Complement anaphylatoxin C5a stimulates release of SRS‐A‐like activity from guinea‐pig lung fragments
Complement anaphylatoxin C5a stimulates release of SRS‐A‐like activity from guinea‐pig lung fragments
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补体过敏毒素 C5a 刺激豚鼠肺碎片释放 SRS-A 样活性
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发表时间：
1980
期刊：
影响因子：
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通讯作者：
T. Hugli
中科院分区：
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作者：
N. Stimler;W. E. Brocklehurst;C. Bloor;T. Hugli
认为过敏性毒素是超敏反应的主要因素的观点和与组胺有关的观点一样古老。过去八年对补体的研究阐明了过敏性毒素分子C3a和C5a的生物化学和功能动力学。以前关于组织对过敏性毒素的药理反应的研究通常在测试中使用不纯的材料，这些测试严重偏向于显示组胺的影响。因此，过敏性毒素被认为是组织组胺的释放剂，而组胺又被认为能引起各种观察到的反应。有关过敏性毒素释放组胺的能力的证据是令人信服的，并转移了人们对它们在调节其他间接效应或引起敏感细胞的直接反应方面可能发挥的作用的关注。我们最近报道(Stimler等，1980)，在1pg·ml~(-1)的C5a存在下，豚鼠肺外周条发生非常强烈的收缩，这一反应不能被高浓度的组胺拮抗剂阻断。我们后来发现，当豚鼠肺无血灌流，切成约0.2毫米厚的碎片，在37℃的泰罗德溶液中孵育10分钟，加入1pgml-L的纯化C5a，可诱导少量组胺(占总数的15%-20%)的释放，尽管发现了大量似乎是白三烯的物质。此外，我们发现豚鼠肠道的收缩，先前表现为对C5a的快速窒息，具有SRS-A的轮廓特征，并被SRS-A的抑制剂fpl 55712阻断(Augstein Et A1 1973)。肺上清液中存在的SRS-A样活性数量不大(120-130U g-‘肺)，但很可能大部分活性在合成后被组织吸收。我们还没有白血病的真正标准或具体的检测方法。三烯(如R.I.A.)因此，活性物质的身份在某种程度上仍然是暂时性的。此外，除了组胺外，介质的释放也不排除C5a也直接作用于组织的可能性。我们的发现表明补体在肺部病理生理学中的作用比先前设想的要广泛得多。C5a将通过补体激活的经典(抗体)和替代(组织酶)途径产生，因此将出现在农民肺和支气管炎等情况下。本工作提示，在哮喘中产生支气管收缩的最终介质物质组胺和SRS-A，也可能与涉及补体激活的肺部疾病的呼吸困难有关。(一九八零年九月三十日)
A belief that anaphylatoxins are major agents in hypersensitivity reactions is as old as that relating to histamine. Studies on complement during the past eight years have elucidated the biochemistry and functional dynamics of the anaphylatoxin molecules, C3a and C5a. Previous studies concerning the pharmacological responses of tissues to anaphylatoxins usually employed impure material in tests which were heavily biased towards showing the effects of histamine. Thus anaphylatoxins have come to be regarded as releasers to tissue histamine which in turn was believed to cause the various observed responses. Evidence for the ability of anaphylatoxins to release histamine is compelling and has diverted attention from their possible role in mediating other indirect effects or of eliciting direct responses of susceptible cells. We recently reported (Stimler et al 1980) that peripheral strips of guinea pig lung underwent a very strong contraction in the presence of C5a at 1 pg ml-', a response that was not blocked by high concentrations of histamine antagonists. We have since found that when guinea-pig lung is perfused free of blood, chopped into fragments about 0.2 mm thick and incubated for lominutes in Tyrode solution at 37 "C, the addition of 1 pg ml-l of purified C5a induces the release of little histamine (15-20% of total; although significant amounts of a substance which appears to be a leukotriene are found. Furthermore, we find that contraction of the guinea-pig gut, previously rendered tachyphylactic to C5a, has a profile characteristic of SRS-A, and is blocked by FPL 55712, an inhibitor of SRS-A (Augstein et a1 1973). The quantities of SRS-A-like activity present in the lung supernatant are not large (120-130 U g-' lung), but it is likely that much of the activity is taken up by the tissue after being synthesized. We do not yet have either authentic standards or specific assays for leuko. trienes (eg R.I.A.) so that identity of the active substance remains somewhat tentative. Furthermore, the release of mediators in addition to histamine does not exclude the possibility that C5a also acts directly on the tissues. Our findings indicate a much wider role for complement in lung pathophysiology than has previously been envisaged. C5a will be generated via both the classical (antibody) and alternative (tissue enzyme) routes of complement activation and will therefore be present in conditions such as farmer's lung and bronchitis. The present work suggests that the final mediator substances histamine and SRS-A, which are known to produce bronchoconstriction in asthma, may also contribute to the dyspnoea in lung diseases which involve activation of complement. September 30, 1980