Abstract
Acute lung injury (ALI) is associated with increased morbidity and mortality in the elderly (> 65 years), but the knowledge about origin and effects of immunosenescence in ALI is limited. Here, we investigated the immune response at pulmonary, systemic and cellular level in young (2-3 months) and old (18-19 months) C57BL/6J mice to localize and characterize effects of immunosenescence in ALI. ALI was induced by intranasal lipopolysaccharide (LPS) application and the animals were sacrificed 24 or 72 h later. Pulmonary inflammation was investigated by analyzing histopathology, bronchoalveolar lavage fluid (BALF) cytometry and cytokine expression. Systemic serum cytokine expression, spleen lymphocyte populations and the gut microbiome were analyzed, as well as activation of alveolar and bone marrow derived macrophages (BMDM) in vitro. Pulmonary pathology of ALI was more severe in old compared with young mice. Old mice showed significantly more inflammatory cells and pro-inflammatory cyto- or chemokines (TNFα, IL-6, MCP-1, CXCL1, MIP-1α) in the BALF, but a delayed expression of cytokines associated with activation of adaptive immunity and microbial elimination (IL-12 and IFNγ). Alveolar macrophages, but not BMDM, of old mice showed greater activation after in vivo and in vitro stimulation with LPS. No systemic enhanced pro-inflammatory cytokine response was detected in old animals after LPS exposure, but a delayed expression of IL-12 and IFNγ. Furthermore, old mice had less CD8+ T-cells and NK cells and more regulatory T-cells in the spleen compared with young mice and a distinct gut microbiome structure. The results of our study show an increased alveolar macrophage activation and pro-inflammatory signaling in the lungs, but not systemically, suggesting a key role of senescent alveolar macrophages in ALI. A decrease in stimulators of adaptive immunity with advancing age might further promote the susceptibility to a worse prognosis in ALI in elderly.
Highlights
Acute lung injury (ALI) is associated with increased morbidity and mortality in the elderly (> 65 years), but the knowledge about origin and effects of immunosenescence in ALI is limited
Pro-inflammatory signaling in ALI is aggravated in the lungs of old compared with young mice
The inflammatory cells were mainly neutrophilic granulocytes with lesser numbers of macrophages and were more abundant in old compared with young mice
Summary
Acute lung injury (ALI) is associated with increased morbidity and mortality in the elderly (> 65 years), but the knowledge about origin and effects of immunosenescence in ALI is limited. The performance of the immune system declines with advancing age and evokes a greater susceptibility to infections and inflammatory diseases in the elderly (< 65 years) This phenomenon is known as immunesenescence and includes age-related disparities in innate and adaptive immunity [1] such as decreased phagocytotic function of macrophages and neutrophils, enhanced serum levels of pro-inflammatory cytokines, more airway neutrophils or decreased T-cell stimulation by dendritic cells [2]. Other age-related investigations in murine models of ALI, induced with bacteria or bacterial components, provided evidence of a greater pulmonary inflammation in old animals, with enhanced neutrophil numbers and inflammatory cytokine levels [10,11,12,13]. In LPS-models of ALI the pro-inflammatory response evolves within the first 24 h and at least some inflammatory parameters are expected to decline or resolve again after 72 h [18]
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