Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury (original) (raw)
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Metabolomics, 2016
Introduction-Older patients are more likely to acquire and die from acute respiratory distress syndrome (ARDS) and muscle weakness may be more clinically significant in older persons. Recent data implicate muscle ring finger protein 1 (MuRF1) in lung injury-induced skeletal muscle atrophy in young mice and identify an alternative role for MuRF1 in cardiac metabolism regulation through inhibition of fatty acid oxidation. Objectives-To develop a model of lung injury-induced muscle wasting in old mice and to evaluate the skeletal muscle metabolomic profile of adult and old acute lung injury (ALI) mice. Methods-Young (2 month), adult (6 month) and old (20 month) male C57Bl6J mice underwent Sham (intratracheal H 2 O) or ALI [intratracheal E. coli lipopolysaccharide (i.t. LPS)] conditions and muscle functional testing. Metabolomic analysis on gastrocnemius muscle was performed using gas chromatography-mass spectrometry (GC-MS). Results-Old ALI mice had increased mortality and failed to recover skeletal muscle function compared to adult ALI mice. Muscle MuRF1 expression was increased in old ALI mice at day 3. Non-targeted muscle metabolomics revealed alterations in amino acid biosynthesis and fatty acid metabolism in old ALI mice. Targeted metabolomics of fatty acid intermediates (acyl-carnitines) and amino acids revealed a reduction in long chain acyl-carnitines in old ALI mice. Conclusion-This study demonstrates age-associated susceptibility to ALI-induced muscle wasting which parallels a metabolomic profile suggestive of altered muscle fatty acid metabolism. MuRF1 activation may contribute to both atrophy and impaired fatty acid oxidation, which may synergistically impair muscle function in old ALI mice.
American Journal of Respiratory Cell and Molecular Biology, 2010
Children have a lower incidence and mortality from acute lung injury (ALI) than adults, and infections are the most common event associated with ALI. To study the effects of age on susceptibility to ALI, we investigated the responses to microbial products combined with mechanical ventilation (MV) in juvenile (21-d-old) and adult (16-wk-old) mice. Juvenile and adult C57BL/6 mice were treated with inhaled Escherichia coli 0111:B4 lipopolysaccharide (LPS) and MV using tidal volume 5 15 ml/kg. Comparison groups included mice treated with LPS or MV alone and untreated age-matched control mice. In adult animals treated for 3 hours, LPS plus MV caused synergistic increases in neutrophils (P , 0.01) and IgM in bronchoalveolar lavage fluid (P 5 0.03) and IL-1b in whole lung homogenates (P , 0.01) as compared with either modality alone. Although juvenile and adult mice had similar responses to LPS or MV alone, the synergistic interactions between LPS and MV did not occur in juvenile mice. Computational analysis of gene expression array data suggest that the acquisition of synergy with increasing age results, in part, from the loss of antiapoptotic responses and the acquisition of proinflammatory responses to the combination of LPS and MV. These data suggest that the synergistic inflammatory and injury responses to inhaled LPS combined with MV are acquired with age as a result of coordinated changes in gene expression of inflammatory, apoptotic, and TGF-b pathways.
Association between Maturation and Aging and Pulmonary Responses in Animal Models of Lung Injury
Anesthesiology, 2015
E PIDEMIOLOGICAL studies reveal striking differences among children, adults, and elderly in risk factors, susceptibility, course, and outcome of the acute respiratory distress syndrome (ARDS). 1-10 Although ARDS is a major contributor to mortality in all age groups, the incidence, morbidity, and mortality tend to gradually increase with age, 4,5,11 which seems partially independent of comorbidity. 9,12-14 These findings suggest potential age-dependent differences in the pathophysiology of ARDS. In the acute phase of ARDS, the innate immune response causes inappropriate accumulation and activation of blood leukocytes, excessive production of inflammatory mediators, and uncontrolled coagulation. 15,16 Interestingly, not only the innate immune response but also intrinsic properties of the lung are known to change during the process of maturation and aging. 17-27 Although newborns have a relatively impaired immune response to bacteria, 24,27 elderly have a persistent low-grade innate immune activation generating a constitutive proinflammatory environment (termed inflammaging). 22,28 Aging is also associated with a gradual deterioration of the immune system (termed immunosenescence). 22,28 Although the interplay between these agedependent immunological and morphological changes correlate with the clinical patterns of disease, 18,23,24,26 the underlying molecular mechanisms are poorly understood. Of the numerous animal models used to elucidate the pathophysiology and treatment of ARDS, 29,30 most of them used adolescent or young-adult animals. However, it is What We Already Know about This Topic • The effects of aging on the lung response to injury is not thought about yet with an increasing aging population, this is an important concern What This Article Tells Us That Is New • An investigation of the literature documents that the inflammatory response to injury is exaggerated in aged animals, and there is more edema and alveolar damage and a higher mortality
Aging impairs alveolar epithelial type II cell function in acute lung injury
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2020
Morbidity and mortality rates in acute lung injury (ALI) increase with age. As alveolar epithelial type II cells (AE2) are crucial for lung function and repair, we hypothesized that aging promotes senescence in AE2 and contributes to the severity and impaired regeneration in ALI. ALI was induced with 2.5 μg lipopolysaccharide/g body weight in young (3 mo) and old (18 mo) mice that were euthanized 24 h, 72 h, and 10 days later. Lung function, pulmonary surfactant activity, stereology, cell senescence, and single-cell RNA sequencing analyses were performed to investigate AE2 function in aging and ALI. In old mice, surfactant activity was severely impaired. A 60% mortality rate and lung function decline were observed in old, but not in young, mice with ALI. AE2 of young mice adapted to injury by increasing intracellular surfactant volume and proliferation rate. In old mice, however, this adaptive response was compromised, and AE2 of old mice showed signs of cell senescence, increased i...
American journal of physiology. Lung cellular and molecular physiology, 2017
Acute respiratory distress syndrome (ARDS) is a devastating critical illness disproportionately affecting the elderly population(higher incidence and mortality). The integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung function. However, mechanisms mediating EC barrier regulation in aging remain unclear. We assessed the severity of acute lung injury (ALI) in young (2 months) and aged (18 months) mice using a two-hit pre-clinical model. Compared to young cohorts, aged mice exhibited increased ALI severity, with greater vascular permeability characterized by elevated albumin influx, levels of bronchoalveolar lavage (BAL) cells (neutrophils) and protein. Aged/injured mice also demonstrated elevated levels of reactive oxygen species (ROS) in the BAL, associated with upregulation of the ROS-generating enzyme, Nox4. We evaluated the role of aging in human lung EC barrier regulation utilizing a cellular model of replicative senescence. Senescent EC pop...
Anesthesiology, 2015
Advanced age is associated with an increased susceptibility and mortality of the acute respiratory distress syndrome. This may be due to the progressive changes in innate immune responses and intrinsic properties of the lung that occur during the process of aging. Therefore, this study assesses the association between maturation and aging and pulmonary responses to injury in animal models of lung injury. A systematic search was conducted in PubMed, EMBASE (up to June 2014) and in the references of relevant articles to identify the studies using in vivo models of lung injury caused by an acute pulmonary insult, in which at least two age groups were compared. Because methodological diversity precluded combining these studies in a quantitative meta-analysis, data are presented based on the qualitative comparison with the adult group. Of the 2,840 identified studies, 51 were included in this review. Most studies showed that, in response to a pulmonary insult, increasing age is associate...
Chronic lung inflammation in aging mice
FEBS Letters, 2007
To determine whether aging is associated with a pro-inflammatory shift in the lung, inflammation and inflammation-related gene expression in the lungs of 12-week-old and 24month-old Balb/c mice were studied. cDNA microarray and quantitative reverse transcription-polymerase chain reaction analyses showed that eight inflammation-related genes, including CD20, Burkitt lymphoma receptor 1, CXCR-3, provirus integration site for Moloney murine leukemia virus-2, CD72, IL-8RB, C-Fgr, and CD8b, were upregulated in the aged mice. Immunohistochemistry showed that the lungs of the aged mice contained increased numbers of CD4 cells, CD8 cells, B cells and macrophages. These results suggest that a pro-inflammatory shift occurs in the lungs of mice with aging.
The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview
Frontiers in Medicine, 2020
Acute respiratory distress syndrome (ARDS) is associated with increased morbidity and mortality in the elderly population (≥65 years of age). Additionally, age is widely reported as a risk factor for the development of ARDS. However, the underlying pathophysiological mechanisms behind the increased risk of developing, and increased severity of, ARDS in the elderly population are not fully understood. This is compounded by the significant heterogeneity observed in patients with ARDS. With an aging population worldwide, a better understanding of these mechanisms could facilitate the development of therapies to improve outcomes in this population. In this review, the current clinical evidence of age as a risk factor and prognostic indicator in ARDS and the potential underlying mechanisms that may contribute to these factors are outlined. In addition, research on age-dependent treatment options and biomarkers, as well as future prospects for targeting these underlying mechanisms, are discussed.