Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

Abstract

Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 month) and aged (18-20 month) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically-ill aged population.

Carnitine Palmitoyltransferase System: A New Target for Anti-Inflammatory and Anticancer Therapy?

“…Elevated age is a risk factor for the poor outcomes of ALI/ARDS. Using an LPS-triggered ALI model in adult and aged mice, Gibbs et al (2021) assessed age-related alterations in lung inflammation, muscle injury, and metabolism. They observed that etomoxir administration resulted in an increase in the mortality of aged but not adult ALI mice, thereby confirming that the CPT system is essential for survival from severe lung injury and indicating that adult mice have improved resilience to FAO inhibition.…”

Redox Dysregulation in Aging and COPD: Role of NOX Enzymes and Implications for Antioxidant Strategies

“…These changes collectively impact on appropriate epithelial responses to environmental pathogens, although the precise impact of ageing on these processes is still incompletely understood. For example, acute airway inflammatory responses to microbial stimuli are somewhat attenuated with age and appear prolonged [ 28 ]. In apparent contrast, ageing dramatically impacts on innate airway epithelial responses to non-microbial injurious triggers, including airborne allergens such as house dust mite, as shown by markedly reduced acute production of epithelial alarmins and subsequent type 2 immune responses that are critical for regenerative processes in response to injury [ 29 ].…”

Long-Term Outcomes in Acute Respiratory Distress Syndrome

“…50 Increasing attention has also been turned to the influence of systemic and muscle metabolism in mediating muscle function in critical illness. [51][52][53] The area of muscle metabolism may have important implications for nutrient delivery during ARDS and how nutrition may influence skeletal muscle function in the acute and longer-term follow-up. [54][55][56] Some ICU exposures may influence the development of ICUAW in ARDS, some of which may be modifiable.…”