Specialized Pro-Resolving Lipid Mediators Regulate Ozone-Induced Pulmonary and Systemic Inflammation

Abstract

Exposure to ozone (O3) induces lung injury, pulmonary inflammation, and alters lipid metabolism. During tissue inflammation, specialized pro-resolving lipid mediators (SPMs) facilitate the resolution of inflammation. SPMs regulate the pulmonary immune response during infection and allergic asthma; however, the role of SPMs in O3-induced pulmonary injury and inflammation is unknown. We hypothesize that O3 exposure induces pulmonary inflammation by reducing SPMs. To evaluate this, male C57Bl/6J mice were exposed to filtered air (FA) or 1 ppm O3 for 3 h and necropsied 24 h after exposure. Pulmonary injury/inflammation was determined by bronchoalveolar lavage (BAL) differentials, protein, and lung tissue cytokine expression. SPMs were quantified by liquid chromatography tandem mass spectrometry and SPM receptors leukotriene B4 receptor 1 (BLT-1), formyl peptide receptor 2 (ALX/FPR2), chemokine-like receptor 1 (ChemR23), and SPM-generating enzyme (5-LOX and 12/15-LOX) expression were measured by real time PCR. 24 h post-O3 exposure, BAL PMNs and protein content were significantly increased compared to FA controls. O3-induced lung inflammation was associated with significant decreases in pulmonary SPM precursors (14-HDHA, 17-HDHA), the SPM PDX, and in pulmonary ALX/FPR2, ChemR23, and 12/15-LOX expression. Exogenous administration of 14-HDHA, 17-HDHA, and PDX 1 h prior to O3 exposure rescued pulmonary SPM precursors/SPMs, decreased proinflammatory cytokine and chemokine expression, and decreased BAL macrophages and PMNs. Taken together, these data indicate that O3-mediated SPM reductions may drive O3-induced pulmonary inflammation.

Exacerbation of Nanoparticle-Induced Acute Pulmonary Inflammation in a Mouse Model of Metabolic Syndrome

“…A previous investigation demonstrated that ozone exposure reduces lung levels of these DHA and EPA-derived LMIR in healthy mice (61). Further, supplementation of mice via intraperitoneal injection of a combination of LMIRs was observed to protect them from ozone-induced inflammation and lung damage (61). Healthy mice in our study did not demonstrate alterations in many of these lipids at the time point evaluated suggesting that MetS mice may be increasingly susceptible to exposures via the dysregulation of specific lipids.…”

“…Our exploratory profile data indicates that AgNP exposure resulted in decreased levels of LMIR produced via metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) solely in the MetS mouse model. A previous investigation demonstrated that ozone exposure reduces lung levels of these DHA and EPA-derived LMIR in healthy mice (61). Further, supplementation of mice via intraperitoneal injection of a combination of LMIRs was observed to protect them from ozone-induced inflammation and lung damage (61).…”

Resolution of Pulmonary Inflammation Induced by Carbon Nanotubes and Fullerenes in Mice: Role of Macrophage Polarization

“…In this connection, it has been shown that dietary supplement of ω-3 polyunsaturated fatty acids, such as DHA, prevented silicainduced inflammatory and autoimmune responses in vitro and in susceptible animal models (70)(71)(72). Pulmonary exposure to ozone caused lung inflammation associated with reduced SPM production; conversely, pretreatment with DHA reduced ozone-caused lung inflammation (73). Certain SPMs have demonstrated efficacy in treating inflammatory diseases caused by infection or sterile insults such as tobacco smoke (18,56,74).…”

Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody

“…SPM precursors and SPMs were injected as previously described at a concentration that leads to elevated levels of 14‐HDHA, 17‐HDHA, and PDX . Briefly, 14(S)‐HDHA (0.1 mg/ml), 17R‐HDHA (0.1 mg/ml), and Protectin DX (0.1 mg/ml) were purchased from Cayman Chemicals (Ann Arbor, MI).…”