Tristetraprolin protects against ozone-induced acute lung injury and inflammation in mice

Abstract

Tristetraprolin (TTP) is an anti-inflammatory protein that mediates messenger RNA (mRNA) decay of certain transcripts, especially those encoding proinflammatory cytokines. TTP modulates various pathological outcomes in diverse inflammatory diseases; however, its role in ozone (O3)-induced acute lung injury (ALI) has never been tested. Here, we hypothesized that the loss of TTP would exacerbate O3-induced ALI and that the systemic overexpression of TTP would mitigate O3-induced ALI. Accordingly, TTP-knockout (TTPKO), airway epithelial cell-specific TTP-deficient (EpiKO), myeloid cell-specific TTP-deficient (MyeKO), and systemic TTP-overexpressing (TTPΔARE) adult male and female mice, along with their respective littermate control TTP-sufficient mice, were exposed to either O3 (3 ppm) or filtered air for 3 h. The endpoints, including bronchoalveolar lavage fluid cellularity, cytokine levels, and histopathological changes, were assessed 21 to 24 h after O3 or filtered air exposure. As compared with the O3-exposed TTP-sufficient mice, the O3-exposed TTPKO and O3-exposed cell-specific TTP-deficient mice exhibited a significant worsening of ALI outcomes (i.e., neutrophil infiltration, cytokine/chemokine production, and lung pathology). The severity of these outcomes was comparatively milder in O3-exposed EpiKO and O3-exposed MyeKO mice than in O3-exposed TTPKO mice. Conversely, the O3-exposed TTPΔARE mice were protected against O3-induced ALI, as indicated by relatively reduced levels of inflammatory cytokines/chemokines, reduced neutrophil infiltration, and mitigated lung pathology. Collectively, our data suggest that TTP is a critical regulator of inflammation in O3-induced ALI. These findings indicate that enhancing TTP expression could be a potential therapeutic strategy for simultaneously targeting multiple inflammatory cytokines in O3-induced ALI and possibly other inflammatory diseases.

Keywords: acute lung inflammation; acute lung injury; ozone; tristetraprolin.