Aspirin-Triggered Resolvin D1 Reduces Chronic Dust-Induced Lung Pathology without Altering Susceptibility to Dust-Enhanced Carcinogenesis.

Abstract

Simple SummaryFarm workers are at an increased risk of developing acute and chronic lung inflammatory diseases from their everyday exposure to organic dust. Previous investigations have examined the inflammatory effects in mice from single and repetitive exposure to dust from swine confinement facilities, however, no study has explored these effects in a chronic model. To address this research gap, we established a chronic dust exposure mouse model of lung tumorigenesis that was also used to measure the efficacy of omega-3 fatty acid-derived lipid mediators as therapeutics for mitigating these induced responses. Our results from these investigations are the first to evaluate the chronic inflammatory, and carcinogenic effects of these dusts, as well as identify a potential therapeutic strategy for mitigating the inflammatory effects by using an omega-3 fatty acid-derived bioactive lipid mediator.Lung cancer is the leading cause of cancer-related deaths worldwide, with increased risk being associated with unresolved or chronic inflammation. Agricultural and livestock workers endure significant exposure to agricultural dusts on a routine basis; however, the chronic inflammatory and carcinogenic effects of these dust exposure is unclear. We have developed a chronic dust exposure model of lung carcinogenesis in which mice were intranasally challenged three times a week for 24 weeks, using an aqueous dust extract (HDE) made from dust collected in swine confinement facilities. We also treated mice with the omega-3-fatty acid lipid mediator, aspirin-triggered resolvin D1 (AT-RvD1) to provide a novel therapeutic strategy for mitigating the inflammatory and carcinogenic effects of HDE. Exposure to HDE resulted in significant immune cell influx into the lungs, enhanced lung tumorigenesis, severe tissue pathogenesis, and a pro-inflammatory and carcinogenic gene signature, relative to saline-exposed mice. AT-RvD1 treatment mitigated the dust-induced inflammatory response but did not protect against HDE + NNK-enhanced tumorigenesis. Our data suggest that chronic HDE exposure induces a significant inflammatory and pro-carcinogenic response, whereas treatment with AT-RvD1 dampens the inflammatory responses, providing a strong argument for the therapeutic use of AT-RvD1 to mitigate chronic inflammation.