Combined repetitive inhalant endotoxin and collagen-induced arthritis drives inflammatory lung disease and arthritis severity in a testosterone-dependent manner

This study aimed to determine whether hormone-dependent differences explained these observations. Arthritis prone male intact and castrated DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for 5 weeks and CIA induction. Arthritis scores and serum pentraxin-2 levels were increased in castrated vs. intact mice. In contrast, airway cell influx, lung tissue infiltrates, and lung levels of pro-inflammatory and pro-fibrotic markers (C5a, IL-33, and matrix metalloproteinases) were reduced in castrated vs. intact mice. CIA+LPS-induced lung histopathology changes and the expression of lung autoantigens including malondialdehyde acetaldehyde (MAA)- and citrulline (CIT)-modified proteins and vimentin were reduced in castrated animals. There were no differences for serum anti-MAA or anti-CIT protein antibody (ACPA) levels or serum pentraxin levels between groups. Testosterone replacement led to reversal of several lung inflammatory/profibrotic endpoints noted above in castrated male CIA+LPS-treated mice with testosterone supplementation promoting neutrophil influx, MAA expression, and TNF-⍺, IL-6, and MMP-9. These findings imply that testosterone contributes to lung and arthritis inflammatory responses following CIA+LPS co-exposure, but not to systemic autoantibody responses. The CIA+LPS model provides a paradigm for investigations focused on the mechanistic underpinnings for epidemiologic and phenotypic sex differences in RA-related lung disease.PMID:380860...
Source: Am J Physiol Lung Ce... - Category: Respiratory Medicine Authors: Source Type: research