Xenobiotic-Induced Lung Toxicity in Mouse Models and the Possible Roles of Macrophage CYP19A1

Abstract

Macrophages are innate immune cells that are critical in maintaining tissue homeostasis. Macrophages are highly plastic and perform a variety of functions including surveillance, inflammation, tissue remodeling, and defending against pathogens. Lung macrophages are adapted to the lung microenvironment and regulate tissue remodeling and microbial clearance in response to pulmonary toxicants or pathogens that enter the lung. Because the lung is continuously exposed to environmental agents and susceptible to injury, proper macrophage function is essential to maintain lung health and prevent the development of chronic inflammatory diseases. This dissertation examines two factors that influence macrophage function and lung tissue repair, 1) macrophage CYP19A1 and 2) arsenic. Arsenic is an environmental pollutant present in contaminated soil and groundwater. CYP19A1 is a cytochrome P450 enzyme that catalyzes the conversion of androgens to estrogens. CYP19A1 is expressed not only in reproductive organs, but also in extragonadal tissues, including the brain, bone, and adipose, as well as in macrophages from multiple sites. While many studies have demonstrated that circulating estrogen regulates macrophage function and inflammation, the functional role of macrophage CYP19A1 in inflammation and lung diseases is unknown. The objectives of these studies were to determine 1) the role of macrophage CYP19A1 in LPS-induced lung inflammation, 2) whether or not macrophage CYP19A1 plays a role in NNK-induced lung carcinogenesis, and 3) whether chronic treatment with arsenic, a chemical known to impair macrophage function and lung epithelial repair at the cellular level, impacts lung tissue repair and carcinogenesis in vivo. Using a novel myeloid-specific CYP19A1-null (Cyp19a1-null) mouse, we observed for the first time that macrophage CYP19A1 is involved in the production of pro-inflammatory cytokines and recruitment of neutrophils to the lung in response to LPS. Inflammation has implications in many diseases, including lung cancer; thus, a mouse model of NNK-induced lung tumorigenesis was used to ascertain the role of macrophage CYP19A1 in lung tumorigenesis. No differences were observed in lung tumor incidence or multiplicity between wild-type (Cyp19a1-lox) and Cyp19a1-null mice. In that connection, the NNK-induced lung tumorigenesis model and a naphthalene (NA)-induced airway injury model were used to determine whether cotreatment with arsenic impacts lung tumor formation and tissue repair, respectively. These studies revealed for the first time that following NA-induced airway injury, arsenic treatment inhibits club cell regeneration in the distal airways of mice. However, co-treatment with arsenic did not affect NNK-induced lung tumorigenesis. Overall, the results of these studies provide insights on novel factors that influence macrophage function and lung tissue repair.