Project description:Background: Obesity has become a worldwide concern. Acute respiratory distress syndrome (ARDS) comprises 10.4% of total intensive care unit admissions and is associated with very high mortality. ARDS incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the clinical and pathologic features observed in patients with ARDS. The aim of this study was to determine the impact of high fat diet-induced obesity on the susceptibility to hyperoxic acute lung injury in mice. Methods: Male C57BL/6 mice received 60% fat versus ingredient matched 10% fat diet. Mice were exposed to >95% oxygen to induce lung damage. RNA was isolated from lung homogenates and by comparing RNA sequencing results with mouse Mitocarta, an inventory of genes encoding proteins with mitochondrial localization, we identified fatty acid synthase (FASN), an enzyme catalyzing de novo fatty acid synthesis, as one of the mitochondrial genes significantly changed with diet and with hyperoxia. We generated mice deficient in FASN in alveolar epithelial cells by using a tamoxifen inducible Cre recombinase construct (FASNflox/flox SPC Cre+/-) and subjected them to hyperoxia and high fat diet. Results: Mice receiving 60% fat diet had significantly higher weight, serum cholesterol and fasting glucose. High fat diet mice had significantly reduced survival and increased lung damage, as assessed by BAL protein and LDH, histology and TUNEL staining. By RNA sequencing of lung homogenates we identified FASN as one of the mitochondrial genes significantly reduced in mice receiving 60% compared to 10% fat diet and further reduced with hyperoxia. We confirmed that FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. After 48 hours of hyperoxia FASNflox/flox SPC Cre+/- mice displayed increased levels of BAL protein and LDH and more severe histologic lung injury. FASNflox/flox SPC Cre+/- mice remained more prone to lung injury after hyperoxic exposure even when they received 60% fat diet. Conclusions: These results demonstrate that obesity increases the severity of hyperoxia induced acute lung injury in mice by altering FASN levels in the lung of high fat diet fed rodents. To our knowledge, this is the first study to show that high fat diet leads to altered FASN expression in the lung and that both high fat diet and reduced FASN in alveolar epithelial cells lead to increased lung injury under hyperoxic conditions.

Project description:Background: Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated. Results: Type 1 diabetes (T1D) or diet-induced obesity (DIO) murine models were generated by injection of streptozotocin or feeding a 45% high-fat diet for 10 weeks, respectively, and subjected to 4-week real-ambient PM exposure in Shijiazhuang, China (mean PM2.5 concentration 95.77 μg/m3). Pulmonary and systemic injury was assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice. Conclusions: These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.

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Impact of Diet Induced Obesity on Hyperoxic Lung Injury

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