resolvin-d1 and Pneumonia

Metabolic syndrome (MetS) exacerbates susceptibility to inhalation exposures such as particulate air pollution, however, the mechanisms responsible remain unelucidated. Previously, we determined a MetS mouse model exhibited exacerbated pulmonary inflammation 24 h following AgNP exposure compared to a healthy mouse model. This enhanced response corresponded with reduction of distinct resolution mediators. We hypothesized silver nanoparticle (AgNP) exposure in MetS results in sustained pulmonary inflammation. Further, we hypothesized treatment with resolvin D1 (RvD1) will reduce exacerbations in AgNP-induced inflammation due to MetS.. To evaluate these hypotheses, healthy and MetS mouse models were exposed to vehicle (control) or AgNPs and a day later, treated with resolvin D1 (RvD1) or vehicle (control) via oropharyngeal aspiration. Pulmonary lung toxicity was evaluated at 3-, 7-, 14-, and 21-days following AgNP exposure. MetS mice exposed to AgNPs and receiving vehicle treatment, demonstrated exacerbated pulmonary inflammatory responses compared to healthy mice. In the AgNP exposed mice receiving RvD1, pulmonary inflammatory response in MetS was reduced to levels comparable to healthy mice exposed to AgNPs. This included decreases in neutrophil influx and inflammatory cytokines, as well as elevated anti-inflammatory cytokines.. Inefficient resolution may contribute to enhancements in MetS susceptibility to AgNP exposure causing an increased pulmonary inflammatory response. Treatments utilizing specific resolution mediators may be beneficial to individuals suffering MetS following inhalation exposures.

Topics: Animals; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Inflammation; Metabolic Syndrome; Metal Nanoparticles; Mice; Pneumonia; Silver

Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways. We therefore hypothesized that proresolving mediators could reduce the burden of inflammation due to chronic lung infection following SHS exposure and restore normal immune responses to respiratory pathogens. To address this question, we exposed mice to SHS followed by chronic infection with nontypeable

Topics: Animals; Antibodies, Bacterial; Disease Models, Animal; Docosahexaenoic Acids; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Lung; Mice; Pneumonia; Tobacco Smoke Pollution

Non-resolving lung inflammation and

Topics: Animals; Cystic Fibrosis; Docosahexaenoic Acids; Humans; Mice; Mice, Knockout; Neutrophil Infiltration; Phagocytosis; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections

Agricultural workers are at risk for the development of acute and chronic lung diseases due to their exposure to organic agricultural dusts. A diet intervention using the omega-3 fatty acid docosahexaenoic acid (DHA) has been shown to be an effective therapeutic approach for alleviating a dust-induced inflammatory response. We thus hypothesized a high-DHA diet would alter the dust-induced inflammatory response through the increased production of specialized pro-resolving mediators (SPMs). Mice were pre-treated with a DHA-rich diet 4 weeks before being intranasally challenged with a single dose of an extract made from dust collected from a concentrated swine feeding operation (HDE). This omega-3-fatty-acid-rich diet led to reduced arachidonic acid levels in the blood, enhanced macrophage recruitment, and increased the production of the DHA-derived SPM Resolvin D1 (RvD1) in the lung following HDE exposure. An assessment of transcript-level changes in the immune response demonstrated significant differences in immune pathway activation and alterations of numerous macrophage-associated genes among HDE-challenged mice fed a high DHA diet. Our data indicate that consuming a DHA-rich diet leads to the enhanced production of SPMs during an acute inflammatory challenge to dust, supporting a role for dietary DHA supplementation as a potential therapeutic strategy for reducing dust-induced lung inflammation.

Topics: Animal Feed; Animals; Arachidonic Acid; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Dust; Inhalation Exposure; Lung; Male; Mice; Mice, Inbred C57BL; Pneumonia; Swine

Tobacco smoke exposure is associated with multiple diseases including, respiratory diseases like asthma and chronic obstructive pulmonary disease. Tobacco smoke is a potent inflammatory trigger and is immunosuppressive, contributing to increased susceptibility to pulmonary infections in smokers, ex-smokers, and vulnerable populations exposed to secondhand smoke. Tobacco smoke exposure also reduces vaccine efficacy. Therefore, mitigating the immunosuppressive effects of chronic smoke exposure and improving the efficacy of vaccinations in individuals exposed to tobacco smoke, is a critical unmet clinical problem. We hypothesized that specialized proresolving mediators (SPMs), a class of immune regulators promoting resolution of inflammation, without being immunosuppressive, and enhancing B cell Ab responses, could reverse the immunosuppressive effects resulting from tobacco smoke exposure. We exposed mice to secondhand smoke for 8 wk, followed by a period of smoke exposure cessation, and the mice were immunized with the P6 lipoprotein from nontypeable

Topics: Animals; Antibodies; Aspirin; Asthma; B-Lymphocytes; Bronchoalveolar Lavage Fluid; Cytokines; Docosahexaenoic Acids; Epithelial Cells; Female; Haemophilus Infections; Haemophilus influenzae; Immune Tolerance; Immunoglobulin A; Immunoglobulin G; Inflammation; Lipoproteins; Lung; Mice; Mice, Inbred C57BL; Pneumonia; Pulmonary Disease, Chronic Obstructive; Tobacco Smoke Pollution

Pseudomonas aeruginosa lung infection is a main cause of disability and mortality worldwide. Acute inflammation and its timely resolution are crucial for ensuring bacterial clearance and limiting tissue damage. Here, we investigated protective actions of resolvin (Rv) D1 in lung infection induced by the RP73 clinical strain of P. aeruginosa. RvD1 significantly diminished bacterial growth and neutrophil infiltration during acute pneumonia caused by RP73. Inoculum of RP73, immobilized in agar beads, resulted in persistent lung infection up to 21 days, leading to a non resolving inflammation reminiscent of human pathology. RvD1 significantly reduced bacterial titer, leukocyte infiltration, and lung tissue damage. In murine lung macrophages sorted during P. aeruginosa chronic infection, RvD1 regulated the expression of Toll-like receptors, downstream genes, and microRNA (miR)-21 and 155, resulting in reduced inflammatory signaling. In vitro, RvD1 enhanced phagocytosis of P. aeruginosa by neutrophils and macrophages, recapitulating its in vivo actions. These results unveil protective functions and mechanisms of action of RvD1 in acute and chronic P. aeruginosa pneumonia, providing evidence for its potent pro-resolution and tissue protective properties on airway mucosal tissue during infection.

Topics: Acute Disease; Animals; Bacterial Load; Cells, Cultured; Chronic Disease; Docosahexaenoic Acids; Female; Humans; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Neutrophil Infiltration; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections

Resolvin D1 (RvD1) is a novel endogenous docosahexaenoic acid (DHA)-derived lipid mediators, which possesses a dual role of anti-inflammation and promotes inflammation resolution. The aim of the present study was to assess the effects of RvD1 on cecal ligation and puncture (CLP) model of sepsis and explore the underlying mechanism. Six-to-eight-week-old male C57BL/6 mice were randomly divided into following three groups: sham-operated group (SO), CLP model group (CLP), and CLP+RvD1 group (RvD1). The SO group underwent the sham operation. The RvD1 groups were administered RvD1 (10-ng/g body weight) by penile vein injection, but the CLP groups were administered the same volume of vehicle (PBS) after CLP. We assessed the survival benefit of RvD1 in CLP-induced septic mice for 7 days. After 24 h, mice were sacrificed, bronchoalveolar lavage fluids (BALF) was collected for proinflammatory cytokines assay, and albumin assay and the lung tissues were harvested for histologic analysis, myeloperoxidase (MPO) activity and the expression of Sirtuin 1 (SIRT1), signal transducers, and activators of transcription 3 (STAT3), nuclear factor-κB (NF-κB), and mitogen-activated protein kinases (MAPKs). RvD1 treatment increased the survival time in mice with sepsis induced by CLP, reducing the MPO activity and albumin level at 24 h. The levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in BALF were significantly decreased by RvD1. RvD1 promoted SIRT1 expression and suppressed the activation of NF-κB, STAT3, ERK, and p38 in lung tissues of septic mice. These results suggest that RvD1 may improve survival and attenuate the degree of lung inflammation reaction in mice with CLP by suppressing STAT3, NF-κB, ERK, and p38 expressions through a mechanism partly dependent on SIRT1.

Topics: Animals; Docosahexaenoic Acids; Lung Injury; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pneumonia; Sepsis; Sirtuin 1; STAT3 Transcription Factor

Chronic obstructive pulmonary disease is characterized, in part, by chronic inflammation that persists even after smoking cessation, suggesting that a failure to resolve inflammation plays an important role in the pathogenesis of the disease. It is widely recognized that the resolution of inflammation is an active process, governed by specialized proresolving lipid mediators, including lipoxins, resolvins, maresins, and protectins. Here, we report that proresolving signaling and metabolic pathways are disrupted in lung tissue from patients with chronic obstructive pulmonary disease, suggesting that supplementation with proresolving lipid mediators might reduce the development of emphysema by controlling chronic inflammation. Groups of mice were exposed long-term to cigarette smoke and treated with the proresolving mediator resolvin D1. Resolvin D1 was associated with a reduced development of cigarette smoke-induced emphysema and airspace enlargement, with concurrent reductions in inflammation, oxidative stress, and cell death. Interestingly, resolvin D1 did not promote the differentiation of M2 macrophages and did not promote tissue fibrosis. Taken together, our results suggest that cigarette smoking disrupts endogenous proresolving pathways and that supplementation with specialized proresolving lipid mediators is an important therapeutic strategy in chronic lung disease, especially if endogenous specialized proresolving lipid mediator signaling is impaired.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Chronic Disease; Docosahexaenoic Acids; Drug Evaluation, Preclinical; Female; Humans; Macrophages, Alveolar; Male; Mice, Inbred C57BL; Middle Aged; Oxidative Stress; Pneumonia; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Signal Transduction; Smoking

Increasing evidence suggests that the novel anti-inflammatory and proresolving mediators such as the resolvins play an important role during inflammation. However, the functions of these lipid mediators in immune complex-induced lung injury remain unknown. In this study, we determined the role of aspirin-triggered resolvin D1 (AT-RvD1) and its metabolically stable analog, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester (p-RvD1), in IgG immune complex-induced inflammatory responses in myeloid cells and injury in the lung. We show that lung vascular permeability in the AT-RvD1- or p-RvD1-treated mice was significantly reduced when compared with values in mice receiving control vesicle during the injury. Furthermore, i.v. administration of either AT-RvD1 or p-RvD1 caused significant decreases in the bronchoalveolar lavage fluid contents of neutrophils, inflammatory cytokines, and chemokines. Of interest, AT-RvD1 or p-RvD1 significantly reduced bronchoalveolar lavage fluid complement C5a level. By EMSA, we demonstrate that IgG immune complex-induced activation of NF-κB and C/EBPβ transcription factors in the lung was significantly inhibited by AT-RvD1 and p-RvD1. Moreover, AT-RvD1 dramatically mitigates IgG immune complex-induced NF-κB and C/EBP activity in alveolar macrophages. Also, secretion of TNF-α, IL-6, keratinocyte cell-derived chemokine, and MIP-1α from IgG immune complex-stimulated alveolar macrophages or neutrophils was significantly decreased by AT-RvD1. These results suggest a new approach to the blocking of immune complex-induced inflammation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigen-Antibody Complex; Aspirin; Bronchoalveolar Lavage Fluid; CCAAT-Enhancer-Binding Proteins; Cell Line; Chemokine CCL3; Complement C5a; Cytokines; Docosahexaenoic Acids; Immunoglobulin G; Macrophages, Alveolar; Mice; Neutrophils; NF-kappa B; Pneumonia

Cigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation.. Primary human lung fibroblasts, small airway epithelial cells and blood monocytes were treated with IL-1β or cigarette smoke extract in combination with RvD1 in vitro, production of pro-inflammatory mediators was measured. Mice were exposed to dilute mainstream cigarette smoke and treated with RvD1 either concurrently with smoke or after smoking cessation. The effects on lung inflammation and lung macrophage populations were assessed.. RvD1 suppressed production of pro-inflammatory mediators by primary human cells in a dose-dependent manner. Treatment of mice with RvD1 concurrently with cigarette smoke exposure significantly reduced neutrophilic lung inflammation and production of pro-inflammatory cytokines, while upregulating the anti-inflammatory cytokine IL-10. RvD1 promoted differentiation of alternatively activated (M2) macrophages and neutrophil efferocytosis. RvD1 also accelerated the resolution of lung inflammation when given after the final smoke exposure.. RvD1 has potent anti-inflammatory and pro-resolving effects in cells and mice exposed to cigarette smoke. Resolvins have strong potential as a novel therapeutic approach to resolve lung injury caused by smoke and pulmonary toxicants.

Topics: Analysis of Variance; Animals; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; DNA Primers; Docosahexaenoic Acids; Female; Fibroblasts; Homeostasis; Humans; Lung; Mice; Mice, Inbred C57BL; Phagocytosis; Pneumonia; Smoking

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary permeability with high mortality. Resolvin D1 (RvD1), which has potent anti-inflammatory and pro-resolving activity, can attenuate pulmonary edema in the animal model of ALI. However, the mechanism underlying the protection of RvD1 on pulmonary edema is still unknown. Here we explore the effects and mechanism of RvD1 on the disruption of tight junction protein that results in the permeability edema in a model of lipopolysaccharide (LPS)-induced ALI. The severity of pulmonary edema was assessed by wet-to-dry rate and Evans blue infiltration; expressions of tight junction (TJ) proteins occludin and zona occludin-1 (ZO-1) were examined by immunofluorescence staining and western blot; mRNA in lung tissue was studied by real time-PCR; the TUNEL kit was performed for the detection of apoptosis of pulmonary barrier. Twenty-four hours after LPS inhalation by mice, wet-to-dry rate and Evans blue infiltration indicated that pretreatment with RvD1 relieved the pulmonary edema and pulmonary capillary permeability. Moreover, RvD1 attenuated the LPS-induced deterioration of TJ protein ZO-1 and occludin significantly. And we found that RvD1 increased heme oxygenase-1 (HO-1) expression contributed to the protection on the deterioration of TJs. In addition, we found that RvD1 could reduce pulmonary cellular apoptosis in LPS-induced mice. In conclusion, RvD1 possesses the ability that relieves the pulmonary edema and restores pulmonary capillary permeability and reduces disruption of TJs in LPS-induced ALI of mice, at least in part, by upregulating HO-1 expression.

Topics: Acute Lung Injury; Analysis of Variance; Animals; Apoptosis; Capillary Permeability; Docosahexaenoic Acids; Heme Oxygenase-1; In Situ Nick-End Labeling; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Pneumonia; Protective Agents; Real-Time Polymerase Chain Reaction; Tight Junction Proteins; Up-Regulation

Docosahexaenoic acid (DHA) and DHA-derived lipid mediators have recently been shown to possess anti-inflammatory and pro-resolving properties. In fact, DHA can down-regulate lipolysaccharide (LPS)-induced activation of NF-κB via a PPARγ-dependent pathway. We sought to investigate the effects of the novel DHA-derived mediator resolvin D1 (RvD1) on LPS-induced acute lung injury and to determine whether these effects occur via a PPARγ-dependent pathway.. BALB/c mice aged 6-8 weeks were randomly divided into seven groups: two control groups receiving saline or RvD1 (600 ng) without LPS; a control group receiving LPS only; an experimental group receiving RvD1 (300 ng) or RvD1 (600 ng), followed by LPS; a group receiving the PPARγ antagonist GW9662; and a group receiving GW9662, then RvD1 (600 ng) and finally LPS. LPS (50 μM) and saline were administered intratracheally. RvD1 was injected intravenously 24 h and 30 min before LPS, while GW9662 was injected intravenously 30 min before RvD1. Mice were killed at 6, 12, and 24 h. Samples of bronchoalveolar lavage fluid (BALF) were analyzed for cell counts and cytokine analysis. Lung tissues were collected for histology, Western blotting and electrophoretic mobility shift assays (EMSAs).. At all three time points, groups receiving either dose of RvD1 followed by LPS had significantly lower total leukocyte counts and levels of TNF-α and IL-6 levels in BALF than did the group given only LPS. RvD1 markedly attenuated LPS-induced lung inflammation at 24 h, based on hematoxylin-eosin staining of histology sections. RvD1 activated PPARγ and suppressed IκBα degradation and NF-κB p65 nuclear translocation, based on Western blots and EMSAs. The PPARγ inhibitor GW9662 partially reversed RvD1-induced suppression of IκBα degradation and p65 nuclear translocation.. These results suggest that RvD1 may attenuate lung inflammation of LPS-induced acute lung injury by suppressing NF-κB activation through a mechanism partly dependent on PPARγ activation.

Topics: Acute Lung Injury; Animals; Docosahexaenoic Acids; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Pneumonia; PPAR gamma; Signal Transduction; Treatment Outcome