Abstract

Neutrophils represent a prominent source of pathology in an array of persistent pulmonary diseases. A recent article published in Science describes a novel anti-inflammatory pathway that degrades the neutrophil chemoattractant Pro-Gly-Pro (PGP) to limit neutrophilic inflammation of the lung. Degradation of PGP was mediated through the action of leukotriene A₄ hydrolase (LTA₄H), an enzyme classically recognised for its capacity to generate another neutrophil chemoattractant, leukotriene B₄ (LTB₄). The same enzyme therefore has opposing proinflammatory (LTB₄ generation) and anti-inflammatory (PGP degradation) activities that govern neutrophilic inflammation. Intriguingly, cigarette smoke, a key risk factor for the development of chronic obstructive pulmonary disease, impedes PGP degradation but not LTB₄ generation by LTA₄H. Cigarette smoke therefore essentially converts LTA₄H into an exclusively proinflammatory enzyme, whereby both PGP and LTB₄ can drive persistent neutrophila observed in chronic obstructive pulmonary disease. In recent years there has been significant pharmaceutical interest in the development of LTA₄H inhibitors to alleviate LTB₄-mediated pathologies. In light of these new findings, such strategies should be viewed with caution since they may inadvertently prevent PGP degradation and promote chronic neutrophilic inflammation.