Acute Respiratory Barrier Disruption by Ozone Exposure in Mice

Abstract

Ozone exposure causes irritation, airway hyperreactivity (AHR), inflammation of the airways, and destruction of alveoli (emphysema), the gas exchange area of the lung in human and mice. This review focuses on the acute disruption of the respiratory epithelial barrier in mice. A single high dose ozone exposure (1 ppm for 1 h) causes first a break of the bronchiolar epithelium within 2 h with leak of serum proteins in the broncho-alveolar space, disruption of epithelial tight junctions and cell death, which is followed at 6 h by ROS activation, AHR, myeloid cell recruitment, and remodeling. High ROS levels activate a novel PGAM5 phosphatase dependent cell-death pathway, called oxeiptosis. Bronchiolar cell wall damage and inflammation upon a single ozone exposure are reversible. However, chronic ozone exposure leads to progressive and irreversible loss of alveolar epithelial cells and alveoli with reduced gas exchange space known as emphysema. It is further associated with chronic inflammation and fibrosis of the lung, resembling other environmental pollutants and cigarette smoke in pathogenesis of asthma, and chronic obstructive pulmonary disease (COPD). Here, we review recent data on the mechanisms of ozone induced injury on the different cell types and pathways with a focus on the role of the IL-1 family cytokines and the related IL-33. The relation of chronic ozone exposure induced lung disease with asthma and COPD and the fact that ozone exacerbates asthma and COPD is emphasized.

Keywords: cell death; inflammation; innate immunity; interleukins; mucus; tight junctions.

Figure 1

Ozone-induced epithelial barrier dysfunction, AHR, ROS production, cell recruitment, cell desquamation, remodeling, and repair in mice. (A) Scheme showing ozone/ROS-induced disruption of bronchiolar epithelium, cell integrity, tight junctions with protein leak, and cell death with the release of IL-33. Neutrophils and macrophages are recruited within 18 h and macrophages release protective amphiregulin (AREG) with resolution of inflammation and remodeling (43). (B) Micrograph of ozone-induced disruption of bronchiolar epithelium with desquamation, cell death, and focal inflammation at 18 h after exposure (1 h, 1 ppm), scale bar 100 μm. (C) Airways hyperreactivity (AHR): ozone enhances methacholine induced bronchoconstriction measured as resistance (RL) using invasive plethysmography 24 h after exposure (1 h, 1 ppm, unpublished data).

Figure 2

High ROS levels induce oxeiptosis, a novel cell death via the phosphatase PGAM5 activating the death effector AIFM1 in mice. While low concentration of ROS (0.1 mM) release the cytoprotective NRF2 from the KEAP1/PGAM5 complex in the cytosol, at high concentration of ROS (1 mM), the phosphatase PGAM5 is released from the mitochondrial KEAP1/NRF2/PGAM5 complex and PGAM5 dephosphorylates AIFM1, which is the effector protein defining the oxeiptosis death pathway (68).

Figure 3

Comparison of IL-1 and IL-33 and their membrane receptors in mice. Scheme of IL-1 (A) and IL-33 (B), showing the different ligands and receptors. (A) IL-1αβ binds to IL-1R1 and induces a conformational change in the extracellular domain of IL-1R1, enabling its interaction with IL-1RAcP, which is required for intracellular signaling, including MyD88-dependent activation. IL-1Ra competes with IL-1αβ for the binding to IL-1R1; the binding of IL-1Ra to IL-1R1 prevents IL-1αβ binding, the recruitment of IL-1RAcP and the activation of intracellular signaling pathways. IL-1R2 acts as a decoy receptor on the cell surface to IL-1RAcP. (B) Interleukin−33 (IL−33) binds to its transmembrane receptor suppression of tumorigenicity 2 (ST2) and induces a conformational change that allows ST2 to interact with IL−1 receptor accessory protein (IL−1RAcP). Activation of ST2 and IL−1RAcP leads to the Toll/IL−1 receptor (TIR) domains clustering and the recruitment of signaling adaptor myeloid differentiation primary response protein 88 (MYD88) (23).