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.