Aging exacerbates acute lung injury-induced changes of the air-blood barrier, lung function, and inflammation in the mouse

Abstract

Acute lung injury (ALI) is characterized by hypoxemia, enhanced permeability of the air-blood barrier, and pulmonary edema. Particularly in the elderly, ALI is associated with increased morbidity and mortality. The reasons for this, however, are poorly understood. We hypothesized that age-related changes in pulmonary structure, function, and inflammation lead to a worse prognosis in ALI. ALI was induced in young (10 wk old) and old (18 mo old) male C57BL/6 mice by intranasal application of 2.5 mg lipopolysaccharide (LPS)/kg body wt or saline (control mice). After 24 h, lung function was assessed, and lungs were either processed for stereological or inflammatory analysis, such as bronchoalveolar lavage fluid (BALF) cytometry and qPCR. Both young and old mice developed severe signs of ALI, including alveolar and septal edema and enhanced inflammatory BALF cells. However, the pathology of ALI was more pronounced in old compared with young mice with nearly sixfold higher BALF protein concentration, twice the number of neutrophils, and significantly higher expression of neutrophil chemokine Cxcl1, adhesion molecule Icam-1, and metalloprotease-9, whereas the expression of tight junction protein occludin significantly decreased. The old LPS mice had thicker alveolar septa attributable to higher volumes of interstitial cells and extracellular matrix. Tissue resistance and elastance reflected observed changes at the ultrastructural level in the lung parenchyma in ALI of young and old mice. In summary, the pathology of ALI with advanced age in mice is characterized by a greater neutrophilic inflammation, leakier air-blood barrier, and altered lung function, which is in line with findings in elderly patients.

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“…These changes fit with our observations in lung function measurements, where an increase in tissue resistance (G) and hysteresis was detected. G is an inverse measure of compliance in the parenchymal lung tissue and its increase in ALI, related to septal edema formation, has been shown previously [29]. Hysteresis might increase due to changes in tissue resistance and elastance or due to changes in surfactant composition [30,31].…”

“…The control mice received equal volume of saline solution (n = 7 per group). The animals were sacrificed 24 h after the induction of ALI, as described previously [29]. All animal procedures were approved by the Lower Saxony State Office for Consumer Protection and Food Safety (LAVES; Authorization number: 33.9-42502-04-14/1623, Approval Date: 26/09/2014) in accordance with the German law for animal protection and with the European Directive, 2010/63/EU.…”

“…Lung function analysis was performed with a FlexiVent rodent ventilator FX1 for mice (SCIREQ) as described previously [29]. In brief, mice were tracheotomized under deep anesthesia and mechanically ventilated with a frequency of 100 breaths/min and a tidal volume of 10 mL/kg body weight.…”

“…The left lung lobes were stored for at least 24 h in the fixative solution, followed by lung volume measurement via volume displacement and systematic uniform random subsampling (SURS) as described previously [29,36]. In brief, lung tissue was sliced in 2 mm sections and every other section, with a random starting point, was processed and embedded in glycol methacrylate (Technovit 7100 resin, Kulzer GmbH) for light microscopic analysis.…”

The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections

“…Aging also causes impaired alveolar barrier integrity after lung injury. In comparison with young mice, old mice had increased response of acute lung injury in association with decreased expressions of tight junction protein after lipopolysaccharide insult [86]. Yin et al demonstrated that aged mice had increased susceptibility to influenza viral pneumonia with exacerbated damage and delayed repair of alveolar epithelial cells (AECs) [87].…”