Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 207, Issue 3, Pages 370-377Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cei/uxab036
Keywords
pioglitazone; Pseudomonas aeruginosa; innate immunity; inflammation
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2019/022240]
- Era-Net Joint Programming Initiative on Antimicrobial Resistance/ZonMW [50-52900-98-201]
- ZonMW [40-00812-98-14016]
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During acute P. aeruginosa pneumonia, the PPAR-gamma agonist pioglitazone exerts a selective proinflammatory effect on bronchial epithelial cells, possibly by enhancing intracellular glycolysis.
Pseudomonas aeruginosa is a common respiratory pathogen that causes injurious airway inflammation during acute pneumonia. Peroxisome proliferator-activated receptor (PPAR)-gamma is involved in the regulation of metabolic and inflammatory responses in different cell types and synthetic agonists of PPAR-gamma exert anti-inflammatory effects on myeloid cells in vitro and in models of inflammation in vivo. We sought to determine the effect of the PPAR-gamma agonist pioglitazone on airway inflammation induced by acute P. aeruginosa pneumonia, focusing on bronchial epithelial cells. Mice pretreated with pioglitazone or vehicle (24 and 1 h) were infected with P. aeruginosa via the airways. Pioglitazone treatment was associated with increased expression of chemokine (Cxcl1, Cxcl2, and Ccl20) and cytokine genes (Tnfa, Il6, and Cfs3) in bronchial brushes obtained 6 h after infection. This pro-inflammatory effect was accompanied by increased expression of Hk2 and Pfkfb3 genes encoding rate-limiting enzymes of glycolysis; concurrently, the expression of Sdha, important for maintaining metabolite flux in the tricarboxylic acid cycle, was reduced in bronchial epithelial cells of pioglitazone treated-mice. Pioglitazone inhibited bronchoalveolar inflammatory responses measured in lavage fluid. These results suggest that pioglitazone exerts a selective proinflammatory effect on bronchial epithelial cells during acute P. aeruginosa pneumonia, possibly by enhancing intracellular glycolysis.
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