JP2014167428A - Novel pulmonary hypertension marker - Google Patents
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Abstract
Description
本発明は、哺乳動物における肺高血圧症の存在や程度の評価方法、さらに発症予防並びに治療効果の評価方法に関する。 The present invention relates to a method for evaluating the presence and degree of pulmonary hypertension in a mammal, and further relates to a method for preventing onset and evaluating a therapeutic effect.
肺高血圧症（Ｐｕｌｍｏｎａｒｙ Ｈｙｐｅｒｔｅｎｓｉｏｎ：以下、ＰＨということがある）は、肺動脈圧の上昇を認める病態の総称であり，様々な要因で肺動脈の血圧が上昇し、その結果心拍出量低下を生じ、進行すると右心不全を引き起こす、未治療の場合、予後が不良の疾患である。２００８年に米国ダナポイントで行われた第４回肺高血圧症ワールドシンポジウムで提案された肺高血圧症の臨床分類では、肺高血圧症は５つのカテゴリーに分類されている。 Pulmonary hypertension (hereinafter sometimes referred to as PH) is a general term for pathological conditions in which an increase in pulmonary arterial pressure is recognized, and blood pressure in the pulmonary artery increases due to various factors, resulting in a decrease in cardiac output. A disease that, when advanced, causes right heart failure and is untreated, has a poor prognosis. In the clinical classification of pulmonary hypertension proposed at the 4th World Symposium on Pulmonary Hypertension held in Dana Point, USA in 2008, pulmonary hypertension is classified into five categories.
この５つのカテゴリーのうち、ダナポイント分類の１群に分類され、肺高血圧症の中心的疾患である肺動脈性肺高血圧症（Ｐｕｌｍｏｎａｒｙ Ａｒｔｅｒｉａｌ Ｈｙｐｅｒｔｅｎｓｉｏｎ：以下、ＰＡＨということがある）は、肺小動脈の狭窄によって肺血管抵抗が増加するため肺動脈の血圧が上昇することにより生じると考えられている。ＰＡＨの確定診断には、右心カテーテル検査が必須であり、平均肺動脈圧（ｍｅａｎ Ｐｕｌｍｏｎａｒｙ Ａｒｔｅｒｉａｌ ｐｒｅｓｓｕｒｅ：以下、ｍＰＡということがある）が２５ｍｍＨｇ以上（肺動脈圧は上昇）であって、肺動脈楔入圧（ｐｕｌｍｏｎａｒｙ ａｒｔｅｒｉａｌ ｗｅｄｇｅ ｐｒｅｓｓｕｒｅ：以下、ＰＣＷＰということがある）が１５ｍｍＨｇ以下（左心房圧は正常）である場合をＰＡＨとしている。さらにＰＡＨは、特発性肺動脈性肺高血圧症（Ｉｄｉｏｐａｔｈｉｃ Ｐｕｌｍｏｎａｒｙ Ａｒｔｅｒｉａｌ Ｈｙｐｅｒｔｅｎｓｉｏｎ：以下、ＩＰＡＨということがある）や、膠原病などの各種疾患に伴う肺動脈性肺高血圧症（Ａｓｓｏｃｉａｔｅｄ ｗｉｔｈ ＰＡＨ：以下、ＡＰＡＨということがある）など、５つのカテゴリーに細分類されている。ＩＰＡＨの発症頻度が１００万人に数人であるのに対し、全身性エリテマトーデス、強皮症、混合性結合組織病などの膠原病疾患でのＰＡＨの合併頻度は１０％前後であり、ＰＡＨのハイリスク群と考えられている。 Among these five categories, pulmonary arterial hypertension (hereinafter referred to as PAH), which is classified into one group of Dana Point classification, is a central disease of pulmonary hypertension, is a pulmonary arterial hypertension. It is considered that the pulmonary vascular resistance increases due to the stenosis and is caused by an increase in blood pressure in the pulmonary artery. Right heart catheterization is essential for the definitive diagnosis of PAH, mean pulmonary arterial pressure (hereinafter sometimes referred to as mPA) is 25 mmHg or more (pulmonary artery pressure rises), and pulmonary artery wedge pressure The case where (pulmonary arterial wedge pressure: hereinafter may be referred to as PCWP) is 15 mmHg or less (the left atrial pressure is normal) is defined as PAH. Furthermore, PAH is idiopathic pulmonary arterial hypertension (hereinafter referred to as IPAH) and pulmonary arterial hypertension associated with various diseases such as collagen disease (hereinafter referred to as APAH). Are subdivided into five categories. The incidence of IPAH is several in 1 million, whereas the frequency of PAH in collagen diseases such as systemic lupus erythematosus, scleroderma, and mixed connective tissue disease is around 10%. It is considered a high risk group.
一方、ダナポイント分類の２群に分類される左心性心疾患による肺高血圧症（ＰＨ ｏｗｉｎｇ ｔｏ ｌｅｆｔ ｈｅａｒｔ ｄｉｅｓｅａｓｅ）は、ｍＰＡが２５ｍｍＨｇ以上であって、ＰＣＷＰが１５ｍｍＨｇより高い（左心房圧も上昇）と定義されている。左心性心疾患による肺高血圧症は、急性心不全などの後天性左心疾患に伴う二次性の肺高血圧症であり、前述したダナポイント分類の１群と区別されている。左心性心疾患による肺高血圧症の機序は、肺静脈圧の上昇に起因し肺小動脈と肺静脈の中膜の肥厚が出現し、やがて肺小動脈、肺静脈の双方に肥厚が起こることによると考えられている。このようにして、肺高血圧症が進行した状態はｏｕｔ ｏｆ ｐｒｏｐｏｒｔｉｏｎと呼ばれ、ｍＰＡとＰＣＷＰの差が１２ｍｍＨｇ以上と定義されている。左心性心疾患による肺高血圧症は、その成因より、収縮不全、拡張不全及び弁膜症の３つに分類されるが、具体的な左心性心疾患としては、左房圧の上昇をきたす僧帽弁狭窄症や僧帽弁閉鎖不全症などが代表的である。 On the other hand, pulmonary hypertension due to left heart heart disease classified into two groups of Dana point classification (PH owing to left heart disease), mPA is 25 mmHg or more, PCWP is higher than 15 mmHg (left atrial pressure is also increased) It is defined as Pulmonary hypertension due to left heart heart disease is secondary pulmonary hypertension associated with acquired left heart disease such as acute heart failure, and is distinguished from the above-mentioned Dana point group. The mechanism of pulmonary hypertension due to left heart disease is due to the increase in pulmonary arterial and medial thickness due to increased pulmonary venous pressure, and eventually thickening of both pulmonary arteriole and pulmonary vein It is considered that. Thus, a state in which pulmonary hypertension has progressed is called out of production, and the difference between mPA and PCWP is defined as 12 mmHg or more. Pulmonary hypertension due to left heart heart disease is classified into three categories: systolic dysfunction, diastolic dysfunction, and valvular disease, depending on its origin. Specific left heart heart disease is a mitral that causes an increase in left atrial pressure. Typical examples include valve stenosis and mitral regurgitation.
近年、肺高血圧症に対する治療薬が開発されたことによりＱｕａｌｉｔｙ ｏｆ ｌｉｆｅの改善、生存率の改善が期待できるようになっており、可逆的な変化にとどまっている、罹患の早期段階で診断をし、治療を開始することが重視されている。肺高血圧症の非侵襲的スクリーニング検査として、心臓エコー検査を用いた推定右室圧測定が実施され、右心系の拡大や左室中隔の扁平化など、右心系負荷の検出を行っているが、肺高血圧症に特異的ではなく擬陽性も多いとされている（非特許文献２など）。前述したように肺高血圧症の確定診断には、右心カテーテル検査が不可欠であるが、侵襲的検査であり、必要最小限に実施されることが望まれる。ＰＡＨでは、血液検査として、低酸素状態であることを表す尿酸や心機能（特に心臓への負荷の有無）を表すＢ型ナトリウム利尿ペプチド（ＢＮＰ）が測定されるが、いずれも二次的な指標であり、これらのマーカーの測定においても、未だ肺動脈病変を伴う肺高血圧症の存在・程度の評価、予防、治療効果の評価が十分になされているとは言えなかった。従って、早期の段階で肺動脈病変を伴う肺高血圧症のリスクが高い患者を正確に検出できる簡易な検査が望まれていた。 In recent years, the development of therapeutic drugs for pulmonary hypertension has made it possible to expect an improvement in quality of life and an improvement in survival rate. The emphasis is on starting treatment. As a non-invasive screening test for pulmonary hypertension, an estimated right ventricular pressure measurement using echocardiography was performed, and right heart system load, such as enlargement of the right heart system and flattening of the left ventricular septum, was detected. However, it is not specific to pulmonary hypertension and many false positives are reported (Non-patent Document 2, etc.). As described above, right heart catheterization is indispensable for the definitive diagnosis of pulmonary hypertension, but it is an invasive examination and it is desired to be performed to the minimum necessary. In PAH, as a blood test, uric acid representing hypoxia and B-type natriuretic peptide (BNP) representing cardiac function (especially the presence or absence of load on the heart) are measured. Even in the measurement of these markers, it cannot be said that the presence, degree, prevention, and therapeutic effect of pulmonary hypertension associated with pulmonary artery lesions have been sufficiently evaluated. Therefore, there has been a demand for a simple test capable of accurately detecting a patient at a high risk of pulmonary hypertension accompanied by a pulmonary artery lesion at an early stage.
一方、ＬＲ１１（ＬＤＬ ｒｅｃｅｐｔｏｒ ｒｅｌａｔｉｖｅ ｗｉｔｈ １１ ｌｉｇａｎｄ−ｂｉｎｄｉｎｇ ｒｅｐｅａｔｓ）は、ＬＤＬ受容体ファミリーに特徴的な構造を有する新規なＬＤＬ受容体類似タンパク質として同定された（特許文献１、非特許文献３）。ＬＲ１１は、アポＥを共通のリガンドとする１１回の繰り返し構造のリガンド結合領域を有し、正常血管壁細胞ではほとんど発現が認められないが、肥厚内膜平滑筋細胞には特異的に発現が認められている（非特許文献４）。さらに、培養平滑筋細胞を用いた検討から、平滑筋細胞の細胞増殖に伴いＬＲ１１の発現量が亢進し、培養液中への分泌が認められ、また、カフ傷害マウスモデルにおいて、抗ＬＲ１１抗体を腹腔内投与することにより、平滑筋細胞の遊走及び増殖によって引き起こされる血管内膜の肥厚が阻害されたことが知られている（非特許文献５）。従って、ＬＲ１１が血管平滑筋細胞の増殖の指標として利用できる可能性が示唆されていた。最近、血液中の可溶性ＬＲ１１濃度が、動脈硬化性疾患患者の冠動脈狭窄病変と有意な相関関係があることが報告された（特許文献２）。通常、動脈硬化は、血管内皮にＬＤＬコレステロールが沈着すると共に沈着部位へマクロファージが遊走され、ＬＤＬコレステロールを貪食したマクロファージが血管に蓄積することにより生じるが、その過程で血管平滑筋細胞も遊走されて内膜肥厚を起こす全身の病態である。 On the other hand, LR11 (LDL receptor relative with 11 binding-binding repeats) has been identified as a novel LDL receptor-like protein having a structure characteristic of the LDL receptor family (Patent Document 1, Non-Patent Document 3). LR11 has a ligand-binding region with 11 repeat structures with apoE as a common ligand and is hardly expressed in normal vascular wall cells, but is specifically expressed in thickened intimal smooth muscle cells. It is recognized (Non-Patent Document 4). Furthermore, from the study using cultured smooth muscle cells, the expression level of LR11 increased with the proliferation of smooth muscle cells, and secretion into the culture medium was observed. In a cuff-injured mouse model, anti-LR11 antibody was Intraperitoneal administration is known to inhibit the intimal thickening caused by smooth muscle cell migration and proliferation (Non-patent Document 5). Therefore, it has been suggested that LR11 may be used as an indicator of vascular smooth muscle cell proliferation. Recently, it has been reported that soluble LR11 concentration in blood has a significant correlation with coronary artery stenosis lesions in patients with arteriosclerotic diseases (Patent Document 2). Normally, arteriosclerosis occurs when LDL cholesterol is deposited on the vascular endothelium and macrophages migrate to the deposition site, and macrophages that have phagocytosed LDL cholesterol accumulate in the blood vessels, but vascular smooth muscle cells also migrate in the process. A systemic condition that causes intimal thickening.
本発明の課題は、新たな肺高血圧症のマーカーを提供することにある。 An object of the present invention is to provide a new marker for pulmonary hypertension.
本発明者らは、動脈硬化性疾患を罹患していない患者の中で、右心カテーテル検査で肺高血圧症と診断され、器質化血栓により肺動脈が慢性的に狭窄・閉塞して肺血管のリモデリングが進行した状態である慢性血栓塞栓性肺高血圧症（ＣＴＥＰＨ）と分類された患者の血中の可溶性ＬＲ１１濃度は、健常者の血中濃度と有意差がないが、ＰＡＨと分類された患者の血中の可溶性ＬＲ１１の濃度は、健常者群及びＣＴＥＰＨ群と比較して、有意に高値化していることを見出した。この知見は、肺高血圧症の発症機序による違い、すなわちＰＡＨが肺動脈の肥厚を伴う疾患に当てはまることを示唆するものである。本発明者らは、この知見を基に、肺動脈肥厚に起因する肺高血圧症を発症する疾患の一つである僧帽弁閉鎖不全症患者の血中の可溶性ＬＲ１１の濃度を測定した結果、肺高血圧症を発症している群では、発症していない群より有意に高値化していることを見出し、本発明を完成するに至った。 The present inventors have diagnosed pulmonary hypertension by right heart catheterization among patients who do not suffer from arteriosclerotic disease, and the pulmonary artery is stenotically occluded and blocked due to an organized thrombus. Patients who are classified as chronic thromboembolic pulmonary hypertension (CTEPH) in which the modeling has progressed are not significantly different from blood levels of healthy individuals, but are classified as PAH It was found that the soluble LR11 concentration in the blood was significantly increased as compared with the healthy subject group and the CTEPH group. This finding suggests that differences due to the pathogenesis of pulmonary hypertension, that is, PAH applies to diseases involving thickening of the pulmonary artery. Based on this finding, the present inventors measured the concentration of soluble LR11 in the blood of patients with mitral regurgitation, which is one of the diseases that develop pulmonary hypertension due to pulmonary artery thickening. The group that developed hypertension was found to have a significantly higher value than the group that did not develop hypertension, and the present invention was completed.
すなわち、本発明は、次の〔１〕〜〔９〕を提供するものである。
〔１〕哺乳動物から採取された生物学的試料中の可溶性ＬＲ１１濃度を測定することを特徴とする、該動物における肺高血圧症の存在、程度、発症予防又は治療効果の評価方法。
〔２〕肺高血圧症が、肺動脈性肺高血圧症である〔１〕記載の方法。
〔３〕生物学的試料が、血液、血清又は血漿である、〔１〕又は〔２〕記載の方法。
〔４〕生物学的試料中の可溶性ＬＲ１１濃度が、基準値より高いことを、肺高血圧症の存在、程度又は発症予防を評価する指標とする〔１〕〜〔３〕のいずれか１項記載の方法。
〔５〕生物学的試料中の可溶性ＬＲ１１の濃度を、治療後に変化することをモニターすることで治療の効果判定を評価する指標とする、〔１〕〜〔４〕のいずれか１項記載の方法。
〔６〕哺乳動物がヒトである、〔１〕〜〔５〕のいずれか１項記載の方法。
〔７〕哺乳動物が膠原病又は左心性心疾患に罹患している、〔１〕〜〔６〕のいずれか１項記載の方法。
〔８〕膠原病が、全身性エリテマトーデス、強皮症又は混合性結合組織病である、〔７〕記載の方法。
〔９〕左心性心疾患が、僧帽弁狭窄症又は僧帽弁閉鎖不全症である、〔７〕記載の方法。
That is, the present invention provides the following [1] to [9].
[1] A method for evaluating the presence, degree, prevention, or treatment effect of pulmonary hypertension in an animal, comprising measuring a soluble LR11 concentration in a biological sample collected from a mammal.
[2] The method according to [1], wherein the pulmonary hypertension is pulmonary arterial pulmonary hypertension.
[3] The method according to [1] or [2], wherein the biological sample is blood, serum or plasma.
[4] Any one of [1] to [3], wherein a soluble LR11 concentration in a biological sample is higher than a reference value is used as an index for evaluating the presence, degree, or prevention of pulmonary hypertension. the method of.
[5] The concentration according to any one of [1] to [4], wherein the soluble LR11 concentration in the biological sample is used as an index for evaluating the effect of treatment by monitoring changes after treatment. Method.
[6] The method according to any one of [1] to [5], wherein the mammal is a human.
[7] The method according to any one of [1] to [6], wherein the mammal suffers from collagen disease or left heart heart disease.
[8] The method according to [7], wherein the collagen disease is systemic lupus erythematosus, scleroderma or mixed connective tissue disease.
[9] The method according to [7], wherein the left heart heart disease is mitral stenosis or mitral regurgitation.
本発明によれば、肺高血圧症のうち、予後不良とされる肺動脈性肺高血圧症、膠原病や左心性心疾患による肺高血圧症等の存在、程度だけでなく、発症予防、治療効果の評価が可能である。特に、肺動脈性肺高血圧症、膠原病による肺高血圧症、左心性心疾患による肺高血圧症の存在、程度、発症予防、治療効果が正確かつ簡易に評価できる。 According to the present invention, among pulmonary hypertension, pulmonary arterial hypertension, which is considered to have a poor prognosis, the presence and degree of pulmonary hypertension due to collagen disease and left heart heart disease, etc., as well as onset prevention, evaluation of therapeutic effect Is possible. In particular, the presence, degree, prevention, and therapeutic effect of pulmonary arterial hypertension, pulmonary hypertension due to collagen disease, and pulmonary hypertension due to left heart heart disease can be accurately and easily evaluated.
本発明方法において可溶性ＬＲ１１濃度の測定対象は、哺乳動物から採取された生物学的試料である。哺乳動物としては、ヒトを含む哺乳動物、例えばヒト、サル、ウマ、ウシ、ブタ、ウサギ、ラット、モルモット、マウス等が挙げられるが、ヒトが好ましい。生物学的試料としては、例えば血液、血漿、血清等のほか、髄液や尿が挙げられるが、血液、血清又は血漿が好ましい。 In the method of the present invention, the measurement target of the soluble LR11 concentration is a biological sample collected from a mammal. Examples of mammals include mammals including humans, such as humans, monkeys, horses, cows, pigs, rabbits, rats, guinea pigs, mice and the like, with humans being preferred. Examples of the biological sample include blood, plasma, serum and the like, as well as cerebrospinal fluid and urine, and blood, serum, or plasma are preferable.
本発明方法の測定対象となる哺乳動物は、肺動脈病変を伴う肺高血圧症が疑われる又は治療中の哺乳動物であることが好ましい。 The mammal to be measured by the method of the present invention is preferably a mammal suspected or being treated for pulmonary hypertension accompanied by pulmonary artery lesions.
生物学的試料中の可溶性ＬＲ１１濃度の測定は、可溶性ＬＲ１１に親和性のある物質を用いて行われる。該親和性物質は、可溶性ＬＲ１１に結合能を有する物質であれば特に制限されず、例えば、ａｐｏ Ｅ、β−ＶＬＤＬ、ＲＡＰ、ｕＰＡ、ＰＡＩ−１、それらの複合体（ｕＰＡ−ＰＡＩ−１）、及び抗可溶性ＬＲ１１抗体等が挙げられるが、ＲＡＰ及び抗可溶性ＬＲ１１抗体が好ましく、抗可溶性ＬＲ１１抗体がより好ましい。 The measurement of the soluble LR11 concentration in the biological sample is performed using a substance having an affinity for the soluble LR11. The affinity substance is not particularly limited as long as it has a binding ability to soluble LR11. For example, apo E, β-VLDL, RAP, uPA, PAI-1, or a complex thereof (uPA-PAI-1) And anti-soluble LR11 antibody, and RAP and anti-soluble LR11 antibody are preferable, and anti-soluble LR11 antibody is more preferable.
抗可溶性ＬＲ１１抗体としては、ポリクローナル抗体、あるいはモノクローナル抗体のいずれでも良く、当該抗体は、周知の方法にて作製できる。また、これらの抗体は、市販品として入手することも可能であり、本発明にも利用できる。例えば、Ｍｏｕｓｅ ａｎｔｉ−ＬＲ１１ ｍｏｎｏｃｌｏｎａｌ ａｎｔｉｂｏｄｙ（ＢＤ ｂｉｏｓｃｉｅｎｃｅｓ社）、Ｒａｂｂｉｔ ａｎｔｉ−ＬＲ１１ Ｐｏｌｙｃｌｏｎａｌ ａｎｔｉｂｏｄｙ（ＣＨＥＭＩＣＯＮ社）、国際公開第２００９／１１６２６８号公報記載の抗ＬＲ１１抗体などが挙げられる。 The anti-soluble LR11 antibody may be either a polyclonal antibody or a monoclonal antibody, and the antibody can be prepared by a known method. Moreover, these antibodies can also be obtained as commercial products and can also be used in the present invention. Examples thereof include Mouse anti-LR11 monoclonal antibody (BD biosciences), Rabbit anti-LR11 Polyantibodies (CHEMICON), and anti-LR11 antibody described in International Publication No. 2009/116268.
本発明における可溶性ＬＲ１１の測定方法としては、抗ＬＲ１１抗体を使用した免疫学的測定方法が好ましい。免疫学的方法としては、例えば免疫染色（ウエスタンブロット）、酵素結合免疫吸着測定法（ＥＬＩＳＡ）、免疫比濁法（ＴＩＡやＬＴＩＡ）、エンザイムイムノアッセイ、化学発光イムノアッセイ、蛍光イムノアッセイなどが挙げられるが、ＥＬＩＳＡが好ましい。ＥＬＩＳＡキットとしては、積水メディカル社から市販されているものを用いることができる。 The method for measuring soluble LR11 in the present invention is preferably an immunological measurement method using an anti-LR11 antibody. Examples of immunological methods include immunostaining (Western blot), enzyme-linked immunosorbent assay (ELISA), immunoturbidimetry (TIA and LTIA), enzyme immunoassay, chemiluminescent immunoassay, fluorescent immunoassay, and the like. ELISA is preferred. As an ELISA kit, those commercially available from Sekisui Medical can be used.
本発明においては、生物学的試料中の可溶性ＬＲ１１濃度により、肺高血圧症の存在、程度、さらに発症予防、治療効果を評価することができる。ここで、「存在、程度の評価」とは、既に肺高血圧症に罹患している場合に限らず、将来的に罹患する可能性があるか否かを判定する場合も包含する概念である。 In the present invention, the presence and degree of pulmonary hypertension, the onset prevention, and the therapeutic effect can be evaluated by the soluble LR11 concentration in the biological sample. Here, “evaluation of the presence and degree” is not limited to the case of having already suffered from pulmonary hypertension, but also includes the case of determining whether or not there is a possibility of suffering in the future.
本発明の肺高血圧症の存在・程度の評価方法としては、例えば、肺高血圧症が疑われる哺乳動物から生物学的試料を採取し可溶性ＬＲ１１濃度を測定し、別に予め肺高血圧症の疑いのない健常哺乳動物集団から同様に採取した生物学的試料中の可溶性ＬＲ１１濃度を算出しておき（基準値）、両者の濃度レベルを比較することによって、肺高血圧症の存在・程度の評価を行うことが望ましい。さらに、例えば、肺高血圧症を患っている哺乳動物から、生物学的試料を経時的に採取し、可溶性ＬＲ１１濃度の経時変化をモニターすることによって、治療の効果判定を行うことも可能である。判定は、可溶性ＬＲ１１の濃度変化によってすることが出来、例えば、増加傾向を示す場合は肺高血圧症が進展していると考えられ、また減少又は横ばい傾向を示す場合は肺高血圧症の進展が抑制されていると考えられる。 As the method for evaluating the presence / degree of pulmonary hypertension according to the present invention, for example, a biological sample is collected from a mammal suspected of having pulmonary hypertension, and the soluble LR11 concentration is measured. Evaluate the presence and extent of pulmonary hypertension by calculating the soluble LR11 concentration in a biological sample similarly collected from a healthy mammal population (reference value) and comparing the concentration levels of both. Is desirable. Furthermore, for example, it is possible to determine the effect of treatment by collecting a biological sample from a mammal suffering from pulmonary hypertension over time and monitoring the change in soluble LR11 concentration over time. The determination can be made based on a change in the concentration of soluble LR11. For example, if it shows an increasing tendency, it is considered that pulmonary hypertension has progressed, and if it shows a decreasing or leveling tendency, the progress of pulmonary hypertension is suppressed. It is thought that.
ここで、「健常」とは、肺高血圧症を有さない個体をいう。肺高血圧症は、前述の第４回肺高血圧症ワールドシンポジウムで提案された基準により５カテゴリーに分類されるが、それぞれの分類診断方法は以下である。先ず、臨床症状、胸部レントゲン、心電図、心エコーなどから肺高血圧症が疑われた場合、右心カテーテルにより肺動脈圧を測定する。ここでｍＰＡが２５ｍｍＨｇ以上であれば肺高血圧と診断される。さらにｍＰＡが２５ｍｍＨｇ以上で、かつＰＣＷＰが１５ｍｍＨｇ以下であれば前毛細血管性肺高血圧症に区分され、ｍＰＡが２５ｍｍＨｇ以上であって、ＰＣＷＰが１５ｍｍＨｇより高い場合、後毛細血管性肺高血圧症（ダナポイントの２群の左心性心疾患による肺高血圧症）と診断される。前毛細血管性肺高血圧症において、肺疾患や、それに基づく低酸素症が存在する場合、ダナポイント３群の肺疾患及び／又は低酸素症による肺高血圧症に区分し、肺疾患が否定された場合には、ＣＴ、肺換気血流シンチグラム、肺動脈楔入造影、光干渉断層撮像法（ｏｐｔｉｃａｌ ｃｏｈｅｒｅｎｃｅ ｔｏｍｏｇｒａｐｈｙ：ＯＣＴ）などで肺動脈内血栓の存在を証明する。血栓が証明されればダナポイント４群のＣＴＥＰＨである。また同時に代謝性疾患、血液疾患など多因子によるダナポイント５群、その他の肺高血圧症を鑑別し、残るダナポイント１群の肺動脈性肺高血圧症は基本的に除外診断となる。 Here, “healthy” refers to an individual who does not have pulmonary hypertension. Pulmonary hypertension is classified into 5 categories according to the criteria proposed in the aforementioned 4th World Symposium on Pulmonary Hypertension. The classification diagnosis methods are as follows. First, when pulmonary hypertension is suspected from clinical symptoms, chest X-rays, electrocardiogram, echocardiography, etc., pulmonary artery pressure is measured with a right heart catheter. If mPA is 25 mmHg or more, pulmonary hypertension is diagnosed. Further, if mPA is 25 mmHg or more and PCWP is 15 mmHg or less, it is classified as precapillary pulmonary hypertension. If mPA is 25 mmHg or more and PCWP is higher than 15 mmHg, postcapillary pulmonary hypertension (Dana Diagnosed as pulmonary hypertension due to left heart disease in 2 groups of points). In the case of precapillary pulmonary hypertension, if there is pulmonary disease or hypoxia based on it, it was classified into Dana Point 3 group pulmonary disease and / or pulmonary hypertension due to hypoxia, and pulmonary disease was denied In some cases, the presence of a thrombus in the pulmonary artery is proved by CT, pulmonary ventilation blood flow scintigram, pulmonary artery wedge imaging, optical coherence tomography (OCT), or the like. If a thrombus is proved, it is CETPH of Dana Point 4 group. At the same time, Dana Point 5 group due to multiple factors such as metabolic disease and blood disease and other pulmonary hypertension are differentiated, and the remaining Dana Point 1 group pulmonary arterial hypertension is basically excluded.
また、本発明で評価できる肺高血圧症には、肺動脈性肺高血圧症、あるいは膠原病又は左心性心疾患による肺高血圧症が挙げられる。ここで膠原病には、全身性エリテマトーデス、強皮症、混合性結合組織病が挙げられる。左心性心疾患には、僧帽弁狭窄症、僧帽弁閉鎖不全症が挙げられる。 The pulmonary hypertension that can be evaluated by the present invention includes pulmonary arterial hypertension or pulmonary hypertension due to collagen disease or left heart disease. Here, the collagen disease includes systemic lupus erythematosus, scleroderma, and mixed connective tissue disease. Left heart heart disease includes mitral stenosis and mitral regurgitation.
以下、実施例により本発明を詳細に説明するが、本発明は以下の実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to a following example.
〔実施例１〕 肺動脈性肺高血圧症並びに慢性血栓塞栓性肺高血圧症に罹患している患者における可溶性ＬＲ１１濃度の測定
１．材料と方法：
右心カテーテル検査でｍＰＡが２５ｍｍＨｇ以上であった肺高血圧症患者の内、ＰＡＨに分類された３３名（特発性１４名、膠原病性１５名、遺伝性３名、先天性心疾患１名）及びＣＴＥＰＨに分類された１４名の血清中の可溶性ＬＲ１１濃度を、可溶性ＬＲ１１測定試薬（積水メディカル社製）を用いて測定した。比較として、健常者ボランティア５７名の血清中の可溶性ＬＲ１１濃度も測定した。
２．結果：
ＰＡＨ患者及びＣＴＥＰＨ患者の血清中の可溶性ＬＲ１１濃度は、それぞれ１１．５±４．７ｎｇ／ｍＬ、７．６±２．４ｎｇ／ｍＬであり、ＰＡＨ患者群はＣＴＥＰＨ患者群と比較して、有意に（ｐ＜０．００５）に高値であった。又、健常者ボランティア群の血清中の可溶性ＬＲ１１濃度は７．８±１．６ｎｇ／ｍＬであり、ＣＴＥＰＨ患者の場合は、有意差は認めないが、ＰＡＨ患者の場合は、健常者ボランティアより、有意に（ｐ＜０．００１）血液中のＬＲ１１濃度が上昇していることが判明した。
Example 1 Measurement of soluble LR11 concentration in patients suffering from pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension Materials and methods:
33 patients classified as PAH among 14 patients with pulmonary hypertension whose mPA was 25mmHg or more by right heart catheterization (14 idiopathic, 15 collagenous, 3 hereditary, 1 congenital heart disease) And the soluble LR11 density | concentration in the serum of 14 persons classified into CTEPH was measured using the soluble LR11 measuring reagent (made by Sekisui Medical). As a comparison, the soluble LR11 concentration in the serum of 57 healthy volunteers was also measured.
2. result:
The soluble LR11 concentration in the serum of PAH patients and CTEPH patients is 11.5 ± 4.7 ng / mL and 7.6 ± 2.4 ng / mL, respectively, and the PAH patient group is significantly higher than the CTEPH patient group (P <0.005). In addition, the soluble LR11 concentration in the serum of the healthy volunteer group is 7.8 ± 1.6 ng / mL, and in the case of CTEPH patients, no significant difference is recognized, but in the case of PAH patients, from the healthy volunteers, It was found that the LR11 concentration in blood was significantly increased (p <0.001).
〔実施例２〕 肺高血圧症非合併・合併膠原病に罹患している患者における可溶性ＬＲ１１濃度の測定
１．材料と方法：
膠原病の患者で、肺高血圧症を合併している１５症例と合併していない（心エコー法）２９症例について、血清中の可溶性ＬＲ１１濃度を、可溶性ＬＲ１１測定試薬（積水メディカル社製）を用いて測定した。
２．結果：
肺高血圧症を合併している患者及び合併していない患者の血清中の可溶性ＬＲ１１濃度は、それぞれ１１．６±４．９ｎｇ／ｍＬ、８．１±２．１ｎｇ／ｍＬであり、肺高血圧症合併群は非合併症患者群と比較して、有意に（ｐ＜０．００５）に高値であったことから、膠原病患者の肺高血圧症合併症リスクの評価に役に立つことが期待される。
[Example 2] Measurement of soluble LR11 concentration in patients suffering from non-complicated pulmonary hypertension / collagenous collagen disease Materials and methods:
For patients with collagen disease, 15 cases with pulmonary hypertension and 29 cases with no pulmonary hypertension (echocardiography), the soluble LR11 concentration in serum was measured using a soluble LR11 measuring reagent (manufactured by Sekisui Medical) Measured.
2. result:
Soluble LR11 concentrations in the serum of patients with and without pulmonary hypertension are 11.6 ± 4.9 ng / mL and 8.1 ± 2.1 ng / mL, respectively. The combined group was significantly (p <0.005) higher than the non-complication patient group, and is expected to be useful for evaluating the risk of pulmonary hypertension complications in patients with collagen disease.
〔実施例３〕 肺高血圧症非合併・合併僧帽弁閉鎖不全症に罹患している患者における可溶性ＬＲ１１濃度の測定
１．材料と方法：
僧帽弁閉鎖不全症の患者で、肺高血圧症を合併していない８症例と合併している６症例について、血清中の可溶性ＬＲ１１濃度を、可溶性ＬＲ１１測定試薬（積水メディカル社製）を用いて測定した。
２．結果：
肺高血圧症を合併している患者及び合併していない患者の血清中の可溶性ＬＲ１１濃度は、それぞれ１０．０±４．３ｎｇ／ｍＬ、５．５±１．８ｎｇ／ｍＬであり、肺高血圧症合併群は非合併症患者群と比較して、有意に（ｐ＜０．０５）に高値であった。
一方、低酸素状態を表す尿酸濃度や心機能を表すＢＮＰ濃度では、この２群間では有意差は認めなかった（尿酸値：６．７±２．２ｍｇ／ｄＬ ｖｓ ６．４±１．１ｍｇ／ｄＬ、ｐ＝０．４６、ＢＮＰ値：１９８±２５０ｐｇ／ｍＬ ｖｓ １８９±１２５ｐｇ／ｍＬ、ｐ＝０．３９）。
[Example 3] Measurement of soluble LR11 concentration in patients suffering from pulmonary hypertension non-complicated / complicated mitral regurgitation Materials and methods:
For 6 patients with mitral regurgitation and 8 cases not complicated with pulmonary hypertension, soluble LR11 concentration in serum was measured using a soluble LR11 measuring reagent (manufactured by Sekisui Medical). It was measured.
2. result:
Soluble LR11 concentrations in the serum of patients with and without pulmonary hypertension are 10.0 ± 4.3 ng / mL and 5.5 ± 1.8 ng / mL, respectively. The combined group was significantly (p <0.05) higher than the non-complication patient group.
On the other hand, there was no significant difference between the two groups in the uric acid concentration representing hypoxia and the BNP concentration representing cardiac function (uric acid value: 6.7 ± 2.2 mg / dL vs 6.4 ± 1.1 mg). / DL, p = 0.46, BNP value: 198 ± 250 pg / mL vs 189 ± 125 pg / mL, p = 0.39).
〔実施例４〕 肺高血圧症治療と可溶性ＬＲ１１濃度の推移
１．材料と方法、並びに結果：
膠原病（ＳＬＥ）増悪時、肺高血圧症と診断され、ＳＬＥ治療としてプレドニゾロン及びエンドキサンハルス療法施行中であり、膠原病（ＳＬＥ）性肺高血圧症に対してはレバチオ（ホスホジエステラーゼ５阻害剤）投与後、追加薬剤として血小板凝集抑制作用および血管拡張作用を有するフローランを投与した患者について、フローラン投与前後の可溶性ＬＲ１１濃度変化をモニターした。フローラン投与前の右心カテーテル検査で平均肺動脈圧４５ｍｍＨｇ、心エコーによる推定右室圧の推定値は７０ｍｍＨｇであった。フローランの投与量を約３週間にわたり段階的に増加（０．５→９ｎｇ／ｋｇ／ｍｉｎ）させて治療した結果、推定右室圧は５０ｍｍＨｇまで緩やかに改善した。一方、可溶性ＬＲ１１濃度に関しても、フローラン投与前の濃度が１２．７ｎｇ／ｍＬであったのに対して、フローラン投与３週間後には７．２ｎｇ／ｍＬまで緩やかに低下していた（表１）。この結果から、肺高血圧症の治療効果の推定に、可溶性ＬＲ１１濃度の測定が有用であることが確認された。
[Example 4] Treatment of pulmonary hypertension and transition of soluble LR11 concentration Materials and methods and results:
Diagnosed as pulmonary hypertension during exacerbation of collagen disease (SLE), prednisolone and endoxanhals are being treated as treatment for SLE, and after administration of levatio (phosphodiesterase 5 inhibitor) for collagen disease (SLE) pulmonary hypertension In addition, for patients treated with Floran having platelet aggregation inhibitory action and vasodilatory action as an additional drug, changes in soluble LR11 concentration before and after Floran administration were monitored. The average pulmonary artery pressure was 45 mmHg and the estimated right ventricular pressure was estimated to be 70 mmHg by echocardiography by right heart catheterization before Floran administration. As a result of treatment by gradually increasing the dose of Floran over about 3 weeks (0.5 → 9 ng / kg / min), the estimated right ventricular pressure gradually improved to 50 mmHg. On the other hand, the soluble LR11 concentration was 12.7 ng / mL before Floran administration, but gradually decreased to 7.2 ng / mL after 3 weeks of Floran administration (Table 1). From this result, it was confirmed that measurement of soluble LR11 concentration is useful for estimating the therapeutic effect of pulmonary hypertension.
これら実施例１〜４の結果は、肺動脈肥厚を伴う肺高血圧症の危険性が高い基礎疾患に罹患している患者の血清中の可溶性ＬＲ１１を検出することで、肺高血圧症の存在や程度の評価、さらに発症予防並びに治療効果の評価を可能にすることを支持するものである。 The results of these Examples 1 to 4 indicate that the presence or degree of pulmonary hypertension is detected by detecting soluble LR11 in the serum of a patient suffering from a basic disease with a high risk of pulmonary hypertension associated with pulmonary artery thickening. It supports to enable evaluation, further onset prevention and evaluation of therapeutic effects.
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