FIGURE 4.

Leukotriene A₄ hydrolase (LTA₄H)-mediated degradation of Pro-Gly-Pro (PGP) is disturbed in chronic lung diseases. Neutrophils recruited to the lung release enzymes (matrix metalloproteinases (MMPs) and prolylendopeptidase (PE)) that proteolytically target collagen to generate PGP. To counteract this, LTA₄H is released to degrade PGP and resolve neutrophilic inflammation. If this balance between PGP-generating and PGP-degrading enzymes is disturbed then PGP can persist and drive pathology. Cigarette smoke, a major risk factor for the development of chronic obstructive pulmonary disease, can promote the expression and/or release of MMPs and PE and ensuing PGP generation. Furthermore, cigarette smoke disturbs the LTA₄H-mediated anti-inflammatory pathway in two ways: 1) chemically acetylating PGP (AcPGP) and protecting it from degradation by LTA₄H; and 2) selective abrogation of LTA₄H PGP-degrading activity. A protease imbalance is a hallmark of many chronic lung diseases, with neutrophil elastase prominently implicated in disease pathologies. Neutrophil elastase can promote MMP activation to facilitate PGP generation, whilst degrading extracellular LTA₄H. Respiratory infections act to further spike PGP generation in a setting where degradation is impaired. As a result, AcPGP/PGP can drive neutrophilic inflammation and pathology. LTB₄: leukotriene B₄; IL: interleukin; BLT₁: Leukotriene B₄ receptor 1.