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Abstract
Diesel exhaust particulates (DEP) adversely affect the respiratory system and exacerbate lung diseases, resulting in high mortality rates. However, its pathogenesis is complicated, and the mechanisms involved are incompletely understood. We investigated the effects of DEP pre-exposure on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and identified the roles of interleukin (IL)-17 in mice. Mice were divided into vehicle control, DEP, LPS, and DEP pre-exposed and LPS-instilled groups. Pre-exposure to DEP enhanced the number of total cells, neutrophils, and lymphocytes in the BAL fluid of LPS-instilled mice. Pre-exposure to DEP synergistically exacerbated pulmonary acute lung inflammation and granulomatous inflammation/pulmonary fibrosis, concomitant with the enhanced expression of inflammatory cytokines in the BAL fluid and of collagen I and TGF-β1 in the lungs of LPS-instilled mice. The number of TGF-β1-positive cells in the DEP pre-exposed and LPS-instilled group was higher than that in the LPS group. The expression of NLR family pyrin domain containing 3 (NLRP3) inflammasome components was markedly increased in the DEP pre-exposed and LPS-instilled group. IL-17 levels in the BAL fluid and IL-17-positive cells in the lungs were significantly increased by pre-exposure to DEP in the LPS-induced group compared to that in the DEP or LPS group. These results suggest that DEP predominantly contributes to fibrotic lung disease in LPS-related acute lung injury by upregulating IL-17 cytokine-mediated collagen I and TGF-β1 and, at least in part, by activating LPS-induced NLRP3 inflammasome signaling. The study should be useful in devising better strategies for prevention and management of ALI.
Highlights
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating disorders of the lung that are characterized by lung inflammation, pulmonary edema, low compliance, and capillary leakage due to increased pulmonary vascular permeability.These disorders affect individuals of all ages [1], and the risk of developing ALI depends on patient characteristics
We investigated whether diesel exhaust particulates (DEP) enhance susceptibility to LPS-induced ALI and examined the role of IL-17 and NLR family pyrin domain containing 3 (NLRP3) inflammasomes in the mechanisms underlying such an effect
To investigate the effect of DEP exposure on LPS-induced ALI and to elucidate the molecular mechanisms underlying the effect, we examined pathological and biological features of ALI in response to DEP pre-exposure by measuring the levels of various proteins, including tumor necrosis factor (TNF)-α, IL-1β, IL-6, IL-17, NLRP3 inflammasome components, and fibrosis markers in the bronchoalveolar lavage (BAL) fluid and lungs
Summary
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating disorders of the lung that are characterized by lung inflammation, pulmonary edema, low compliance, and capillary leakage due to increased pulmonary vascular permeability. These disorders affect individuals of all ages [1], and the risk of developing ALI depends on patient characteristics. ALI is triggered by events, such as pneumonia, gastric aspiration, inhalation of smoke and toxic gases, reperfusion, and severe sepsis [2]. Because of its small size, it can be inhaled with breath and get deposited in the terminal bronchioles and alveoli
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