Abstract Rationale Despite advances in idiopathic pulmonary fibrosis (IPF) therapeutics, there remains a significant gap in the availability of treatments that prevent or reverse lung fibrosis. We previously showed that the BH3-only protein, Noxa, protects from allergen-induced lung inflammation. The present study investigated whether Noxa is associated with the IPF risk of in humans and whether inducible or conditional deletion of Noxa specifically in club cells of mice either protects or enhances bleomycin-induced lung injury and inflammation. Methods We analyzed Noxa mRNA levels from Lung Tissue Research Consortium (LTRC) cohort, focusing on former smokers who had stopped smoking for over 2 years (n = 691). Also, we generated a Noxafl/fl mouse by inserting LoxP sites flanking exons 2 and 3 of the Noxa gene. This mouse enabled us to conditionally knockout Noxa specifically in club cells by crossing Noxafl/fl mice with SCGB1A1-CreERT mice and inducing Cre recombinase expression by tamoxifen administration. Mice were instilled via oropharyngeal route with 1U/kg of bleomycin three times, every other week to induce fibrosis, and control mice were instilled with saline. Mice were euthanized 2 weeks after the third instillation and the left lungs were used for histological analyses while the right lungs were lavaged to assess lung inflammation. Inflammatory cells were quantified from the recovered bronchoalveolar lavage (BAL) fluid and IPF was assessed by assessing collagen deposition. Results After adjusting for race, sex and smoking pack-years, individuals with no IPF demonstrated a significantly higher Noxa mRNA levels compared to those with IPF. Moreover, higher relative Noxa mRNA levels were associated with a lower risk for IPF (OR = 0.33; 95% CI 0.17, 0.64). Despite similar age and BMI profiles between the groups, study participants with IPF exhibited lower post FEV1pp, lower % post FVCpp, and a higher FEV1/FVC ratio compared to those without IPF. Bleomycin-induced lung inflammation was significantly reduced in SCGB1A1-CreERT/Noxa+/- mice compared with SCGB1A1-CreERT/Noxa-/- (Noxa knockout) littermate controls, as evidenced by increased counts of total leukocytes, macrophages, and lymphocytes; further supporting our previous findings that when Noxa is inducibly expressed in club cells, mice were protected from bleomycin-induced inflammation and pulmonary fibrosis. Conclusions These findings suggest that elevated Noxa expression in the lungs may confer protection against IPF. In mice, club cell-specific deletion of Noxa enhances bleomycin-induced pulmonary inflammation, suggesting protective role for Noxa in lung injury responses. The molecular mechanisms how Noxa protects from IPF is under investigation. Funding source: RO1-HL068111 and R01-HL166992 This abstract is funded by: NIH
Negasi et al. (Fri,) studied this question.
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