Ozone and pulmonary innate immunity

Abstract

Ambient ozone (O(3)) is a commonly encountered environmental air pollutant with considerable impact on public health. Many other inhaled environmental toxicants can substantially affect pulmonary immune responses. Therefore, it is of considerable interest to better understand the complex interaction between environmental airway irritants and immunologically based human disease. The innate immune system represents the first line of defense against microbial pathogens. Intact innate immunity requires maintenance of an intact barrier to interface with the external environment, effective phagocytosis of microbial pathogens, and precise detection of pathogen-associated molecular patterns. We use ambient O(3) as a model to highlight the importance of understanding the role of exposure to ubiquitous air toxins and regulation of basic immune function. Inhalation of O(3) is associated with impaired antibacterial host defense, in part related to disruption of epithelial barrier and effective phagocytosis of pathogens. The functional response to ambient O(3) seems to be dependent on many components of the innate immune signaling. In this article, we review the complex interaction between inhalation of O(3) and pulmonary innate immunity.

Figure 1.

Ozone (O₃) modifies antibacterial defense in many cell types in the lung. O₃ can disrupt epithelial tight junctions and mucociliary clearance and can induce production of proinflammatory factors. O₃ is directly cytotoxic to macrophages. O₃ can modify macrophage phagocytosis, intracellular killing, and levels of secreted factors. O₃ can impair neutrophil phagocytosis and intracellular killing.

Figure 2.

Ozone disrupts epithelial barrier function to protein. Lung clearance of soluble radiolabeled albumin in a subject evaluated after exposure to filtered air (A) or ozone (B) when compared with baseline. Lung retention is expressed as natural log of activity level in right lung at time zero with retention points fitted to a linear regression. Data points represent lung retention of soluble marker at the indicated times. Lung retention is expressed as natural log of the fractional retention of the activity level of the radiomarker deposited at time zero. Superimposed color images represent scintigraphy scans of the lung acquired from the posterior aspect and demonstrate dynamics of the clearance process with color intensity equivalent to radiolabel activity levels: blue > green > yellow. As activity clears the lung from epithelial airway and alveolar surfaces by transport via paracellular pathways into the systemic and pulmonary vasculatures, bilateral accumulation is visualized below the diaphragms, representing cleared activity filtered by the kidneys. (Adapted by permission from Reference 46.)

Figure 3.

Functional response to ozone is dependent on Toll-like receptor 4 (TLR4). Mice were exposed to 300 ppb ozone (O₃) for 72 hours. (A) Airway injury was determined by level of protein in the bronchoalveolar lavage (BAL) fluid in the C3H/OuJ (tlr4-sufficient) and the C3H/HeJ (tlr4-deficient) over time. Statistical comparison: air versus O₃ treatment groups (*p < 0.05); C3H/HeJ versus C3H/HeOuJ (†p < 0.05). (B) After completion of exposure to O₃, physiologic response to intravenous methacholine in wild-type and tlr4 knockout mice were evaluated by direct measurements of tracheal pressures. Increased airway pressure–time index (APTI) values in O₃ exposed C57BL/6 animals when compared with tlr4^−/− were seen at all doses of intravenous methacholine, including 25 μg/ml (*p < 0.01), 100 μg/ml (*p = 0.02), 250 μg/ml (*p = 0.001). (B) TLR4^+/+ O₃, upper solid line, solid squares; TLR4^−/− O₃, dotted line, open triangles; TLR4^+/+ air, lower solid line, solid squares; TLR4^−/− air, dotted line, open diamonds. (Adapted by permission from References 24 and 86.)