling and necrosis of the alveoli; 2 (severe), necrosis with evidence of neutrophil infiltration in the alveoli; 3 (major), necrosis with massive neutrophil infiltration; 4 (highly severe), is widespread necrosis with presence of contraction bands, neutrophil infiltrate, and hemorrhage. All of the histological studies were performed in a blinded fashion.

Example 1. RvEl is an effective therapy in pseudomonal infection

[0092] Male Balb/c mice were subjected to 40 million P. aeruginosa (in 40 μΐ), via intratracheal (IT) administration. One hour post bacterial inoculation, treatment groups were administered RvEl via interperitoneal (IP) route. Groups (n=6) were as follows: Sham, Vehicle, RvEl at 100 μg/kg, RvEl at 30 μg/kg, RvEl at 10 μg/kg. Mice were sacrificed at 24 hours. Lung histology, lung MPO levels, TNFa levels, and lung bacterial colony forming units (CFUs) were determined.

[0093] Fig. 2 shows high levels of infection in mouse lungs infected with P. aeruginosa, and RvEl -induced reduction of the infection that is dose-dependent. Figs. 3 and 4 show high levels of the neutrophil marker MPO and the inflammatory cytokine TNFa, respectively, in P. aeruginosa-infected lungs, and RvEl reduction of both neutrophil- associated MPO and TNFa that is dose-dependent. Figs. 5A-5F show lung histology indicating high levels of damage in mouse lungs infected with P. aeruginosa, and RvEl- induced reduction of the damage that is dose-dependent.

[0094] The pseudomonal infection model can also be utilized, following exactly the same experimental procedure described above, for assessing the therapeutic effects of RvE other than RvEl and RvD, as well as of non-hydroxylated EPA or DHA. In particular such cases, the experimental procedure is followed wherein RvE2, RvE3, RvD, or EPA (100 μg/kg, 30 μg/kg, and 10 μg/kg) is administered via an intra-peritoneal route. Example 2. Lung delivered RvEl alone reduces inflammation pathology as well as pseudomonal load in CFTR knockout mice

[0095] AF508 (delta- F508) is a specific mutation within the gene for a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), more specifically a deletion of three nucleotides spanning positions 507-508 of the CFTR gene on chromosome 7, which ultimately results in the loss of a single codon for the amino acid phenylalanine. Having two copies of this mutation is the most common cause of cystic fibrosis, responsible for nearly two-thirds of cases worldwide.

[0096] In this study, adult female knockout mice harboring a deletion at F508 were treated intraperitoneally with either the vehicle or RvEl (1 mg/kg), 4 hours post induction of pneumonia with P. aeruginosa. The mice were sacrificed 24 hours following the induction of infection, with the following endpoints being assessed: MPO, bacterial CFU and lung histology. The lungs of mice treated with RvEl demonstrated a 67% decrease in MPO activity as compared with the vehicle group (Fig. 6), indicating that RvEl greatly reduces inflammatory injury to lung tissue.

[0097] Tissue histology was performed to assess the extent of damage to alveolar cells by P. aeruginosa and determine whether RvEl provides a therapeutic benefit to this type of insult. In the vehicle group, the infection caused highly severe damage to alveolar cells, with high levels of neutrophil infiltration along with widespread necrosis. In contrast, the mice that received a single dose of RvEl were significantly healthier, with notably less neutrophil infiltration, edema and necrosis (Fig. 7A). These findings are reflected in the histological score, which was improved from a score of 3.67 (severe) to a score of 1.67 (mild) in the group that received RvEl (Fig. 7B).

[0098] The lungs of mice were also tested for bacterial load, to see if levels of bacteria were reduced in mice treated with RvEl. Indeed, a 100-order of magnitude reduction was observed in mice treated with a single dose of RvEl, as measured in colony-forming units (CFU) (Fig. 8).

Example 3. Oral RvEl alone or in combination with oseltamivir extends survival following lethal influenza challenge

[0099] Animals (5-6 week old male C57B1/6 mice) were quarantined for 14 days. Mice under isoflurane anesthesia were infected by intranasal instillation (per LRRI SOP TXP- 0559) with a lethal dose of influenza A virus (IAV; 5x10 plaque-forming unit (PFU)/mouse; HK/2/68 mouse-adapted H3N2). The virus was delivered in less than 200 microliters/ 100 grams body weight (per LRRI SOP TXP-0559) of cell culture medium. Therapeutic treatments, administered by oral gavage per LRRI SOP TXP-0671, were given starting on experimental day 2 post infection and continued two or three times daily ending on day 4 or 6. Eight mice per treatment group were euthanatized on day 5. Ten mice per treatment group were euthanatized on day 14 (survival study).

[00100] Blood was collected post-mortem by cardiac puncture and aspiration. Bronchoalveolar lavage (BAL) was performed post-mortem to collect cells and fluid from the animal. Total BAL cell number was calculated and differentials (macrophages, neutrophils, lymphocytes and eosinophils) determined based on morphological features and differential staining. Viral load was determined by PCR (IAV M gene expression) in lung tissue homogenates.

[00101] Mice challenged with a lethal dose of IAV were protected when RvEl was given orally (3.3 mg/kg based on initial pre-infection body weight; three times a day [TID]) for 5 days beginning 48 hours after IAV (days 2-6 post viral challenge). RvEl alone resulted in a 1 day survival increase. RvEl in combination with the antiviral agent oseltamivir (2 mg/kg; twice a day [BID] for 5 days; days 2-6) resulted in improved survival in comparison to oseltamivir alone, 80% vs. 40%, respectively (Fig. 9). These results are in contrast to the previous published results with similar but distinct lipid mediators, RvDl, RvD2, and lipoxin A4 which showed no impact on survival (Morita et al. 2013). Yet, the previous study did not likely appreciate the need for increased dose-frequency to achieve optimal therapeutic benefit. In some embodiments, an even greater survival benefit might be achieved with RvEl if dosing is continued past study day 6.

Example 4. Oral RvEl alone or in combination with oseltamivir reduces

inflammation in the absence of a significant impact on viral load

[00102] The composition of BAL cells (neutrophils, macrophages, and lymphocytes) was assessed to determine the level of lung inflammation. This was accomplished using a procedure well-known by those skilled in the art. Briefly, in rodents, BAL fluid and cells are collected by cannulating the trachea (postmortem), washing the lungs with fluid, and subsequently collecting for analysis.

[00103] Fig. 10 shows BAL cells on day 5 post infection (5.0xl0³ PFU/mouse; HK/2/68 mouse-adapted H3N2). RvEl and/or oseltamivir was delivered by the oral route (TID; 3.3 mg/kg or BID; 2 mg/kg, respectively, based on initial pre-infection body weight) starting on day 2 post infectious challenge. Fig. 11 shows IAV viral M gene expression in lung tissue on day 5 post infection.

[00104] Significant reductions in inflammation can be shown even if treatment with RvEl is started 2 days post infection (Fig. 10). While there was no reduction in viral load as determined by IAV M gene expression, perhaps more importantly there was no increase either (Fig. 11). This suggests that while being effective at reducing overall inflammation, RvEl does not impair viral host defense as other current anti-inflammatory drugs such as corticosteroids (Treanor et ah, 2012). Further, when RvEl is combined with oseltamivir there is an even greater reduction in inflammation than either treatment given alone (Fig. 10).

[00105] Thus, administration of RvEl in combination with existing antivirals may provide a unique additive/synergistic therapeutic benefit.

Example 5. Lung delivered RvEl alone reduces inflammation in the absence of a significant impact on viral load

[00106] The present study shows that RvEl delivered to the lungs of mice either prophylactically or therapeutically can reduce influenza-induced lung inflammation and associated lung hyperresponsiveness, in the absence of any adverse impact on viral clearance. Mice were challenged with a lethal dose of IAV (5.0x10 PFU/mouse; HKx31 mouse-adapted H3N2) by intranasal instillation, and treatment (administered intranasally, BID, 25 μg/kg based on initial pre-infection body weight) started either 1 day prior to infection (prophylactic) or 2 days post infection (therapeutic). Similar to current antiviral approaches, RvEl shows the greatest benefit when given prophylactically; however, significant reductions in inflammation can still be shown when given 2 days post infection. As with oral delivery, there was no reduction in viral load as determined by IAV M gene expression, suggesting that while being effective at reducing overall inflammation, RvEl does not impair viral host defense as other current anti-inflammatory drugs such as corticosteroids (Treanor et ah, 2012).

[00107] Fig. 12 shows BAL cells (neutrophils, macrophages, and lymphocytes) on day 5 post infection (Hkx31; H3N2 influenza A; 5x10 PFU); Fig. 13 shows airway hyperresponsiveness (methacholine challenge day 5 post infectious challenge); and Fig. 14 shows viral load on day 5 post infection, indicating that RvEl did not affect the viral load on day 5 post infection.

[00108] All publications, patents, patent applications, public databases, public database entries, and other references cited in this application are herein incorporated by reference in their entirety as if each individual publication, patent, patent application, public database, public database entry, or other reference was specifically and individually indicated to be incorporated by reference. The publications, patents, patent applications, public databases, public database entries, and other references are cited for the purpose of describing and disclosing the information, databases, chemical compounds, proteins, and methodologies, which are described in the publications which might be used in connection with the presently described invention. The publications discussed anywhere herein are provided solely for their disclosure prior to the filing date of the present invention. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.

[00109] While in the foregoing specification, this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for the purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details herein may be varied considerably without departing from the basic principles of the invention. One skilled in the art will be able to envision that the present invention encompasses the exemplary methods and compounds and use of the same as well as other aspects that are within the spirit of the invention.

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Claims

1. A method for preventing or treating lung inflammation due to pseudomonal infection or a viral infection in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a resolvin molecule selected from a mono- or poly-hydroxylated eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or n-3 docosapentanoic acid (n-3 DPA), or a pharmaceutically acceptable salt, ester, or amide thereof.

2. The method of claim 1, wherein said resolvin molecule is a mono- or poly- hydroxylated EPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

3. The method of claim 1, wherein said resolvin molecule is a mono- or poly- hydroxylated DHA, or a pharmaceutically acceptable salt, ester, or amide thereof.

4. The method of claim 1, wherein said resolvin molecule is a mono- or poly- hydroxylated n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

5. The method of claim 1, wherein each one of the hydroxyl groups of said resolvin molecule or pharmaceutically acceptable salt, ester, or amide thereof independently has either R or S configuration, or is a racemic mixture.

6. The method of claim 1, wherein in said resolvin molecule or pharmaceutically acceptable salt or ester thereof: the carboxyl group is of the formula -COOR, wherein R is H, (Ci-C₈)alkyl, (C₃-Ci₀)cycloalkyl, -CH₂-CHOH-CH₂OH, or -CH-(CH₂OH)₂; and each one of the hydroxyl groups independently is of the formula -OP, wherein P is H or a hydroxyl protecting group.

7. The method of claim 6, wherein said resolvin molecule is a mono-, di- or tri- hydroxylated EPA of the formula (l)-(5), a mono- or tri-hydroxylated DHA of the formula (6)-(13), or a mono- or di-hydroxylated n-3 DPA of the formula (14)-(24), or a pharmaceutically acceptable salt thereof:

/=\/- ^COOR ^^^COOR

Ί

1 2 _^

OP OP

34

8. The method of claim 7, wherein said resolvin molecule is a tri-hydroxylated EPA of the formula (3), wherein R is H, or (Ci-C₈)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein R is H; and P is H, preferably wherein said resolvin molecule is 5S,12R,18R-trihydroxy EPA (RvEl) or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein said resolvin molecule is administered intravenously, intraarterially, intramuscularly, intraperitoneally, intrathecally, intrapleurally, intratracheally, subcutaneously, transdermally, intranasally, inhalationally, orally, sublingually, or rectally.

11. The method of any one of claims 1 to 10, for preventing or treating lung inflammation due to pseudomonal infection.

12. The method of claim 11, further comprising administering to said individual a therapeutically effective amount of at least one antibiotic agent such as ceftazidime, ciprofloxacin, imipenem, gentamicin, tobramycin, mezlocillin or piperacillin.

13. The method of claim 11 or 12, for preventing or treating primary pseudomonal pneumonia.

14. The method of claim 13, wherein said individual is an individual having preexisting lung disease such as bronchiectasis, chronic bronchitis, chronic obstructive pulmonary disease, or cystic fibrosis, or an individual who has experienced aspiration pneumonia, or endotracheal intubation.

15. The method of claim 14, wherein said individual is an individual having cystic fibrosis, and said method further comprises colistin inhalations.

16. The method of claim 11 or 12, for preventing or treating secondary pseudomonal pneumonia.

17. The method of claim 16, wherein said individual is (i) an individual currently receiving or having completed a course of antibiotic treatment; or (ii) an individual having neutropaenia.

18. The method of any one of claims 1 to 10, for preventing or treating lung inflammation due to a viral infection.

19. The method of claim 18, wherein said viral infection is caused by influenza virus A or B, respiratory syncytial virus, rhinovirus, coronavirus, a human parainfluenza virus, an adenovirus, a metapneumovirus, severe acute respiratory syndrome virus (SARS- coronovirus), Epstein-Barr virus, cytomegalovirus, measles, hantaviruses, bocavirus, or middle east respiratory syndrome virus.

20. The method of claim 18, further comprising administering to said individual a therapeutically effective amount of at least one antiviral agent such as oseltamivir, paramavir, zanamivir, rimantadine, aspirin, palivizumab or ribavirin.

21. The method of any one of claims 18 to 20, for preventing or treating lung inflammation due to a viral infection caused by influenza virus A or B, wherein said resolvin molecule is a tri-hydroxylated EPA of the formula (3), wherein R is H, or (Q- C₈)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein R is H; and P is H, preferably wherein said resolvin molecule is RvEl or a pharmaceutically acceptable salt thereof.

23. The method of claim 21 or 22, further comprising administering to said individual a therapeutically effective amount of oseltamivir.

24. A pharmaceutical composition for preventing or treating lung inflammation due to pseudomonal infection or a viral infection, comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof, and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24, wherein said resolvin molecule is a mono- or poly-hydroxylated EPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

26. The pharmaceutical composition of claim 24, wherein said resolvin molecule is a mono- or poly-hydroxylated DHA, or a pharmaceutically acceptable salt, ester, or amide thereof.

27. The pharmaceutical composition of claim 24, wherein said resolvin molecule is a mono- or poly-hydroxylated n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof.

28. The pharmaceutical composition of claim 24, wherein each one of the hydroxyl groups of said resolvin molecule or pharmaceutically acceptable salt, ester, or amide thereof independently has either R or S configuration, or is a racemic mixture.

29. The pharmaceutical composition of claim 24, wherein in said resolvin molecule or pharmaceutically acceptable salt or ester thereof: the carboxyl group is of the formula - COOR, wherein R is H, (Ci-C₈)alkyl, (C₃-Ci₀)cycloalkyl, -CH₂-CHOH-CH₂OH, or -CH- (CH₂OH)₂; and each one of the hydroxyl groups independently is of the formula -OP, wherein P is H or a hydroxyl protecting group.

30. The pharmaceutical composition of claim 29, wherein said resolvin molecule is a mono-, di- or tri-hydroxylated EPA of the formula (l)-(5), a mono-or tri-hydroxylated DHA of the formula (6)-(13), or a mono- or dihydroxylated n-3 DPA of the formula (14)- (24), or a pharmaceutically acceptable salt thereof:

/=\/- ^COOR ^^^COOR

Ί

1 2 _^

OP OP

38

31. The pharmaceutical composition of claim 30, wherein said resolvin molecule is a tri-hydroxylated EPA of the formula (3), wherein R is H, or (Ci-C₈)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition of claim 31, wherein R is H; and P is H, preferably herein said resolvin molecule is RvEl or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition of claim 24, formulated for intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, transdermal, intranasal, inhalational, oral, sublingual, or rectal administration.

34. The pharmaceutical composition of any one of claims 24 to 33, for preventing or treating lung inflammation due to pseudomonal infection.

35. The pharmaceutical composition of claim 34, for preventing or treating primary pseudomonal pneumonia.

36. The pharmaceutical composition of claim 34, for preventing or treating secondary pseudomonal pneumonia.

37. The pharmaceutical composition of any one of claims 24 to 33, for preventing or treating lung inflammation due to a viral infection.

38. The pharmaceutical composition of claim 37, wherein said viral infection is caused by influenza virus A or B, respiratory syncytial virus, rhinovirus, coronavirus, a human parainfluenza virus, an adenovirus, a metapneumovirus, severe acute respiratory syndrome virus (SARS-coronovirus), Epstein-Barr virus, cytomegalovirus, measles, hantaviruses, bocavirus, or middle east respiratory syndrome virus.

39. The pharmaceutical composition of claim 37 or 38, for preventing or treating lung inflammation due to a viral infection caused by influenza virus A or B, wherein said resolvin molecule is a tri-hydroxylated EPA of the formula (3), wherein R is H, or (Q- C₈)alkyl such as methyl, ethyl, or isopropyl; and P is H or a hydroxyl protecting group, or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition of claim 39, wherein R is H; and P is H, preferably wherein said resolvin molecule is RvEl or a pharmaceutically acceptable salt thereof.

41. Use of a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof, for the preparation of a pharmaceutical composition for preventing or treating lung inflammation due to pseudomonal infection or a viral infection.

42. A kit for preventing or treating lung inflammation due to pseudomonal infection or a viral infection, wherein:

said kit for preventing or treating lung inflammation due to pseudomonal infection comprises: (i) a pharmaceutical composition comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof; (ii) at least one antibiotic agent; and (iii) instructions to administer said resolvin molecule and said at least one antibiotic agent sequentially in any order, or simultaneously, and

said kit for preventing or treating lung inflammation due to a viral infection comprises: (i) a pharmaceutical composition comprising a resolvin molecule selected from a mono- or poly-hydroxylated EPA, DHA or n-3 DPA, or a pharmaceutically acceptable salt, ester, or amide thereof; (ii) an antiviral agent; and (iii) instructions to administer said resolvin molecule and said antiviral agent sequentially in any order, or simultaneously.