A combination of alveolar type 2-specific p38α activation with a high-fat diet increases inflammatory markers in mouse lungs.

Abstract

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) afflict millions of individuals globally and are significant sources of disease mortality. While the molecular mechanisms underlying such diseases are unclear, environmental and social factors, such as cigarette smoke and obesity, increase the risk of disease development. Yet not all smokers or obese individuals will develop chronic respiratory diseases. The MAPK p38α is abnormally active in such maladies, but its contribution, if any, to disease aetiology is unknown. To assess whether p38α activation per se in the lung could impose disease symptoms, we generated a transgenic mouse model allowing controllable expression of an intrinsically active variant, p38α^D176A+F327S, specifically in lung alveolar type 2 (AT2) pneumocytes. Sustained expression of p38α^D176A+F327S did not appear to induce obvious pathological outcomes or to exacerbate inflammatory outcomes in mice challenged with common respiratory disease triggers. However, mice expressing p38α^D176A+F327S in AT2 cells and fed with a high-fat diet (HFD) exhibited increased numbers of airway eosinophils and lymphocytes, upregulated levels of pro-inflammatory cytokines and chemokines including interleukin-1β and eotaxin, as well as a reduction in levels of leptin and adiponectin within the lung. Neither HFD nor p38α^D176A+F327S alone induced such outcomes. Perhaps in obese individuals with associated respiratory diseases, elevated p38α activity which happens to occur is the factor that promotes their development.