Parenchymal and Inflammatory Cell Responses to Single and Repeated Ozone Exposure in Healthy and Surfactant Protein-C Mutant Lung
TOXICOLOGICAL SCIENCES(2022)
Abstract
Mutations in the alveolar epithelial-specific gene encoding for surfactant protein C (SP-C) are linked to pulmonary disease. Ozone (O-3) is a ubiquitous pollutant known to exacerbate stress through oxidative injury and inflammation. To comprehend the structural, functional, and immunological impact of single and repeated O-3 exposure, SP-C-WT and surfactant protein-C I73T mutant (SP-C-I73T) mice were exposed to air or O-3 (0.8 ppm, 3 h, up to x4 consecutive days). O-3 was associated with mitochondrial and autophagic activation (PINK1, LC3B, and p62), focal remodeling, and inflammation localized at the terminal bronchiole-to-alveolar junctions. Histological damage was exacerbated by repeated exposure. Single O-3 challenge resulted in transient elastin fiber loss, whereas repeated exposure resulted in marked increases in elastance in SP-C-I73T mice. Flow cytometric analysis revealed increases in classical monocyte and monocyte-derived macrophages recruitment in conditions of repeated exposure, which peaked earlier (24 h) in SP-C-I73T mice. Immunohistochemical analysis also showed clustering of Arg-1(+) and CD206(+) activated cells within regions of remodeled lung. Lymphoid cell analysis identified CX(3)CR1(-)B220(+) B cells accumulating after single (24/72 h). Repeated exposure produces a switch in the phenotype of these B cells CX(3)CR1(+) (72 h) only in SP-C-WT mice. SP-C-I73T mutants also displayed depletion in NK1.1(+) NKp46(+) natural killer cells in lung, as well as bone marrow, blood, and spleen. These results illustrate the cumulative impact of O-3 on lung structure and function in healthy lung, and aberrant myeloid and lymphoid recruitment in SP-C mutants responding to challenge. Together, this work highlights the significance of modeling environmental exposure across the spectrum of genetic susceptibility, consistent with human disease.
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Key words
ozone,environmental exposure,inflammation,pulmonary toxicity
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