prolyl-glycyl-proline and Pulmonary-Disease--Chronic-Obstructive

The lack of a well-characterized biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD) has increased interest toward finding one, because this would provide potential insight into disease pathogenesis and progression. Since persistent neutrophilia is an important hallmark in COPD Pro-Gly-Pro (PGP), an extracellular matrix-derived neutrophil chemoattractant, has been suggested to be a potential biomarker in COPD. The purpose of this review is to critically examine both biological and clinical data related to the role of PGP in COPD, with particular focus on its role as a clinical biomarker and potential therapeutic target in disease. The data provided in this review will offer insight into the potential use of PGP as end point for future clinical studies in COPD lung disease. Following PGP levels during disease might serve as a guide for the progression of lung disorders.

Topics: Animals; Biomarkers; Chemokines; Extracellular Matrix; Humans; Leukotriene A4; Neutrophils; Oligopeptides; Proline; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide and is characterized by an excessive airway neutrophilic response. The neutrophil chemoattractant proline-glycine-proline (PGP) and its more potent acetylated form (acPGP) have been found to be elevated in patients with COPD and act via CXCR2. Here, we investigated the impact of neutralizing PGP peptides in a murine model for emphysema. The PGP-neutralizing peptide l-arginine-threonine-arginine (RTR) was used first in a 6-week model of cigarette smoke exposure, where it attenuated lung inflammation. Then, in a model of chronic smoke exposure, mice were exposed to cigarette smoke and RTR treatment was initiated after 10 weeks of smoke exposure. This treatment was continued together with smoke exposure for another 13 weeks, for a total of 23 weeks of smoke exposure. RTR significantly inhibited neutrophil and macrophage influx into the lungs in the 6-week model of exposure. RTR also attenuated the development of emphysema, normalized lung volumes, and reduced right ventricular hypertrophy in the chronic exposure model. Murine epithelia expressed CXCR2, and this expression was increased after smoke exposure.

Topics: Animals; Cells, Cultured; Humans; Inflammation; Lung; Mice; Neutrophils; Oligopeptides; Proline; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Smoke

Cigarette smoking induces inflammatory responses in all smokers and is the major risk factor for lung disease such as chronic obstructive pulmonary disease (COPD). In this progressive disease, chronic inflammation in the lung contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated Proline-Glycine-Proline (N-ac-PGP). The generation of this tripeptide is mediated by a multistep pathway involving matrix metalloproteases (MMPs) 8 and 9 and prolyl endopeptidase (PE). Here we investigated whether cigarette smoke extract (CSE) stimulates human PMNs to breakdown whole matrix collagen leading to the generation of the chemotactic collagen fragment N-ac-PGP.. Incubating PMNs with CSE led to the release of chemo-attractant CXCL8 and proteases MMP8 and MMP9. PMNs constitutively expressed PE activity as well as PE protein. Incubating CSE-primed PMNs with collagen resulted in collagen breakdown and in N-ac-PGP generation. Incubation of PMNs with the tripeptide N-ac-PGP resulted in the release of CXCL8, MMP8 and MMP9. Moreover, we tested whether PMNs from COPD patients are different from PMNs from healthy donors. Here we show that the intracellular basal PE activity of PMNs from COPD patients increased 25-fold compared to PMNs from healthy donors. Immunohistological staining of human lung tissue for PE showed that besides neutrophils, macrophages and epithelial cells express PE.. This study indicates that neutrophils activated by cigarette smoke extract can breakdown collagen into N-ac-PGP and that this collagen fragment itself can activate neutrophils, which may lead in vivo to a self-propagating cycle of neutrophil infiltration, chronic inflammation and lung emphysema. MMP-, PE- or PGP-inhibitors can serve as an attractive therapeutic target and may open new avenues towards effective treatment of COPD.

Topics: Aged; Case-Control Studies; Cell Survival; Collagen; Collagen Type I; Female; Humans; Inflammation; Interleukin-8; Leukocytes, Mononuclear; Lung; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Middle Aged; Neutrophils; Oligopeptides; Proline; Prolyl Oligopeptidases; Pulmonary Disease, Chronic Obstructive; Serine Endopeptidases; Smoking; Tobacco Products

Leukotriene A(4) hydrolase (LTA(4)H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B(4) (LTB(4)). LTA(4)H also possesses aminopeptidase activity with unknown substrate and physiological importance; we identified the neutrophil chemoattractant proline-glycine-proline (PGP) as this physiological substrate. PGP is a biomarker for chronic obstructive pulmonary disease (COPD) and is implicated in neutrophil persistence in the lung. In acute neutrophil-driven inflammation, PGP was degraded by LTA(4)H, which facilitated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA(4)H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. These studies imply that therapeutic strategies inhibiting LTA(4)H to prevent LTB(4) generation may not reduce neutrophil recruitment because of elevated levels of PGP.

Topics: Acetylation; Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chemokines, CXC; Chemotaxis, Leukocyte; Epoxide Hydrolases; Female; Humans; Inflammation; Leukotriene B4; Lung; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutrophils; Nicotiana; Oligopeptides; Orthomyxoviridae Infections; Pneumococcal Infections; Pneumonia; Proline; Pulmonary Disease, Chronic Obstructive; Smoke

Topics: Acetylation; Animals; Chemokines, CXC; Chemotaxis, Leukocyte; Epoxide Hydrolases; Humans; Inflammation; Leukotriene B4; Lung; Mice; Neutrophil Activation; Neutrophils; Nicotiana; Oligopeptides; Orthomyxoviridae Infections; Pneumococcal Infections; Pneumonia; Proline; Pulmonary Disease, Chronic Obstructive; Smoke