Leukotriene A4 hydrolase: an anti-inflammatory role for a proinflammatory enzyme

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.