Macrophage-mediated inflammation and disease: a focus on the lung

Abstract

The lung is exposed to a vast array of inhaled antigens, particulate matter, and pollution. Cells present in the airways must therefore be maintained in a generally suppressive phenotype so that excessive responses to nonserious irritants do not occur; these result in bystander damage to lung architecture, influx of immune cells to the airways, and consequent impairment of gas exchange. To this end, the resident cells of the lung, which are predominantly macrophages, are kept in a dampened state. However, on occasion the suppression fails and these macrophages overreact to antigenic challenge, resulting in release of inflammatory mediators, induction of death of lung epithelial cells, deposition of extracellular matrix, and development of immunopathology. In this paper, we discuss the mechanisms behind this macrophage-mediated pathology, in the context of a number of inflammatory pulmonary disorders.

Figure 1

Alveolar macrophage-mediated disease in the lung. AMs are the dominant cell type in the uninfected airway. Following virus infection (1), AMs are restrained from overreacting and inducing bystander damage to tissues by the CD200R on their surface (2) which induces a negative signalling cascade. (3) Pandemic influenza strains induce the upregulation of TRAIL on the AM surface and of its receptor DR5 on the alveolar epithelial cells, which leads to increased apoptosis in the epithelium and consequent morbidity. Both the presence of TRAIL and the absence of CD200R can induce epithelial damage and spread of virus out of the alveolus (4). Bacterial infection (5) induces AM to produce inflammatory cytokines (6), leading to activation of bystander cells and tissue damage. AMs are also triggered to produce growth factors (7) which leads to epithelial hyperplasia, deposition of ECM and fibrosis.