Friday, November 22, 2024
11/22/2024
Project Summary/Abstract Exposure to wood smoke (WS) is common in the US because of inefficient residential wood burning devices during the winter heating season and large forest fires during the summer. Our studies in a cohort of well- characterized smokers living in Albuquerque, NM, found that a polymorphism that modifies a proline at codon 72 to arginine within the proline-rich domain (PRD) of p53 is associated with approximately 2-fold increased risk for chronic bronchitis for those who report being exposed to WS and are homozygous for the p53Arg variant. We showed that WS preferentially activates the p53Arg compared to the p53Pro variant in primary human airway epithelial cells (HAECs) and increases epidermal growth factor receptor (EGFR) and SPDEF, a transcription factor that governs the mucus regulatory phenotype. In mice, the PRD consists of 2 PXXP motifs and replacing the prolines in the p53 PRD (p53WT) with alanines (p53AXXA mice) also results in WS increasing mucin gene expression more in p53AXXA mice. By fractionating the WS extract, we identified oxalate and levunilate as constituents that induce mucin gene expression. When screening for proximal mediators we found that inhibitors of the anion exchanger solute carrier protein, SLC26A9, enhanced oxalate/levunilate- induced SPDEF promoter activation and suppression of SLC26A9 levels enhanced SPDEF promoter activation. These preliminary studies support the hypotheses that the WS constituents, oxalate and levunilate, activate p53 and EGFR more in HAECp53Arg compared to HAECPro and thereby increase expression of MUC5AC and MUC5B. Further, inhibiting uptake of oxalate and levunilate and the downstream pathway may reduce WS-induced mucus production. Aim 1 will identify WS constituents that may inhibit EGFR and/or p53 activation and compare MCM in p53WT and p53AXXA mice exposed to oxalate and levunilate. Aim 2 will compare SLC26A9 mRNA levels in nasal epithelial cells from participants of the Lovelace Smokers Cohort homozygous for p53Arg and p53Pro variants. Further, we will investigate whether increasing SLC26A9 levels in HAECp53Arg cultures will reduce uptake of oxalate and levunilate and reduce mucin gene expression. Because the EGFR and SPDEF pathways independently affect the MUC5B and MCU5AC expression, Aim 3 will explore the contribution of MUC5B and MCU5AC to the WS-induced MCM by using inhibitors of EGFR/ERK1/2 activation and suppression of SPDEF in HAECArg cultures. These studies will lay the foundation for understanding the mechanisms underlying WS-induced mucous hypersecretion and may serve as a springboard for strategies to lessen severity of chronic bronchitis and COPD exacerbations.
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