Short‐chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR GPR 41&43

摘要

Summary Background Chronic rhinosinusitis ( CRS ) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps ( NP s). One of the features of NP s is excessive fibrin deposition, which is associated with down‐regulation of tissue plasminogen activator (t‐ PA ) in NP s. As t‐ PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t‐ PA would be a potential new strategy for the treatment of NP s. Objective The objective of this study was to determine whether short‐chain fatty acids ( SCFA s) can induce t‐ PA in airway epithelial cells via their known receptors GPR 41 and GPR 43. Methods We performed immunohistochemistry ( IHC ) to determine whether receptors for SCFA s, known as G protein‐coupled receptor 41/free fatty acid receptor 3 ( GPR 41/ FFAR 3) and GPR 43/ FFAR 2, are expressed in nasal tissue. Primary normal human bronchial epithelial ( NHBE ) cells were stimulated with different concentrations of SCFA s to test induction of t‐ PA , which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with si RNA . Results Immunohistochemistry study revealed that airway epithelial cells expressed GPR 41 and GPR 43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t‐ PA expression from two‐ to tenfolds. The strongest inducer of t‐ PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t‐ PA into the supernatant in its active form. Gene silencing of GPR 41 and GPR 43 revealed that induction of t‐ PA by SCFA s was dependent upon both GPR 41 and GPR 43. Conclusions and Clinical Relevance Short‐chain fatty acids were shown to induce airway epithelial cell expression of t‐ PA via GPR 41 and GPR 43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.