prostaglandin-d2 and Pneumonia

To explore the mechanism of moxibustion in the treatment of asthmatic inflammation from the point of short-chain fatty acids (SCFAs) in rats with asthma.. A total of 48 SD rats (half male and half female) were randomly divided into 4 groups： normal, model, lung treatment and joint-treatment of lung and intestine (joint-treatment), with 12 rats in each group. The asthma model was made by subcutaneous (bilateral back and inguinal regions) and intraperitoneal injection of mixture solution of ovalbumin and aluminium hydroxide gel (on day 1 and 8) and followed by inhalation of atomized 1% ovalbumin (20 min from day 15, once daily for one week). Moxibustion was applied to bilateral "Feishu" (BL13) for rats of the lung treatment group or bilateral "Feishu" (BL13) and "Tianshu" (ST25) for rats of the joint treatment group. One hour after the intervention, the rats in the later three groups were separately given atomized 1% ovalbumin solution inhalation for 20 min. The treatment was conducted for 30 min, once daily for 14 consecutive days. At the end of the intervention, the percentage of inflammatory cells in blood was detected by biochemical method and histopathological changes of the lung were observed after H.E. staining. The inflammatory cells in the bronchoalveolar lavage fluid (BALF) were counted after Wright-Giemsa staining. The mRNA expressions of interleukin (IL)-4, IL-5, IL-13, IL-17, IL-33, leukotriene (LT), thymic stromal lymphopoietin (TSLP) and prostaglandin D2 (PGD2) were detected by real-time PCR, and the contents of SCFAs in rats' feces were detected by gas chromatography-mass spectrometry.. Relevant to the normal group, the model group had an obvious increase in the percentages of neutrophils, lymphocytes and eosinophils in the blood, the percentages of neutrophils and eosinophils in the BALF, and in the expression levels of PGD2, TSLP, LT, IL-4, IL-5, IL-13, IL-17 and IL-33 mRNAs in the lung tissues (. Joint treatment of asthma from the lung and intestine can better regulate the contents of intestinal SCFAs and alleviate the inflammatory response of asthmatic model rats, thus, intestinal SCFAs may be involved in the process of moxibustion in improving inflammatory response.

Topics: Acupuncture Points; Animals; Asthma; Fatty Acids, Volatile; Female; Interleukin-13; Interleukin-17; Interleukin-33; Interleukin-4; Interleukin-5; Intestines; Isobutyrates; Lung; Male; Moxibustion; Ovalbumin; Pneumonia; Propionates; Prostaglandin D2; Rats; Rats, Sprague-Dawley

The precise role of prostaglandin D (PGD)

Topics: Animals; Asthma; Chronic Disease; Epithelial Cells; Gene Expression Regulation; Inflammation; Intramolecular Oxidoreductases; Lipopolysaccharides; Lung; Mice; Mice, Knockout; Pneumonia; Prostaglandin D2; Signal Transduction; Tumor Necrosis Factor-alpha

We have reported that von Hippel-Lindau protein (pVHL) expression is elevated in human and mouse fibrotic lungs and that overexpression of pVHL stimulates fibroblast proliferation. We sought to determine whether loss of pVHL in fibroblasts prevents injury and fibrosis in mice that are treated with bleomycin. We generated heterozygous fibroblast-specific pVHL (Fsp-VHL) knockdown mice (Fsp-VHL(+/-)) and homozygous Fsp-VHL knockout mice (Fsp-VHL(-/-)) by crossbreeding vhlh 2-lox mice (VHL(fl/fl)) with Fsp-Cre recombinase mice. Our data show that Fsp-VHL(-/-) mice, but not Fsp-VHL(+/-) mice, have elevated red blood cell counts, hematocrit, hemoglobin content, and expression of hypoxia-inducible factor (HIF) targets, indicating HIF activation. To examine the role of pVHL in bleomycin-induced lung injury and fibrosis in vivo, we administered PBS or bleomycin to age-, sex-, and strain-matched 8-week-old VHL(fl/fl), Fsp-VHL(+/-), and Fsp-VHL(-/-) mice. In Fsp-VHL(+/-) and Fsp-VHL(-/-) mice, bleomycin-induced collagen accumulation, fibroblast proliferation, differentiation, and matrix protein dysregulation were markedly attenuated. Suppression of pVHL also decreased bleomycin-induced Wnt signaling and prostaglandin E2 signaling but did not affect bleomycin-induced initial acute lung injury and lung inflammation. These results indicate that pVHL has a pivotal role in bleomycin-induced pulmonary fibrosis, possibly via an HIF-independent pathway. Paradoxically, pVHL does not affect bleomycin-induced lung injury and inflammation, indicating a separation of the mechanisms involved in injury/inflammation from those involved in pulmonary fibrosis.

Topics: Animals; Bleomycin; Cell Differentiation; Cell Proliferation; Dinoprostone; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Injury; Mice, Knockout; Models, Biological; Pneumonia; Prostaglandin D2; Pulmonary Fibrosis; Von Hippel-Lindau Tumor Suppressor Protein; Wnt Signaling Pathway

In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion.. This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response.. RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC50 of 2.5 ± 0.7 nM and PGD2 production from mast cells with an IC50 of 8.3 ± 1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC50(RN983) = 59 μg/kg) than the β-agonist salbutamol (IC50(salbutamol) = 15 μg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC50(RN983) = <3 μg/kg) than the inhaled corticosteroid budesonide (IC50(budesonide) = 27 μg/kg) in the mouse model of the LAR.. Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and β-agonists in severe asthmatics due to its potent inhibition of mast cell activation.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Agammaglobulinaemia Tyrosine Kinase; Albuterol; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; B-Lymphocytes; Bronchial Hyperreactivity; Bronchoconstriction; Bronchodilator Agents; Budesonide; Cell Degranulation; Cells, Cultured; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Dry Powder Inhalers; Glucocorticoids; Humans; Immunoglobulin G; Lung; Male; Mast Cells; Mice, Inbred BALB C; Ovalbumin; Phthalazines; Pneumonia; Prostaglandin D2; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridazines

Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

Topics: Animals; Bleomycin; Chemokine CCL2; Collagen; Cyclooxygenase 2; Disease Models, Animal; Gene Knockout Techniques; Intramolecular Oxidoreductases; Isomerases; Lung; Macrophages; Mice; Neutrophil Infiltration; Pneumonia; Prostaglandin D2; Pulmonary Fibrosis; Tumor Necrosis Factor-alpha

Sphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models of this disease. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung.. BALB/c, mast cell-deficient and Nude mice were injected with S1P (s.c.) on days 0 and 7. Functional, molecular and cellular studies were performed.. S1P administration to BALB/c mice increased airway smooth muscle reactivity, mucus production, PGD2 , IgE, IL-4 and IL-13 release. These features were associated to a higher recruitment of mast cells to the lung. Mast cell-deficient Kit (W) (-sh/) (W) (-sh) mice injected with S1P did not display airway smooth muscle hyper-reactivity. However, lung inflammation and IgE production were still present. Treatment in vivo with the anti-CD23 antibody B3B4, which blocks IgE production, inhibited both S1P-induced airway smooth muscle reactivity in vitro and lung inflammation. S1P administration to Nude mice did not elicit airway smooth muscle hyper-reactivity and lung inflammation. Naïve (untreated) mice subjected to the adoptive transfer of CD4+ T-cells harvested from S1P-treated mice presented all the features elicited by S1P in the lung.. S1P triggers a cascade of events that sequentially involves T-cells, IgE and mast cells reproducing several asthma-like features. This model may represent a useful tool for defining the role of S1P in the mechanism of action of currently-used drugs as well as in the development of new therapeutic approaches for asthma-like diseases.

Topics: Animals; Bronchial Hyperreactivity; CD4-Positive T-Lymphocytes; Immunoglobulin E; Interleukin-13; Interleukin-4; Lysophospholipids; Mast Cells; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; Pneumonia; Prostaglandin D2; Sphingosine

Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation, and tissue repair. Although epithelial cell-derived cytokines regulate ILC2 effector functions, the pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D2 (PGD2) receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. Although a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from nondiseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated toward PGD2 in vitro, and accumulated in the lung in response to PGD2 in vivo. Furthermore, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD2-CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung.

Topics: Adoptive Transfer; Animals; Cell Separation; Chemotaxis, Leukocyte; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Immunity, Innate; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; Prostaglandin D2; Real-Time Polymerase Chain Reaction; Receptors, Immunologic; Receptors, Prostaglandin

We investigated the role of prostaglandin D2 (PGD2) signaling in acute lung injury (ALI), focusing on its producer-effector interaction in vivo. Administration of endotoxin increased edema and neutrophil infiltration in the WT mouse lung. Gene disruption of hematopoietic PGD synthase (H-PGDS) aggravated all of the symptoms. Experiments involving bone marrow transplantation between WT and H-PGDS-deficient mice showed that PGD2 derived from alveolar nonhematopoietic lineage cells (i.e., endothelial cells and epithelial cells) promotes vascular barrier function during the early phase (day 1), whereas neutrophil-derived PGD2 attenuates its own infiltration and cytokine expression during the later phase (day 3) of ALI. Treatment with either an agonist to the PGD2 receptor, DP, or a degradation product of PGD2, 15-deoxy-Δ(12,14)-PGJ2, exerted a therapeutic action against ALI. Data obtained from bone marrow transplantation between WT and DP-deficient mice suggest that the DP signal in alveolar endothelial cells is crucial for the anti-inflammatory reactions of PGD2. In vitro, DP agonism directly enhanced endothelial barrier formation, and 15-deoxy-Δ(12,14)-PGJ2 attenuated both neutrophil migration and cytokine expression. These observations indicate that the PGD2 signaling between alveolar endothelial/epithelial cells and infiltrating neutrophils provides anti-inflammatory effects in ALI, and suggest the therapeutic potential of these signaling enhancements.

Topics: Acute Disease; Acute Lung Injury; Animals; Bone Marrow Transplantation; Endothelial Cells; Epithelial Cells; Female; Intramolecular Oxidoreductases; Lipocalins; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Pneumonia; Prostaglandin D2; Pulmonary Alveoli; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Time Factors; Transplantation, Homologous

Chemoattractant receptor homologous molecule expressed on T helper type 2 cells (CRTH2) is a PGD2 receptor found on eosinophils, basophils, and Th2 type T cells which exhibits chemotaxis and functions in activation cascades. However, while a number of CRTH2 antagonists, including ramatroban, are known to exert activity in certain animal models, activity in a guinea pig model of EA-induced airway hyperresponsiveness has not been demonstrated. The newly developed CRTH2 antagonist ASP5642 has shown antagonistic activity against human and guinea pig CRTH2 in previous studies and has also been found effective in treating guinea pig models of airway inflammation and airway hyperresponsiveness. While previous studies have used animals such as rats and mice to evaluate CRTH2 antagonist effects, ours is the first attempt to evaluate CRTH2 function in a guinea pig asthma model, which may prove useful in evaluating the compound's effects in humans, given the comparable airway function between the two species taken together, these data from the present study strongly suggest the utility of ASP5642 in investigating the role of CRTH2 in inflammatory responses and as a drug treatment for human asthma.

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Antigens; Benzhydryl Compounds; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Carbazoles; Cell Count; Eosinophilia; Guinea Pigs; HEK293 Cells; Humans; K562 Cells; Male; Ovalbumin; Pneumonia; Prostaglandin D2; Pyridazines; Receptors, Immunologic; Receptors, Prostaglandin; Sulfonamides

Nrf2 is a transcription factor that protects against inflammatory diseases, but the underlying mechanism of this effect remains unclear. Here, we report that Nrf2 uses lipocalin-prostaglandin D synthase (L-PGDS) as a mechanism for suppressing inflammation. Exogenously added prostaglandin D2 (PGD2) induced L-PGDS expression in bone-marrow-derived macrophages (BMDMs), suggesting a positive feedback loop between L-PGDS expression and PGD2. Unlike lipopolysaccharide (LPS)-induced L-PGDS expression, PGD2-mediated expression was independent of MAPK, PU.1, or TLR4. Sequence analysis located a putative Nrf2 binding site in the murine L-PGDS promoter, to which Nrf2 bound when treated with PGD2. Chemical activation, or overexpression, of Nrf2 was sufficient to induce L-PGDS expression in macrophages, BMDMs, or lungs of Nrf2-knockout (KO) mice, but treatment with PGD2 failed to do so, suggesting a pivotal role for Nrf2 in the expression of L-PGDS. Consistent with this, expression of Nrf2 in the lungs of Nrf2-KO mice was sufficient to induce the expression of L-PGDS and to reduce neutrophilic lung inflammation elicited by LPS. Furthermore, expression of L-PGDS in mouse lungs decreased neutrophilic infiltration, ameliorating lung inflammation in mice. Together, our results show that Nrf2, activated by PGD2, induced L-PGDS expression, resulting in decreased inflammation. We suggest that the positive feedback induction of L-PGDS by PGD2 is part of the mechanism by which Nrf2 regulates inflammation.

Topics: Amino Acid Sequence; Animals; Base Sequence; Binding Sites; Cell Line; Cyclooxygenase 2; Intramolecular Oxidoreductases; Lipocalins; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Neutrophils; NF-E2-Related Factor 2; Pneumonia; Promoter Regions, Genetic; Prostaglandin D2; Protein Binding; RNA Interference; RNA, Small Interfering; Sequence Analysis, DNA; Toll-Like Receptor 4

Growing evidence indicates that influenza pathogenicity relates to altered immune responses and hypercytokinemia. Therefore, dampening the excessive inflammatory response induced after infection might reduce influenza morbidity and mortality.. Considering this, we investigated the effect of the anti-inflammatory molecule 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) in a mouse model of lethal influenza infection.. Administration of 15d-PGJ(2) on day 1 after infection, but not on day 0, protected 79% of mice against lethal influenza infection. In addition, this treatment considerably reduced the morbidity associated with severe influenza infection. Our results also showed that treatment with 15d-PGJ(2) decreased influenza-induced lung inflammation, as shown by the diminished gene expression of several proinflammatory cytokines and chemokines. Unexpectedly, 15d-PGJ(2) also markedly reduced the viral load in the lungs of infected mice. This could be attributed to maintained type I interferon gene expression levels after treatment. Interestingly, pretreatment of mice with a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist before 15d-PGJ(2) administration completely abrogated its protective effect against influenza infection.. Our results demonstrate for the first time that treatment of mice with 15d-PGJ(2) reduces influenza morbidity and mortality through activation of the PPARγ pathway. PPARγ agonists could thus represent a potential therapeutic avenue for influenza infections.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Female; Lung; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections; Pneumonia; PPAR gamma; Prostaglandin D2; Survival Analysis

Cerium oxide (CeO₂) represents an important nanomaterial with wide ranging applications. However, little is known regarding how CeO₂ exposure may influence pulmonary or systemic inflammation. Furthermore, how mast cells would influence inflammatory responses to a nanoparticle exposure is unknown. We thus compared pulmonary and cardiovascular responses between C57BL/6 and B6.Cg-Kit(W-sh) mast cell deficient mice following CeO₂ nanoparticle instillation. C57BL/6 mice instilled with CeO₂ exhibited mild pulmonary inflammation. However, B6.Cg-Kit(W-sh) mice did not display a similar degree of inflammation following CeO₂ instillation. Moreover, C57BL/6 mice instilled with CeO₂ exhibited altered aortic vascular responses to adenosine and an increase in myocardial ischemia/reperfusion injury which was absent in B6.Cg-Kit(W-sh) mice. In vitro CeO₂ exposure resulted in increased production of PGD₂, TNF-α, IL-6 and osteopontin by cultured mast cells. These findings demonstrate that CeO₂ nanoparticles activate mast cells contributing to pulmonary inflammation, impairment of vascular relaxation and exacerbation of myocardial ischemia/reperfusion injury.

Topics: Adenosine; Analysis of Variance; Animals; Aorta, Thoracic; Bronchoalveolar Lavage Fluid; Cerium; Chemokine CCL3; Gene Expression Regulation; Histocytochemistry; Interleukin-10; Interleukin-13; Interleukin-6; Lung; Male; Mast Cells; Metal Nanoparticles; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; Osteopontin; Particle Size; Pneumonia; Prostaglandin D2; Reperfusion Injury; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Microparticles (MP) are phospholipid vesicles shed by cells upon activation or apoptosis. Monocyte-derived MP upregulate the synthesis of proinflammatory mediators by lung epithelial cells; the molecular bases of such activity are unknown. Peroxisome proliferator-activated receptors (PPAR) have been demonstrated to be involved in the modulation of nuclear factor (NF)-κB transcriptional activity and inflammation. We investigated whether the upregulation of the synthesis of proinflammatory cytokines by human lung epithelial cells induced by monocyte/macrophage-derived MP involves NF-κB activation and is modulated by PPAR-γ. MP were generated by stimulation of human monocytes/macrophages with the calcium ionophore, A23187. MP were incubated with human lung epithelial cells. NF-κB translocation was assessed by electrophoretic mobility shift assay. Interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1 synthesis was assessed by ELISA and RT-PCR. Stimulation of A549 alveolar cells with monocyte/macrophage-derived MP caused an increase in NF-κB activation and IL-8 and MCP-1 synthesis that was inhibited by pre-incubation with the PPAR-γ agonists, rosiglitazone and 15-deoxy-Δ12,14-prostaglandin-J2. Parallel experiments with normal human bronchial epithelial cells largely confirmed the results. The effects of PPAR-γ agonists were reversed by the specific antagonist, GW9662. Upregulation of the synthesis of proinflammatory mediators by human lung epithelial cells induced by monocyte/macrophage-derived MP is mediated by NF-κB activation through a PPAR-γ dependent pathway.

Topics: Anilides; Bronchi; Calcimycin; Cell Line; Cell-Derived Microparticles; Cells, Cultured; Chemokine CCL2; Humans; Interleukin-8; Ionophores; Monocytes; NF-kappa B; Pneumonia; PPAR gamma; Prostaglandin D2; Rosiglitazone; Thiazolidinediones; Up-Regulation

We report here that 4-dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine (AT-56) is an orally active and selective inhibitor of lipocalin-type prostaglandin (PG) D synthase (L-PGDS). AT-56 inhibited human and mouse L-PGDSs in a concentration (3-250 microm)-dependent manner but did not affect the activities of hematopoietic PGD synthase (H-PGDS), cyclooxygenase-1 and -2, and microsomal PGE synthase-1. AT-56 inhibited the L-PGDS activity in a competitive manner against the substrate PGH(2) (K(m) = 14 microm) with a K(i) value of 75 microm but did not inhibit the binding of 13-cis-retinoic acid, a nonsubstrate lipophilic ligand, to L-PGDS. NMR titration analysis revealed that AT-56 occupied the catalytic pocket, but not the retinoid-binding pocket, of L-PGDS. AT-56 inhibited the production of PGD(2) by L-PGDS-expressing human TE-671 cells after stimulation with Ca(2+) ionophore (5 microm A23187) with an IC(50) value of about 3 microm without affecting their production of PGE(2) and PGF(2alpha) but had no effect on the PGD(2) production by H-PGDS-expressing human megakaryocytes. Orally administered AT-56 (<30 mg/kg body weight) decreased the PGD(2) production to 40% in the brain of H-PGDS-deficient mice after a stab wound injury in a dose-dependent manner without affecting the production of PGE(2) and PGF(2alpha) and also suppressed the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice.

Topics: Administration, Oral; Animals; Calcimycin; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Eosinophils; Humans; Intramolecular Oxidoreductases; Ionophores; Lipocalins; Male; Megakaryocytes; Membrane Proteins; Mice; Mice, Knockout; Monocytes; Pneumonia; Prostaglandin D2; Wound Healing; Wounds, Stab

Multiple factors contribute to the pathogenesis and prognosis of chronic obstructive pulmonary disease(COPD), still requiring new therapeutic strategies and medications for the disease. The aim of the present study is to investigate the model of lipopolysaccharide (LPS)-induced chronic lung injury and hyperinflation and test therapeutic effects of peroxisome proliferator-activated receptor (PPAR)-gamma agonist. Wister rats were challenged with intra-tracheal instillation of LPS at concentrations of 0.006, 0.060, 0.600, and 6.000 mg/ml per kg, twice a week, for 1, 2, 4 and 6 weeks. PPAR activator, 15-deoxy-Delta12,14-prostaglandin J2 (15D-PGJ2), or vehicle (PBS) was administered orally and daily at the dose of 1 and 10 mg/ml per kg in animals challenged with LPS or PBS at the dose of 0.060 mg/ml per kg body weight twice a week for 4 weeks. We found that intra-tracheal exposure of LPS resulted in a dose-dependent pattern of chronic lung hyperinflation and hypertrophy, increased alveolar enlargement, reduced vascular endothelial growth factor (VEGF) and elevated tissue inhibitor of metalloproteinases (TIMP)-1 levels in bronchoalveolar lavage (BAL) fluid, and early changes of leukocyte influx and interferon (IFN)-gamma levels in bronchoalveolar lavage (BAL) fluid. PPAR-gamma agonist ameliorated these changes related with the dose used.LPS-induced lung disease model shows some similarities with human disease, and PPAR-gamma agonist maybe an alternative for COPD therapy.

Topics: Animals; Bronchoalveolar Lavage Fluid; Female; Interferon-gamma; Leukocyte Count; Lipopolysaccharides; Lung; Lung Diseases; Lung Volume Measurements; Pneumonia; PPAR gamma; Prostaglandin D2; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Rats; Rats, Wistar; Tissue Inhibitor of Metalloproteinase-1

As part of an ongoing investigation to find bioactive medicinal herbs exerting anti-inflammation activity, the effect of an ethanol extract from the parts of Ailanthus altissima (Simaroubaceae) was evaluated in both in vitro and in in vivo system. The ethanol extract of A. altissima (EAa) inhibited generation of the cyclooxygenase-2 (COX-2) dependent phases of prostaglandin D2 in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner with an IC50 value of 214.6 microg/ml. However, this compound did not inhibit COX-2 protein expression up to a concentration of 400 microg/ml in the BMMC, indicating that EAa directly inhibits COX-2 activity. In addition, EAa inhibited leukotriene C4 production with an IC50 value of 25.7 microg/ml. Furthermore, this compound inhibited degranulation reaction in a dose dependent manner, with an IC50 value of 27.3 microg/ml. Ovalbumin (OVA)-sensitized mice were orally pretreated with EAa before aerosol challenges. EAa reduced the eosinophil infiltration into the airway and the eotaxin, IL-4, and IL-13 mRNA expression levels. These results suggest that the anti-inflammation activity of A. altissima in OVA-induced lung inflammation may occur in part via the down regulation of T(H)2 cytokines and eotaxin transcripts as well as the inhibition of inflammatory mediators.

Topics: Ailanthus; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Arachidonic Acid; beta-N-Acetylhexosaminidases; Blotting, Western; Bone Marrow Cells; Bronchoalveolar Lavage Fluid; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; DNA, Complementary; Eosinophils; Female; Leukocyte Count; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; Pneumonia; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction

Acute lung injury (ALI) is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Recent studies demonstrated that cyclooxygenase-2 (COX-2) induced at the late phase of inflammation aids in the resolution of inflammation by generating 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes.. Because 15d-PGJ2 is an endogenous electrophile, we hypothesized that it protects against ALI by activating Nrf2.. To test this hypothesis, we generated a reversible ALI model by intratracheal injection of carrageenin, an inducer of acute inflammation, whose stimulation has been known to induce COX-2.. We found that ALI induced by carrageenin was markedly exacerbated in Nrf2-knockout mice, compared with wild-type mice. Analysis of bronchoalveolar lavage fluids also revealed that the magnitude and the duration of acute inflammation, indicated by albumin concentration and the number of neutrophils, were significantly enhanced in Nrf2-knockout mice. Treatment of wild-type mice with NS-398, a selective COX-2 inhibitor, significantly exacerbated ALI to the level of Nrf2-knockout mice. In the lungs of NS-398-treated wild-type mice, both the accumulation of 15d-PGJ2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ2 reversed the exacerbating effects of NS-398 with the induction of antioxidant genes.. These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Topics: Animals; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; DNA-Binding Proteins; Macrophages; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Nitrobenzenes; Pneumonia; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Respiratory Distress Syndrome; Sulfonamides; Trans-Activators

The release of inflammatory mediators (histamine, PGD2, TxB2, and LTC4) from purified human lung mast cells was characterized by kinetic and anti-IgE dose-response parameters. The relative rate of mediator release was histamine greater than PGD2 = TxB2 greater than LTC4, with one half maximal release occurring at approximately 2, 5, and 10 min, respectively. In 2 experiments, stimulation with anti-IgE caused significant quantities of platelet-activating factor (PAF) to appear rapidly (2 min) in the cell pellet; cell-associated PAF declined to low levels by 45 min. The optimal concentration of anti-IgE for the release of the arachidonate cyclooxygenase metabolites PGD2 and TxB2 (0.3 microgram/ml) was 10- to 30-fold less than that required for the release of histamine and LTC4 (3 to 10 micrograms/ml), suggesting that these release processes may have differential IgE Fc receptor cross-linking requirements. At optimal histamine release, the magnitude of the release of each arachidonate metabolite was found to correspond to the magnitude of histamine release, however, suggesting that the 2 processes are linked either in series or in parallel.

Topics: Antibodies, Anti-Idiotypic; Cell Separation; Histamine; Humans; Immunoglobulin E; Kinetics; Lung; Mast Cells; Platelet Activating Factor; Pneumonia; Prostaglandin D2; Prostaglandins D; SRS-A; Thromboxane B2