Weathington Nathaniel M, van Houwelingen Anneke H, Noerager Brett D, Jackson Patricia L, Kraneveld Aletta D, Galin F Shawn, Folkerts Gert, Nijkamp Frans P, Blalock J Edwin
Department of Physiology and Biophysics, University of Alabama at Birmingham, 1918 University Boulevard, Birmingham, Alabama 35294, USA.
Nat Med. 2006 Mar;12(3):317-23. doi: 10.1038/nm1361. Epub 2006 Feb 12.
We describe the tripeptide neutrophil chemoattractant N-acetyl Pro-Gly-Pro (PGP), derived from the breakdown of extracellular matrix (ECM), which shares sequence and structural homology with an important domain on alpha chemokines. PGP caused chemotaxis and production of superoxide through CXC receptors, and administration of peptide caused recruitment of neutrophils (PMNs) into lungs of control, but not CXCR2-deficient mice. PGP was generated in mouse lung after exposure to lipopolysaccharide, and in vivo and in vitro blockade of PGP with monoclonal antibody suppressed PMN responses as much as chemokine-specific monoclonal antibody. Extended PGP treatment caused alveolar enlargement and right ventricular hypertrophy in mice. PGP was detectable in substantial concentrations in a majority of bronchoalveolar lavage samples from individuals with chronic obstructive pulmonary disease, but not control individuals. Thus, PGP's activity links degradation of ECM with neutrophil recruitment in airway inflammation, and PGP may be a biomarker and therapeutic target for neutrophilic inflammatory diseases.
我们描述了一种三肽中性粒细胞趋化因子N-乙酰基脯氨酰-甘氨酰-脯氨酸（PGP），它源自细胞外基质（ECM）的降解产物，与α趋化因子上的一个重要结构域具有序列和结构同源性。PGP通过CXC受体引起趋化作用并产生超氧化物，肽的给药导致中性粒细胞（PMN）募集到对照小鼠的肺中，但不能募集到CXCR2缺陷小鼠的肺中。暴露于脂多糖后，小鼠肺中会产生PGP，用单克隆抗体在体内和体外阻断PGP对PMN反应的抑制作用与趋化因子特异性单克隆抗体一样大。延长PGP治疗会导致小鼠肺泡增大和右心室肥大。在大多数慢性阻塞性肺疾病患者的支气管肺泡灌洗样本中可检测到高浓度的PGP，但在对照个体中则检测不到。因此，PGP的活性将ECM的降解与气道炎症中的中性粒细胞募集联系起来，并且PGP可能是嗜中性粒细胞炎症性疾病的生物标志物和治疗靶点。
