Macrophages, reactive nitrogen species, and lung injury

Abstract

Evidence has accumulated over the past several years demonstrating that lung injury following inhalation of irritants like ozone is due, not only to direct effects of the chemical, but also indirectly to the actions of inflammatory mediators released by infiltrating macrophages. Among the mediators involved in the cytotoxic process, reactive nitrogen species (RNS) are of particular interest because of their well-documented cytotoxic potential. Findings that macrophage suppression blocks RNS production and ozone-induced toxicity provide strong support for a role of these cells and inflammatory mediators in lung injury. Recent investigations have focused on understanding pathways by which macrophages become activated to release RNS. One protein that has attracted considerable attention is caveolin-1, a membrane scaffolding molecule that functions to negatively regulate cell signaling. The fact that expression of caveolin-1 is down-regulated in macrophages after ozone inhalation suggests a mechanism controlling the release of cytotoxic mediators by these inflammatory cells.

Figure 1

Effects of ozone on lung function. Female Wistar rats were exposed to air (white bars) or ozone (black bars; 2 ppm, 3 h) in whole body Plexiglas divided chambers. After 24 h, animals were anesthetized and tracheotomy performed. Animals were attached to a flexiVent (SciReq) and measurements of whole lung resistance and compliance, and tissue damping and elastance were made. Each bar is the mean ± SE (n = 3).

Figure 2

Effects of ozone on iNOS and Arginase1 mRNA expression. Alveolar macrophages collected from animals exposed to ozone were analyzed by real-time PCR for iNOS and Arginase1 (Arg1) gene expression. Data are presented relative to GAPDH and expressed as fold-change over air control. Each bar is the mean ± SE (n = 3).

Figure 3

Model for the role of macrophages and RNS in lung injury. Macrophages responding to ozone-induced lung injury become phenotypically polarized into M1 cells; TNFα released from M1 macrophages acts in an autocrine and paracrine manner to downregulate Cav-1, leading to activation of PI3 K/PKB signaling, NF-κB, and induction of iNOS. RNS generated via iNOS contributes to ozone-induced lung injury.