Leukotriene C4 Synthase Deficiency Causes Spontaneous Emphysema in Female Mice

Emphysema, an important component of chronic obstructive pulmonary disease (COPD), whereby there is progressive destruction of alveolar tissues, remains poorly understood. 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 cysLT 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 BAL fluid cells. Emphysema-related gene expression was assessed by qRT-PCR. 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 SOD-2 (superoxide dismutase 2), increase in MMP8 (matrix metalloproteinase 8), 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.