The Induction of Autoimmune Arthritis and Sex Differences in Mice Impact the Lung Inflammatory Response to Repetitive Inhalant Organic Dust Extract Exposures

Abstract

Inflammatory lung diseases are often associated with systemic autoimmunity, and sex differences have been independently described. Men are at increased risk of occupational exposure-associated rheumatoid arthritis (RA) and extra-articular manifestations. Because agriculture work is associated with both chronic lung disease and RA, we sought to determine whether induction of autoimmune arthritis and sex influence airway response to organic dust extract (ODE). Arthritis prone, DBA/1J male and female mice (8 week), were treated daily with ODE or saline for 5 weeks with collagen-induced arthritis (CIA) induced on days 1 and 21. Treatment groups included Sham (saline injection/saline inhalation), CIA (CIA/saline), ODE (saline/ODE); CIA+ODE (CIA/ODE). Bronchoalveolar lavage fluids, lung tissues, serum, and bones were collected. ODE induced airway neutrophil influx, increases in inflammatory mediators (TNF-α, IL-6, CXCL1, CXCL2), release of fibronectin (but not hyaluronan), and increased lung collagen staining as compared to sham. Co-exposure (CIA+ODE) resulted in reduced neutrophil and inflammatory mediator responses as compared to ODE alone, but lung tissue levels of hyaluronan, fibronectin and collagen staining were either augmented or remained increased in CIA+ODE. Arthritis inflammatory scores and serum anti-cyclic citrullinated peptide antibody were greatest in CIA+ODE. Compared to male mice, female mice demonstrated reduced ODE-induced mediator release, hyaluronan and fibronectin as well as lower arthritis scores and serum autoantibody levels with co-exposure. Autoimmune arthritis induction modulates the lung response to inhalant ODE exposure, impacting the inflammatory-interstitial disease process. Congruent with epidemiologic findings, male mice were most susceptible to lung and articular disease resulting from ODE.