生物谷報(bào)道：急性肺損傷（ALI）是一種相對(duì)比較常見(jiàn)的能危及生命的疾病。它可以由膿血癥,、創(chuàng)傷和吸入酸性物質(zhì)引起,，后者是全身麻醉的并發(fā)癥之一。當(dāng)前對(duì)ALI的治療尚未有好的辦法,，但是,，《臨床研究》雜志的12月刊上發(fā)表的一項(xiàng)研究已經(jīng)證實(shí)治療ALI病人有新的并具前景的治療方向。
弗吉尼亞大學(xué)的Klaus Ley和同事們發(fā)現(xiàn)在用吸入酸性物質(zhì)誘導(dǎo)的急性肺損傷小鼠模型中,，血小板-中性粒細(xì)胞間相互作用在病情發(fā)展中起著關(guān)鍵作用,。通過(guò)減少小鼠體內(nèi)的血小板數(shù)量或者阻止血小板-中性粒細(xì)胞間相互作用，減少了中性粒細(xì)胞向肺部聚集的數(shù)量,，降低了肺泡通透性,，提高了肺部氣體交換率，從而延長(zhǎng)生存期,。其機(jī)制在于血小板表達(dá)的一種分子—P-選擇素在調(diào)節(jié)血小板-中性粒細(xì)胞相互作用中至關(guān)重要,，后者誘導(dǎo)血小板產(chǎn)生各種前炎癥因子例如TXA2。因此,，研究者稱,，終止血小板-中性粒細(xì)胞間相互作用或者阻滯前炎癥因子的產(chǎn)生有可能為ALI患者的治療提供新的方向。
在一則相關(guān)評(píng)論中,，Wolfgang Kuebler認(rèn)為,，雖然這項(xiàng)研究強(qiáng)調(diào)了血小板在ALI發(fā)病中的重要性，血小板在其它肺部炎性疾病的發(fā)病中也可能很重要,，包括哮喘,、慢性阻塞性肺部疾病、囊性纖維化,。
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.
原文出處：
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]
作者簡(jiǎn)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: [email protected]
Biomedical Sciences Graduate Program(s)
· Biomedical Engineering
· Molecular Medicine
· Microbiology, Immunology and Infectious Diseases
--------------------------------------------------------------------------------
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.
--------------------------------------------------------------------------------
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
--------------------------------------------------------------------------------
Intranet Profile
NIH Style Biographical Sketch Current Techniques and Protocols (UVA Intranet log-in required)
[To add/update Intranet profile information, read these instructions.]
