KR20130089417A

KR20130089417A - Pharmaceutical compositions for preventing and treating acute lung injury or acute respiratory distress syndrome comprising soluble rage as active ingredient

Info

Publication number: KR20130089417A
Application number: KR1020120010752A
Authority: KR
Inventors: 김영삼; 박병훈; 정경수; 이수환; 최동훈; 박성하; 홍성유
Original assignee: 연세대학교 산학협력단
Priority date: 2012-02-02
Filing date: 2012-02-02
Publication date: 2013-08-12

Abstract

PURPOSE: A pharmaceutical composition for preventing or treating acute lung injury or an acute respiratory failure has excellent effect for preventing or treating acute lung injury or an acute respiratory failure by reducing lung edema and lung damage. CONSTITUTION: A pharmaceutical composition for preventing or treating acute lung injury or an acute respiratory failure includes a soluble RAGE (sRAGE) in a first sequence capable of being coupled to a ligand of a receptor for advanced glycation end products (RAGE), as an active ingredient. The sRAGE obstructs the coupling between the ligand of the RAGE and the RAGE. The RAGE is coupled to the Fc side of an immunoglobulin. The composition suppresses an inflammation. [Reference numerals] (AA) Normal type I & II alveolar epithelium cell; (BB) Neutroph, infiltration of monocyte and erythrocyte cell increase; (CC) Edema of alveolar epithelium cell is observed; (DD) Infiltration in alveolar decreases; (EE) Alveolar epithelium cell doesn't get demaged

Description

Pharmaceutical Compositions for Preventing and Treating Acute Lung Injury or Acute Respiratory Distress Syndrome Comprising Soluble RAGE as Active Ingredient}

The present invention relates to a pharmaceutical composition for the prevention or treatment of acute lung injury or acute respiratory failure syndrome comprising a soluble RAGE as an active ingredient.

Acute lung injury and acute respiratory distress syndrome are alveolar epithelial cells and vascular endothelium that are not deteriorated in heart function but are induced by inflammatory reactions caused by severe medical stress or surgical damage. Pulmonary edema occurs due to increased cell permeability, and the oxygen content of arterial blood is not maintained despite high oxygen inhalation (Artigas, A, et al, Am J Respir Crit Care Med , 157: 1332 (1998). Acute lung injury and acute respiratory insufficiency syndrome are the result of general damage to the alveoli. These alveolar injuries are cytokines that cause inflammation such as TNF-alpha, interleukin-1 (IL-1), IL-6, IL-8, and IL-10, which are stimulated by activated neutrophils or chemotaxis. By Hudson, LD, et al. Am J Respir Crit Care Med , 151: 293 (1995), Ware LB, et al, N Engl J Med 342: 13341349 (2000). Neutrophils secrete activated oxygen or proteolytic enzymes, causing damage to capillary endothelial cells and alveolar epithelial cells. Despite significant developments in pathophysiology and acute care for acute lung injury and acute respiratory failure syndrome, mortality is approximately 26-58% (Suresh, R., et al, N Engl J Med , 343 ( 9): 660-661 (2000), Tsushima, K., et al., Intern Med , 48 (9): 621-30 (2009), Matthay, MA et al., Am J Respir Crit Care Med . 181 (10): 1027-32 (2009), Matthay, MA, Proc Am Thorac Soc , 5 (3): 297-9 (2008)). And still, treatment of acute lung injury and acute respiratory distress syndrome is mostly conservative, improving gas exchange and preventing complications (Finfer, S., et al., N Engl J Med , 350 (22): 2247-56 (2004), Spragg, RG, et al., N Engl J Med , 351 (9): 884-92 (2004), Sprung, CL, et al., N Engl J Med , 358 (2): 111-24 (2008), Steinberg, KP, et al., N Engl J Med , 354 (16): 1671-84 (2006)). Research has been conducted on potential therapeutics specific for acute respiratory failure syndrome, such as cytokines and adhesion molecules, but most of them have not shown clinically meaningful results (Webster, NR). et al., Br J Anaesth , 103 (1): 70-81 (2009), Laterre, PF, Crit Care , 11 Suppl 5: S5 (2007).

Receptors for advanced glycation end products (RAGE) belonging to the family of immunoglobulins have been identified as molecules involved in the inflammatory process. It consists of an extracellular portion consisting of one Ig-like V-type domain and two Ig-like C-type domains, a single membrane-spanning domain and a cytosolic tail. It is. RAGE is not only an advanced glycation end product (AGE), but also an endogenous ligand receptor such as the S100 / cal granulin family, high-mobility group B1 (HMGB1), and nuclear proteins secreted by necrotic cells. Activation of the reactive oxygen species (ROS) system, activation of the MAPK system, and NF-κB activity have been shown to promote inflammatory responses and promote vascular smooth muscle proliferation (Jensen, LJ, et al. The Journal of endocrinology 188: 493-501 (2006), Mukherjee, TK, et al, Respir Physiol Neurobiol , 162 (3): 210-5 (2008)). The action between RAGE and cells is mediated by specific receptors for RAGE on the cell surface. RAGE is expressed in all cells involved in the development of atherosclerosis, including monocyte-derived macrophages, endothelial cells and smooth muscle cells. This RAGE is expressed in all tissues, but is particularly distributed in lung tissues (Tapan K, et al, Respiratory Physiology & neurology 162: 210-215 (2008)). On the other hand, the expression of RAGE is constantly increased in certain pathological conditions. The increase in RAGE expressing cells in pathological lesions is associated with the accumulation of RAGE ligands.

In recent studies, the use of HNGB1 antibodies and soluble RAGEs to block inflammatory pathways originating from RAGEs has been shown to reduce cellular inflammation (Kim, JY, et al., Am J Physiol Lung Cell Mol Physiol , 288 (5): L958-65 (2005), Lutterloh, EC, et al., Crit Care , 11 (6): R122 (2007)). RAGE has a larger distribution than other tissues and is thought to play an important role in the inflammatory process in the lungs, but the exact mechanism is still unknown.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have made diligent research efforts to find novel therapeutic agents for acute lung injury or acute respiratory failure syndrome. As a result, the inventors have found that soluble RAGE is effective in treating acute lung injury or acute respiratory failure syndrome.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of acute lung injury or acute respiratory failure syndrome.

Other objects and advantages of the present invention will become apparent from the following detailed description and claims.

According to an aspect of the present invention, the present invention provides an acute lung injury comprising an sRAGE of the first sequence sequence sequence capable of binding to a ligand of a receptor for advanced glycation end products (RAGE). A pharmaceutical composition for preventing or treating lung injury or acute respiratory distress syndrome is provided.

The present inventors have made intensive studies to find a novel therapeutic agent for acute lung injury or acute respiratory failure syndrome, and as a result, sRAGE has been found to be effective in treating acute lung injury or acute respiratory failure syndrome.

The sRAGE of the present invention includes the amino acid sequence of SEQ ID NO: 1 sequence capable of binding to a ligand. Preferably sRAGE of the present invention consists essentially of the amino acid sequence of SEQ ID NO: 1 sequence.

The sRAGE used in the present invention includes the amino acid sequence of SEQ ID NO: 1, but within the range that sRAGE can bind to the RAGE ligand, a variant (ie, a biological equivalent) of the amino acid sequence of SEQ ID NO: 1 It will be apparent to those skilled in the art that it may include.

In the present invention, it will be apparent to those skilled in the art that biological function equivalents that may be included in the sRAGE range will be limited to variations in amino acid sequences that exert biological activity equivalent to sRAGE of the present invention.

Such amino acid variations are made based on the relative similarity of the amino acid side chain substituents, such as hydrophobicity, hydrophilicity, charge, size, and the like. By analysis of the size, shape and type of amino acid side chain substituents, arginine, lysine and histidine are both positively charged residues; Alanine, glycine and serine have similar sizes; Phenylalanine, tryptophan and tyrosine have similar shapes. Thus, based on these considerations, arginine, lysine and histidine; Alanine, glycine and serine; And phenylalanine, tryptophan and tyrosine are biologically functional equivalents.

In introducing mutations, hydropathic idex of amino acids may be considered. Each amino acid is assigned a hydrophobicity index according to its hydrophobicity and charge: isoleucine (+4.5); Valine (+4.2); Leucine (+3.8); Phenylalanine (+2.8); Cysteine / cysteine (+2.5); Methionine (+1.9); Alanine (+1.8); Glycine (-0.4); Threonine (-0.7); Serine (-0.8); Tryptophan (-0.9); Tyrosine (-1.3); Proline (-1.6); Histidine (-3.2); Glutamate (-3.5); Glutamine (-3.5); Aspartate (-3.5); Asparagine (-3.5); Lysine (-3.9); And arginine (-4.5). The hydrophobic amino acid index is very important in imparting the interactive biological function of proteins. It is known that substitution with an amino acid having a similar hydrophobicity index can retain similar biological activities. When a mutation is introduced with reference to a hydrophobic index, substitution is made between amino acids showing a hydrophobic index difference preferably within ± 2, more preferably within ± 1, even more preferably within ± 0.5.

On the other hand, it is also well known that the substitution between amino acids having similar hydrophilicity values leads to proteins with homogeneous biological activity. As disclosed in US Pat. No. 4,554,101, the following hydrophilicity values are assigned to each amino acid residue: arginine (+3.0); Lysine (+3.0); Aspartate (+ 3.0 ± 1); Glutamate (+ 3.0 ± 1); Serine (+0.3); Asparagine (+0.2); Glutamine (+0.2); Glycine (0); Threonine (-0.4); Proline (-0.5 ± 1); Alanine (-0.5); Histidine (-0.5); Cysteine (-1.0); Methionine (-1.3); Valine (-1.5); Leucine (-1.8); Isoleucine (-1.8); Tyrosine (-2.3); Phenylalanine (-2.5); Tryptophan (-3.4). When a mutation is introduced with reference to the hydrophilicity value, the amino acid is substituted preferably within ± 2, more preferably within ± 1, even more preferably within ± 0.5.

Amino acid exchange in proteins that do not globally alter the activity of the molecule is known in the art (H. Neurath, R. L. Hill, The Proteins, Academic Press, New York, 1979). The most commonly occurring exchanges are amino acid residues Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Thr / Phe, Ala / Exchange between Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, Asp / Gly.

Considering the above-described variations with biologically equivalent activity, the sRAGE of the present invention is also construed to include sequences that exhibit substantial identity with the sequences listed in the Sequence Listing. The above-mentioned substantial identity is determined by aligning the above-described sequence of the present invention with any other sequence as much as possible, and analyzing the aligned sequence using an algorithm commonly used in the art, at least 80% Homology, more preferably 90% homology, and most preferably 98% homology. Alignment methods for sequence comparison are well known in the art. Various methods and algorithms for alignment are described by Smith and Waterman, Adv . Appl . Math . 2: 482 (1981) ; Needleman and Wunsch, J. Mol . Bio . 48: 443 (1970); Pearson and Lipman, Methods in Mol . Biol . 24: 307-31 (1988); Higgins and Sharp, Gene 73: 237-44 (1988); Higgins and Sharp, CABIOS 5: 151-3 (1989); Corpet et al., Nuc . Acids Res . 16: 10881-90 (1988); Huang et al., Comp . Appl . BioSci . 8: 155-65 (1992) and Pearson et al., Meth . Mol . Biol . 24: 307-31 (1994). The NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., J. Mol . Biol . 215: 403-10 (1990)) is accessible from National Center for Biological Information (NBCI) It can be used in conjunction with sequence analysis programs such as blastx, tblastn and tblastx. BLSAT is available at http://www.ncbi.nlm.nih.gov/BLAST/. A method for comparing sequence homology using this program can be found at http://www.ncbi.nlm.nih.gov/BLAST/blast_help.html.

SRAGE used in the present invention is a RAGE protein that does not include the transmembrane region or the cytoplasmic tail portion (Park et al., Nature Med ., 4: 1025-1031 (1998). For example, sRAGE used in the present invention may include human sRAGE or fragments thereof, involving glycine and not methionine as the first residue (e.g., Neeper et al, (1992). As used in sRAGE may comprise human sRAGE or part of such amino acid sequence from which the signal sequence has been removed.

The sRAGE of the present invention interferes with the binding between the RAGE ligand and RAGE. sRAGE acts as a decoy receptor (decoy receptor) and binds to the RAGE ligands present in the blood and antagonizes the binding of the cell membrane RAGE receptor. sRAGE is formed due to selective splicing of RAGE mRNA or deletion of the membrane portion and accounts for 1-2% of the total RAGE.

According to a preferred embodiment of the invention, the sRAGE in the composition of the invention is provided in the form of a fusion protein fused with a polypeptide derived from the Fc region of an immunoglobulin. Fusion proteins may include several types of peptides not derived from RAGE or fragments thereof. Fusion proteins can include polypeptides derived from immunoglobulins. Preferably, the immunoglobulin polypeptide may comprise an immunoglobulin heavy chain or portion (ie, fragment) thereof. For example, the heavy chain fragment may comprise a polypeptide derived from the Fc region of an immunoglobulin, which comprises the heavy chain hinge polypeptide and the CH ₂ and CH ₃ domains of the immunoglobulin heavy chain as monomers. The heavy chain (or portion thereof) may be derived from any of the following known heavy chain isotypes: IgG (γ), IgM (μ), IgD (δ), IgE (ε), or IgA (α). In addition, the heavy chain (or portion thereof) may be derived from any of the following known heavy chain subtypes: IgG1 (γ1), IgG2 (γ2), IgG3 (γ3), IgG4 (γ4), IgA1 (α1), IgA2 (α2), or mutants of these isotypes or subtypes that alter biological activity.

The sRAGE of the present invention exhibits better stability than the native sRAGE in the form of a fusion protein in which the Fc region is fused.

In the present invention, acute respiratory distress syndrome (ARDS) is an acute hypoxic respiratory failure caused by pulmonary edema caused by increased permeability of alveolar capillary barrier and is most severe of acute lung injury (ALI). Say the case. Diagnosis of acute lung injury or acute respiratory distress syndrome showed an increase in the pulmonary edema in both lungs on chest X-ray under chest X-ray examination according to the diagnostic criteria of the American-European consensus conference, and the PaO2 / FiO2 value was 300. Below, it is defined as acute lung injury and below 200 as acute respiratory failure syndrome. The causes of acute lung injury are very diverse and can be caused by lesions of the lungs themselves, but they can also occur secondary to sepsis or pancreatitis. The pathological findings of acute lung injury are mainly due to inflammatory reactions, which fill the alveoli with inflammatory cells and proteinaceous substances instead of air, create a vitreous membrane, and infiltrate pulmonary interstitium. Various cytokines play a role in this process, and often show abnormalities in blood clotting function.

According to a preferred embodiment of the present invention, the composition comprising the soluble RAGE of the present invention inhibits the inflammatory response. Preferably inhibits pulmonary inflammatory responses. According to the present invention, lung injury is obtained by removing lungs from a normal control group administered PBS to a mouse, an LPS administered group, and an LPS + sRAGE group administered an LPS and a recombinant sRAGE binding protein (YK602-mouse RAGE-Fc-His). As a result of comparing the degree under H & E staining, the LPS treated group formed a large amount of exudates and vitreous membranes in the alveoli compared with the normal control group, and the infiltration of a large number of inflammatory cells in the alveolar wall and alveoli was observed. In contrast, the LPS + sRAGE group had a smaller lung injury range than the LPS group, and the number of inflammatory cells and the thickening and edema of stromal cells were smaller than those of the LPS group (FIG. 2).

According to a preferred embodiment of the invention, the composition comprising the soluble RAGE of the invention reduces lung hardening and pulmonary edema. According to the present invention, the micro CT findings of the normal control group administered PBS, the LPS administered group, the LPS and the LPS + sRAGE group administered the recombinant sRAGE binding protein (YK602-mouse RAGE-Fc-His) were compared. As a result, no pulmonary stiffness was found in the normal control group, and pulmonary stiffness and edema occurred in both the airway and main bronchus of the LPS treated group. In contrast, in the LPS + sRAGE group, small amounts of lung hardening and edema occurred locally (Figure 1).

According to a preferred embodiment of the invention, the composition comprising the soluble RAGE of the invention inhibits lung cell damage. According to the present invention, electron microscopy findings of the normal control group to which mice were administered PBS, the group to which LPS was administered, and the LPS + sRAGE group to which LPS and recombinant sRAGE binding protein (YK602-mouse RAGE-Fc-His) were administered were compared. As a result, clear edema and damage of alveolar cells were observed in the LPS group compared to the normal control group. In addition, mitochondrial edema due to intracellular edema was observed, and no cells maintaining the structure of normal cells were observed. On the other hand, LPS + sRAGE (recombinant sRAGE binding protein) group was observed inflammatory cells between cells compared to the normal control group, but the structure of the cells was maintained (Fig. 3). Based on these results, it is believed that the composition comprising the soluble RAGE of the present invention maintains the structure of the cells by inhibiting damage to lung cells.

When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19 th ed., 1995).

The pharmaceutical compositions of the present invention may be administered orally or parenterally, preferably by parenteral administration, and most preferably intravenously.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . Preferred dosages of the pharmaceutical compositions of the invention are in the range of 0.001-100 mg / kg on an adult basis.

The pharmaceutical compositions of the present invention may be prepared in unit dose form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container. The formulation may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or may be in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.

In summary, the features and advantages of the present invention are as follows:

(a) The composition of the present invention shows an excellent effect in the prevention or treatment of acute lung injury or acute respiratory failure syndrome.

(b) The compositions of the present invention reduce pulmonary edema and lung cell damage by inhibiting pulmonary inflammatory responses.

(c) The composition of the present invention effectively reduces lung cure.

1 is a diagram showing the results of performing micro CT imaging 48 hours after the administration of PBS, LPS or LPS and recombinant sRAGE binding protein to the mouse.
FIG. 2 is a diagram showing the results of H & E staining and comparison of lung damage after 48 hours of administration of PBS, LPS or LPS and recombinant sRAGE binding protein to mice.
Figure 3 is a diagram showing the results of comparing the degree of damage of alveolar cells under an electron microscope after 48 hours after the administration of PBS, LPS or LPS and recombinant sRAGE binding protein to the mouse.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Materials and methods

Induction of Acute Lung Injury Using Lipopolysaccharide (LPS)

Male C57BL6 mice (20-25 g, Orient Bio), 56 days old, were subjected to inhalation anesthesia using isoflurane. Thereafter, 40 μg / mouse weight (g) of LPS ( E. coli 0127: B8; Sigma, St. Louis, Mo., USA) was calculated and dissolved in 50 μl of phosphate buffered solution through the nasal cavity.

Identification of Acute Lung Injury

Acute lung injury was confirmed by imaging the lungs using micro CT before dissection and by comparing the number of inflammatory cells by obtaining alveolar lavage fluid from the incision of the airways. After dissection, the lungs were extracted and examined by light and electron microscopy.

Micro CT

Lungs of C57BL6 mice were photographed using micro CT (nanofocusray). Inhalation anesthesia with isoflurane reduced the number of breaths up to 40 times / min and photographed and compared the extent of lung hardening.

Pathological Analysis and TEM

After peritoneal anesthesia, 10% neutral paraffin was administered through the trachea to the left lung. Thereafter, lung tissue embedded in paraffin was stained with hematoxylin and eosin (H & E) to compare the degree of inflammatory cells. Right lung tissue was extracted and compared with the alveolar cells observed through an electron microscope.

Experimental design

After confirming acute lung injury using LPS, the experiment was constructed as follows. 1) PBS was administered to the nasal cavity instead of LPS to form a normal control group (n = 20), 2) LPS (n = 10) 40 μg / g into the nasal cavity, 3) and LPS (n = 10) to the nasal cavity. Acute lung injury was induced by administering 40 μg / g, and the recombinant sRAGE binding protein (YK602-mouse RAGE-Fc-His) (n = 10) was divided into 10 μg intraperitoneally. Each of the three groups underwent micro CT and organ harvesting 48 hours after drug administration.

Effect of Recombinant sRAGE Binding Protein in Acute Lung Injury Animal Model

Acute lung injury animal models were constructed using male C57BL / 6 mice. The experiment was divided into three groups. 1) The sham group shed PBS through the airways under anesthesia and intraperitoneally inject PBS. 2) In the control group, LPS was flowed through the airways under anesthesia, and PBS was injected by intraperitoneal injection. 3) The sRAGE treated group flowed LPS through the airways under anesthesia and injected with recombinant sRAGE binding protein (YK602-mouse RAGE-Fc-His) by intraperitoneal injection. After 48 hours, mouse lungs were scanned using micro-computered tomography (CT). A bronchoalveolar lavage (BAL) sample was then obtained for cell counting. After dissecting the mice, the pathological differences in the lungs were compared.

Experiment result

Confirmation of Recombinant sRAGE Binding Protein Effect in Acute Lung Injury Animal Model

Comparison of micro CT findings in the normal control group, LPS group and LPS + sRAGE (recombinant sRAGE binding protein) group showed no lung consolidation in the normal control group (FIG. 1). In contrast, LPS group showed pulmonary sclerosis and swelling in both the airways and the main bronchus of the lungs. In contrast, a small amount of pulmonary sclerosis and edema occurred locally in the group intraperitoneally administered LPS + sRAGE (recombinant sRAGE binding protein).

Pathological analysis

As a result of comparing the degree of lung damage under H & E staining, the LPS treated group was observed to form a large amount of exudates and vitreous capillaries throughout the alveoli compared to the normal control group (FIG. 2). Infiltration of large numbers of inflammatory cells in the alveolar wall and alveoli, bleeding around the capillaries, thickening of epilepsy and edema were also observed. The LPS + sRAGE (recombinant sRAGE binding protein) group had a smaller extent of lung injury at low magnification compared to the LPS group. In terms of high magnification of the damaged area, the number of inflammatory cells and the thickening and edema of stromal cells were smaller than those of the LPS group.

TEM

As a result of examining the degree of damage under an electron microscope, a clear edema and damage of alveolar cells was observed in the LPS group compared to the normal control group (FIG. 3). Mitochondrial edema was observed due to intracellular edema and no cells maintained the structure of normal cells. In contrast, LPS + sRAGE (recombinant sRAGE binding protein) group showed inflammatory cells between the cells compared to the normal control group, but the structure of the cells was maintained. Lung pathology and transmission electron microscopy (TEM) confirmed that inflammatory cell infiltration and cell death were reduced in mice injected with sRAGE (recombinant sRAGE binding protein). RAGE plays an important role in the development of LPS-induced lung injury in mice. Blocking RAGE interaction by sRAGE is thought to reduce lung damage by endotoxin.

The results of the present invention shows that the sRAGE group is less inflammatory and edema, the degree of damage to the cell than the group not. It was once again confirmed in the results of the present invention that RAGE plays an important role in LPS-induced acute lung injury in situations where the response pathway of RAGE is not clear.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

<110> INDUSTRY-ACADEMIC COOPERATION FOUNDATION, Yonsei University <120> PN110500 <130> PN110500 <160> 1 <170> Kopatentin 2.0 <210> 1 <211> 319 <212> PRT <213> sRAGE extra cellular domain amino acid sequence <400> 1 Gly Gln Asn Ile Thr Ala Arg Ile Gly Glu Pro Leu Val Leu Ser Cys 1 5 10 15 Lys Gly Ala Pro Lys Lys Pro Pro Gln Gln Leu Glu Trp Lys Leu Asn 20 25 30 Thr Gly Arg Thr Glu Ala Trp Lys Val Leu Ser Pro Gln Gly Gly Pro 35 40 45 Trp Asp Ser Val Ala Gln Ile Leu Pro Asn Gly Ser Leu Leu Leu Pro 50 55 60 Ala Thr Gly Ile Val Asp Glu Gly Thr Phe Arg Cys Arg Ala Thr Asn 65 70 75 80 Arg Arg Gly Lys Glu Val Lys Ser Asn Tyr Arg Val Arg Val Tyr Gln 85 90 95 Ile Pro Gly Lys Pro Glu Ile Val Asp Pro Ala Ser Glu Leu Thr Ala 100 105 110 Ser Val Pro Asn Lys Val Gly Thr Cys Val Ser Glu Gly Ser Tyr Pro 115 120 125 Ala Gly Thr Leu Ser Trp His Leu Asp Gly Lys Leu Leu Ile Pro Asp 130 135 140 Gly Lys Glu Thr Leu Val Lys Glu Glu Thr Arg Arg His Pro Glu Thr 145 150 155 160 Gly Leu Phe Thr Leu Arg Ser Glu Leu Thr Val Ile Pro Thr Gln Gly 165 170 175 Gly Thr Thr His Pro Thr Phe Ser Cys Ser Phe Ser Leu Gly Leu Pro 180 185 190 Arg Arg Arg Pro Leu Asn Thr Ala Pro Ile Gln Leu Arg Val Arg Glu 195 200 205 Pro Gly Pro Pro Glu Gly Ile Gln Leu Leu Val Glu Pro Glu Gly Gly 210 215 220 Ile Val Ala Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ile Ser Ala 225 230 235 240 Gln Pro Pro Pro Gln Val His Trp Ile Lys Asp Gly Ala Pro Leu Pro 245 250 255 Leu Ala Pro Ser Pro Val Leu Leu Leu Pro Glu Val Gly His Ala Asp 260 265 270 Glu Gly Thr Tyr Ser Cys Val Ala Thr His Pro Ser His Gly Pro Gln 275 280 285 Glu Ser Pro Pro Val Ser Ile Arg Val Thr Glu Thr Gly Asp Glu Gly 290 295 300 Pro Ala Glu Gly Ser Val Gly Glu Ser Gly Leu Gly Thr Leu Ala 305 310 315

Claims

Acute lung injury comprising as an active ingredient a soluble RAGE (sRAGE) of the first sequence in the sequence that can bind to a ligand of a receptor for advanced glycation end products (RAGE), or Pharmaceutical composition for the prevention or treatment of acute respiratory distress syndrome.

The composition of claim 1, wherein the sRAGE of the first sequence of the sequence listing interferes with the binding between the ligand of RAGE and RAGE.

The composition of claim 1, wherein the sRAGE is associated with an Fc region of an immunoglobulin.

The composition of claim 1, wherein the composition inhibits an inflammatory response.

6. The composition of claim 5, wherein the inflammatory response is a lung inflammatory response.

The composition of claim 1, wherein the composition reduces lung hardening.

The composition of claim 1, wherein the composition reduces pulmonary edema.

The composition of claim 1, wherein the composition inhibits lung cell damage.