Inflammaging and the Lung

Abstract

With the coming of the "silver tsunami," expanding the knowledge about how various intrinsic and extrinsic factors affect the immune system in the elderly is timely and of immediate clinical need. The global population is increasing in age. By the year 2030, more than 20% of the population of the United States will be older than 65 years of age. This article focuses on how advanced age alters the immune systems and how this, in turn, modulates the ability of the aging lung to deal with infectious challenges from the outside world and from within the host.

Keywords: Elderly; Host defense; Immunosenescence; Infection; Inflammaging; Inflammation; Macrophage; Neutrophils.

Figure 1. Innate immune phenotype of the aged lung

Regardless of age, under healthy conditions, the major leukocyte of the distal lung is the alveolar macrophage. These multifaceted cells exist in an anti-inflammatory state to limit inflammation and maintain pulmonary homeostasis. A variety of pathogenic conditions alter alveolar macrophage function. In the young, alveolar macrophages can rapidly respond to external stimuli such as bacteria, clear infections and return to their anti-inflammatory state. In contrast, in the elderly, alveolar macrophages fail to mount an adequate response infectious insult, are slow at recruiting neutrophils to help combat the respiratory pathogens and are unable to return to their anti-inflammatory phenotype, thus leaving the lung in a compromised state.

Figure 2. The gut, liver, lung axis

Under healthy conditions, the epithelial cells lining the intestine maintain tight junctions preventing luminal contents from invading the underlying mucosal tissues. In the aged, it is thought that epithelial cell tight junctions loosen, possibly in response to the presence of the pro-inflammatory cytokines associated with inflamm-aging. This loosening of junctional complexes and subsequent increase in paracellular permeability allows gut-derived bacteria, bacterial products and endotoxins to enter the mesenteric lymph and the bloodstream. Bacteria and their products then trigger Kupffer cells and other cells in the liver to produce and secrete pro-inflammatory cytokines, including IL-6. Hepatic-derived IL-6, along with the gut-derived bacteria products in the circulation, promotes baseline lung inflammation which can then be further exacerbated in the aged after injury or infection.