生物谷报道：急性肺损伤（ALI）是一种相对比较常见的能危及生命的疾病。它可以由脓血症、创伤和吸入酸性物质引起，后者是全身麻醉的并发症之一。当前对ALI的治疗尚未有好的办法，但是，《临床研究》杂志的12月刊上发表的一项研究已经证实治疗ALI病人有新的并具前景的治疗方向。
弗吉尼亚大学的Klaus Ley和同事们发现在用吸入酸性物质诱导的急性肺损伤小鼠模型中，血小板-中性粒细胞间相互作用在病情发展中起着关键作用。通过减少小鼠体内的血小板数量或者阻止血小板-中性粒细胞间相互作用，减少了中性粒细胞向肺部聚集的数量，降低了肺泡通透性，提高了肺部气体交换率，从而延长生存期。其机制在于血小板表达的一种分子—P-选择素在调节血小板-中性粒细胞相互作用中至关重要，后者诱导血小板产生各种前炎症因子例如TXA2。因此，研究者称，终止血小板-中性粒细胞间相互作用或者阻滞前炎症因子的产生有可能为ALI患者的治疗提供新的方向。
在一则相关评论中，Wolfgang Kuebler认为，虽然这项研究强调了血小板在ALI发病中的重要性，血小板在其它肺部炎性疾病的发病中也可能很重要，包括哮喘、慢性阻塞性肺部疾病、囊性纤维化。
Figure 1 Platelets control PMN recruitment into the lung in acid-induced ALI.
(A–C) Platelet depletion (by 40%) prior to acid application by busulfan (n = 4–10 mice per group) significantly improved gas exchange (A), reduced intravascular and interstitial PMN accumulation (data not shown), diminished PMNs in the BAL fluid (B), and partially prevented increased vascular permeability (C). Platelet depletion (85%) caused by a polyclonal Ab diminished PMN recruitment into the alveolar space (B) and permeability (C). (D–G) Photomicrographs of lung tissue. H&E-stained paraffin sections from control mice (D) and mice 2 hours after acid administration (E). Acid application induced increased permeability with an influx of protein-rich fluid and cells (E, arrow) into the alveolar space, swelling of the interstitium, and cell accumulation in the interstitial space (E). Glycol pretreatment (F) prior to initiation of ALI induced the same histological changes seen in untreated mice after acid application whereas the pretreatment with busulfan led to reduced morphological changes (G). Original magnification, x65. Gly, glycol; Bu, busulfan; pre, preimmune serum; Ab, polyclonal anti-platelet Abs. #P < 0.05. Scale bars, 50.0 mm.
原文出处：
Journal of Clinical Investigation December 1 2006, Volume 116, Issue 12
Commentaries:
Wolfgang M. Kuebler
Selectins revisited: the emerging role of platelets in inflammatory lung disease
J. Clin. Invest. 2006 116: 3106-3108. [Abstract] [Full Text] [PDF]
Research article:
Alexander Zarbock, Kai Singbartl, and Klaus Ley
Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation
J. Clin. Invest. 2006 116: 3211-3219. [Abstract] [Full Text] [PDF]
作者简介：
Klaus Ley
Degree(s): M.D.
Graduate School:
Julius-Maximilians-Univ of Wurzburg, Germany
Primary Appointment: Professor of Biomedical Engineering
Research Interests:
Leukocyte and Monocyte Adhesion and Activation in Inflammation and Atherosclerosis
Email Address: kfl3f@virginia.edu
Biomedical Sciences Graduate Program(s)
· Biomedical Engineering
· Molecular Medicine
· Microbiology, Immunology and Infectious Diseases
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Research Description
Inflammatory cell recruitment requires the concerted action of at least four major sets of adhesion molecules: integrins, immunoglobulin-like molecules, selectins, and carbohydrate structures serving as selectin ligands. Selectin-mediated adhesion represents the first step in the cascade required for leukocyte recruitment. The three known selectins (E-, L- and P-selectin) have been shown to be involved in mediating leukocyte rolling, which is a transient adhesion event during early inflammation. My laboratory investigates the involvement of the selectins in initial leukocyte attachment and emigration in vivo, mainly by using the method of intravital microscopy. We use blocking monoclonal antibodies, cell lines transfected with selectin molecules and selectin-deficient mice made by gene targeting and homologous recombination. Inflammation is experimentally induced by tissue trauma and/or injection of the pro-inflammatory cytokine TNF-alpha. Atherosclerotic lesions develop and progress through recruitment of monocytes into the arterial wall. This process appears to also involve adhesion molecules. Preliminary data suggest that P-selectin, L-selectin, and the immunoglobulin-like molecule VCAM-1 may be involved in monocyte recruitment into atherosclerotic lesions. We use an isolated perfused mouse carotid artery to study adhesion of monocytes and monocyte-like cell lines with the aim of identifying the relevant molecular mechanisms. The mouse model is useful because gene-targeted mice lacking apolipoprotein E (apoE) are available which develop atherosclerotic lesions. The results of this research are expected to augment the basic understanding of the inflammatory process as well as the potential for developing anti- inflammatory and anti-atherogenic therapies for future clinical use in patients.
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Selected Publications
· Huo Y, Zhao L, Hyman MC, Shashkin P, Harry BL, Burcin T, Forlow SB, Stark MA, Smith DF, Clarke S, Srinivasan S, Hedrick CC, Pratico D, Witztum JL, Nadler JL, Funk CD, Ley K. Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2004 Oct 5;110(14):2024-31.
· Smith ML, Olson TS, Ley K. CXCR2- and E-Selectin-induced Neutrophil Arrest during Inflammation In Vivo. J Exp Med. 2004 Oct 4;200(7):935-9.
· Olson TS, Bamias G, Naganuma M, Rivera-Nieves J, Burcin TL, Ross W, Morris MA, Pizarro TT, Ernst PB, Cominelli F, Ley K. Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease. J Clin Invest. 2004 Aug;114(3):389-98.
· Ley K, Kansas GS. Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat Rev Immunol. 2004 May;4(5):325-35.
· PubMed Listings for this Faculty Member
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