The Role of Pulmonary and Systemic Immunosenescence in Acute Lung Injury

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.

MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

“…Recent studies reported that inflammatory response played important roles in initiation and maintenance of ALI [46,47]. Pro-inflammatory cytokines such as TNF-α and IL-1β increase the permeability of pulmonary epithelium, furthermore induced lung tissue damage and accumulation of neutrophils which lead to lung edema [31].…”

The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview

“…Immune cell activation is a major mediator of inflammation in ARDS and immunosenescence may impact on the pathogenesis and outcomes in the aged ARDS subpopulation. Experimental murine models of ARDS induced by endotoxin indicate that aged mice display increased bronchoalveolar lavage fluid (BALF) cell counts, protein concentration, and cytokines such as the neutrophil chemoattractant CXCL1/KC in comparison to younger mice (49)(50)(51). Alterations in innate immune cell function, such as macrophage and neutrophils, may contribute to this heightened inflammatory response (52,53).…”

“…Alveolar macrophages (AMs) have increased expression of genes associated with lung injury and fibrosis (54) and defective phagocytic ability (26). In one study of lipopolysaccharide (LPS)-induced acute lung injury (ALI), expression of the M1macrophage markers, CD80 and CD86, were increased in AMs from older mice and in vitro these cells had increased propensity to produce MIP-1α in response to LPS (50). Impairment of antigen presentation in aging macrophages has also been observed and resulting loss of bacterial and viral clearance from the lung could further promote inflammation and damage (55).…”

“…The output of adaptive immune cells, particularly T cells, reduces over time. However, regulatory T (Treg) cells, which are responsible for regulation of immune responses, increased with age (50,59). In experimental ARDS, aged groups show concomitant increases in both Tregs and inflammatory markers in comparison to younger groups (50).…”

miR-21-KO Alleviates Alveolar Structural Remodeling and Inflammatory Signaling in Acute Lung Injury

“…Total protein concentration of the supernatant of the lung homogenate was examined with the Pierce TM BCA Protein Assay Kit (Thermo Fisher Scientific, Waltham, MA, USA). The cytokine concentration was then analyzed with the LEGENDplex bead array ELISA (# 740621, BioLegend, San Diego, CA, USA) according to the supplier's manual and as described previously [39]. Cytokine measurements (pg/mL) were then normalized to the total protein concentration (mg/mL) to pg/mg.…”