Role of Macrophages in Acute Lung Injury and Chronic Fibrosis Induced by Pulmonary Toxicants

Abstract

A diverse group of toxicants has been identified that cause injury to the lung including gases (eg, ozone, chlorine), particulates/aerosols (eg, diesel exhaust, fly ash, other combustion products, mustards, nanomaterials, silica, asbestos), chemotherapeutics (eg, bleomycin), and radiation. The pathologic response to these toxicants depends on the dose and duration of exposure and their physical/chemical properties. A common response to pulmonary toxicant exposure is an accumulation of proinflammatory/cytotoxic M1 macrophages at sites of tissue injury, followed by the appearance of anti-inflammatory/wound repair M2 macrophages. It is thought that the outcome of the pathogenic responses to toxicants depends on the balance in the activity of these macrophage subpopulations. Overactivation of either M1 or M2 macrophages leads to injury and disease pathogenesis. Thus, the very same macrophage-derived mediators, released in controlled amounts to destroy injurious materials and pathogens (eg, reactive oxygen species, reactive nitrogen species, proteases, tumor necrosis factor α) and initiate wound repair (eg, transforming growth factor β, connective tissue growth factor, vascular endothelial growth factor), can exacerbate acute lung injury and/or induce chronic disease such as fibrosis, chronic obstructive pulmonary disease, and asthma, when released in excess. This review focuses on the role of macrophage subsets in acute lung injury and chronic fibrosis. Understanding how these pathologies develop following exposure to toxicants, and the contribution of resident and inflammatory macrophages to disease pathogenesis may lead to the development of novel approaches for treating lung diseases.

Keywords: Macrophages; cytokines; fibrosis; inflammatory mediators; lung injury; oxidants.

Figure 1.

Proinflammatory/cytotoxic (M1) and anti-inflammatory/wound repair (M2) macrophages in acute injury and chronic fibrosis. Immature inflammatory mouse macrophages originating from blood and precursors express the integrin CD11b, high or low levels of the surface antigen Ly6C, and chemokine receptors, CCR2 or CX3CR1, respectively. In response to environmental cues (eg, cytokines, growth factors, TLR agonists, and lipids) and intracellular/nuclear regulatory pathways (eg, kinases, transcription factors, epigenetic regulators, metabolic factors) that are activated, these CD11b⁺ cells mature into F4/80⁺Ly6C^hiCCR2⁺ proinflammatory/cytotoxic M1 macrophages, which express markers such as inducible nitric oxide synthase (iNOS) and ARL11, or F4/80⁺Ly6C^loCX3CR1⁺ anti-inflammatory/wound repair M2 macrophages which express CD68, CD163, CD206, Arginase (Arg)-1, Ym1, and/or Fizz1. The extent to which macrophages develop into these subpopulations depends on the activities of M1 and M2 inducers/regulatory factors. As these vary over the course of the inflammatory response, macrophages exist along a continuum with subpopulations expressing varying levels of M1 and M2 markers and activities. The process of M1 and M2 macrophage activation is also highly dynamic; thus, as environmental cues, signaling molecules, transcription factors, and cellular metabolism change, macrophages readily modify their phenotype and function. The outcome of inflammatory responses to tissue injury depends on the relative activities of M1 and M2 macrophage subpopulations. In this context, overactivation of M1 macrophages and/or aberrant M2 anti-inflammatory/wound repair activity can exacerbate and perpetuate acute injury, while excessive activity of M2 macrophages can lead to chronic diseases such as fibrosis.