Leukotriene C4 Synthase Deficiency Causes Spontaneous Emphysema in Female Mice

Emphysema, an important component of chronic obstructive pulmonary disease (COPD) remains poorly understood whereby there is progressive destruction of alveolar tissues. Cysteinyl-leukotrienes (cysLTs) and their receptors have been extensively investigated in asthma but not in COPD. Whether cysLTs influence emphysema is unknown. To investigate the influence of the constitutive synthesis of cysLTs on airspace integrity we assessed lung structure and function in leukotriene C₄ synthase-deficient (Ltc4s^-/-) mice, lacking the pivotal enzyme for cysLTs biosynthesis. Mice ranged in age from 5-20 weeks. Emphysema was assessed from the mean linear intercept and pulmonary mechanics. Differential cell counts and iron staining were performed on bronchoalveolar lavage fluid cells. Emphysema-related gene expression was assessed by RT-qPCR. Oxidative stress and oxygen consumption in alveolar macrophages were evaluated by flow cytometry and Seahorse™ assay. Ltc4s^-/- female mice developed extensive emphysema by 10 weeks of age histologically and by lung function. There was evidence of abnormal alveolar macrophage function comprising a reduction of superoxide dismutase 2 (SOD-2), increase in matrix metalloproteinase 8 (MMP8), an enhanced mitochondrial oxidative stress and an increase in iron deposition. Treatment with sulforaphane, an activator of the transcription of antioxidant genes, prevented the development of emphysema. We conclude that spontaneous emphysema in female mice deficient in LTC4S is associated with enhanced mitochondrial oxidative stress. These findings indicate a homeostatic role for cysLTs in preserving alveolar structure and provide a novel model to explore mechanisms of emphysema.