Modulatory effects of ozone on THP-1 cells in response to SP-A stimulation

Abstract

, a major component of air pollution and a strong oxidizing agent, can lead to lung injury associated with edema, inflammation, and epithelial cell damage. The effects of O 3 on pulmonary immune cells have been studied in various in vivo and in vitro systems. We have shown previously that O 3 exposure of surfactant protein (SP)-A decreases its ability to modulate proinflammatory cytokine production by cells of monocyte/macrophage lineage (THP-1 cells). In this report, we exposed THP-1 cells and/or native SP-A obtained from bronchoalveolar lavage of patients with alveolar proteinosis to O 3 and studied cytokine production and NF-B signaling. The results showed 1) exposure of THP-1 cells to O 3 significantly decreased their ability to express TNF-␣ in response to SP-A; TNF-␣ production, under these conditions, was still significantly higher than basal (unstimulated) levels in filtered air-exposed THP-1 cells; 2) exposure of both THP-1 cells and SP-A to O 3 did not result in any significant differences in TNF-␣ expression compared with basal levels; 3) O 3 exposure of SP-A resulted in a decreased ability of SP-A to activate the NF-B pathway, as assessed by the lack of significant increase and decrease of the nuclear p65 subunit of NF-B and cytoplasmic I B␣, respectively; and 4) O 3 exposure of THP-1 cells resulted in a decrease in SP-A-mediated THP-1 cell responsiveness, which did not seem to be mediated via the classic NF-B pathway. These findings indicate that O 3 exposure may mediate its effect on macrophage function both directly and indirectly (via SP-A oxidation) and by involving different mechanisms.inflammation; tumor necrosis factor-␣; nuclear factor-B; I B␣; surfactant protein A OZONE (O 3 ) IS A MAJOR COMPONENT of photochemical air pollution. Approximately 113 million people live in areas with O 3 levels above the National Ambient Air Quality (NAAQ) standards for the daily exposure limit, noted as a maximum of 0.12 ppm for 1 h or 0.08 ppm cumulative for 8 consecutive hours (1). O 3 is a strong oxidizing agent that can be rapidly converted into a number of reactive oxygen species (ROS). O 3 exposure has been associated with impaired lung function (53) and with the majority of pathological changes localized in the lower airways. Due to its very low water solubility, O 3 cannot effectively penetrate through the thick epithelial lining fluid in the upper airways. However, the thinner lining in the lower airways allows O 3 to interact with various elements of the fluid and the underlying cells.O 3 and other oxidants exhibit their toxicity by reacting with cell proteins and lipids. This interaction often results in edema, inflammation, and epithelial cell damage causing lung injury and surfactant derangement (66, 67). Furthermore, both morphological (6, 7) and biochemical (26, 27) changes in surfactant are observed following O 3 exposure. An extensive body of work has been generated by various groups to support the hypothesis that O 3 -induced changes lead to a compromised immune response in the lung. However,...

Ozone Inhalation Promotes CX3CR1-Dependent Maturation of Resident Lung Macrophages That Limit Oxidative Stress and Inflammation

“…We and others have identified macrophage-derived mediators present in the lung after ozone exposure (27, 28). However, this observation remains somewhat inconsistent and may be dependent on the intensity and duration of exposure, as other groups have demonstrated that ozone exposure results in a decrease in macrophage-derived cytokines (29–31). Macrophages can also serve a protective role in the setting of ozone-induced lung injury.…”

Effect of ozone exposure and infection on bronchoalveolar lavage: Sex differences in response patterns

“…In contrast, the levels of oxidized SP-A, and specifically the levels of the dimeric form of SP-A, were significantly higher in FA-exposed, infected female mice compared to their male counterparts. Whether this is a consequence of a robust macrophage antimicrobial activity (as suggested above for the oxidation of total BAL protein) resulting in SP-A functional deficits [20,23,25,35] or whether the oxidized dimeric form mediates important signaling pathways is not known. However, SP-A and some other proteins (as proposed by us and others) may serve as sacrificial antioxidants [33,36-39].…”

Impact of ozone exposure on the phagocytic activity of human surfactant protein A (SP-A) and SP-A variants

“…Quantitative differences include differences between the SP-A1 and SP-A2 genes and/or variants in basal mRNA levels and in response to dexamethasone (22,33,48,58) and in protein levels in bronchoalveolar lavage (BAL) fluids from different individuals (52). Mechanisms involving NF-B activation (21,28) and mRNA stability and translational control (57) may contribute to quantitative differences.…”

“…Ozone-induced oxidation of SP-A reduces its ability to interact with alveolar macrophages (AMs; Ref. 46), inhibits phosphatidylcholine secretion from alveolar type II cells (45,56), and has an impact on cytokine production in THP-1 cells (61) via ineffective activation of the NF-B cell signaling pathway (21). After ozone exposure of SP-A, its aggregation pattern, absorption spectra, gel electrophoretic pattern (50,56), and SP-A-dependent extracellular surfactant morphology (45,46) are also changed.…”