leukotriene-b4 and prolyl-glycyl-proline

The pro-inflammatory mediator leukotriene B

Topics: Amino Acid Motifs; Animals; Anti-Inflammatory Agents; beta-Alanine; Binding Sites; Bone Marrow Cells; Crystallography, X-Ray; Enzyme Inhibitors; Epoxide Hydrolases; Female; Gene Expression; Humans; Hydrolysis; Inflammation; Leukotriene B4; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Neutrophils; Oligopeptides; Proline; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Recombinant Proteins; Substrate Specificity

Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline-glycine-proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.

Topics: Animals; Epoxide Hydrolases; Extracellular Matrix; Flow Cytometry; Haemophilus Infections; Haemophilus influenzae type b; Inflammation; Leukocyte Elastase; Leukotriene B4; Lung; Macrophages, Alveolar; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Neutrophils; Oligopeptides; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Proline; Receptors, Leukotriene B4; Streptococcus pneumoniae

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