15-deoxy-delta(12-14)-prostaglandin-j2 and Asthma

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Asthma; Humans; Ion Channel Gating; Neurons; Pain; Peripheral Nervous System Diseases; Pulmonary Disease, Chronic Obstructive; Transient Receptor Potential Channels

Diisocyanate is a leading cause of occupational asthma (OA). Diisocyanate-induced OA is an inflammatory disease of the airways that is associated with airway remodelling. Although the pathogenic mechanisms are unclear, oxidative stress may be related to the pathogenesis of diisocyanate-induced OA. In our previous report, we observed that the expression of ferritin light chain (FTL) was decreased in both of bronchoalveolar lavage fluid and serum of patients with diphenyl-methane diisocyanate (MDI)-induced OA compared to those of asymptomatic exposed controls and unexposed healthy controls. In this study of toluene diisocyanate (TDI)-OA, we found identical findings with increased transferrin and decreased ferritin levels in the serum of patients with TDI-OA. To elucidate whether diisocyanate suppresses FTL synthesis directly, we tested the effect of TDI on the FTL synthesis in A549 cells, a human airway epithelial cell line. We found that haem oxygenase-1 as well as FTL was suppressed by treatment with TDI in dose- and time-dependent manners. We also found that the synthesis of other anti-oxidant proteins such as thioredoxin-1, glutathione peroxidase, peroxiredoxin 1 and catalase were suppressed by TDI. Furthermore, TDI suppressed nuclear translocation of Nrf2 through suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs); extracellular-regulated kinase 1/2 (ERK1/2); p38; and c-Jun N-terminal kinase (JNK). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, 15-deoxy-Delta(12,14)-PGJ2 and rosiglitazone rescued the effect of TDI on HO-1/FTL expression. Collectively, our findings suggest that TDI suppressed HO-1/FTL expression through the MAPK-Nrf2 signalling pathway, which may be involved in the pathogenesis of TDI-induced OA. Therefore, elucidating these observations further should help to develop the therapeutic strategies of diisocyanate-induced OA.

Topics: Active Transport, Cell Nucleus; Adult; Apoferritins; Asthma; Catalase; Cell Line; Cell Nucleus; Chemical Industry; Female; Gene Expression Regulation; Glutathione Peroxidase; Heme Oxygenase-1; Humans; Hypoglycemic Agents; Immunologic Factors; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinase Kinases; NF-E2-Related Factor 2; Occupational Exposure; Peroxiredoxins; PPAR gamma; Prostaglandin D2; Respiratory Mucosa; Rosiglitazone; Thiazolidinediones; Thioredoxins; Toluene 2,4-Diisocyanate; Transferrin

Asthma is characterized by a predominant T(H)2 type immune response to airborne allergens. Controlling T(H)2 cell function has been proposed as therapy for this disease. We show here that ligands for the nuclear receptor peroxisome proliferator activated receptor (PPAR)gamma significantly reduced the immunological symptoms of allergic asthma in a murine model of this disease. A PPARgamma ligand, 15-deoxy-delta(12,14)-prostaglandin J(2), significantly inhibited production of the T(H)2 type cytokine IL-5 from T cells activated in vitro. More importantly, in a murine model of allergic asthma, mice treated orally with ciglitazone, a potent synthetic PPARgamma ligand, had significantly reduced lung inflammation and mucous production following induction of allergic asthma. T cells from these ciglitazone treated mice also produced less IFNgamma, IL-4, and IL-2 upon rechallenge in vitro with the model allergen. Our results suggest that ligands for PPARgamma may be effective treatments for asthmatic patients.

Topics: Administration, Oral; Animals; Antigen-Antibody Complex; Asthma; Cells, Cultured; Cytokines; Female; Interleukin-5; Ligands; Lymph Nodes; Male; Mice; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Reference Values; Spleen; T-Lymphocytes; Th2 Cells; Thiazolidinediones; Transcription Factors; Treatment Outcome

Topics: Animals; Anti-Inflammatory Agents; Asthma; Humans; Immunologic Factors; Mice; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Respiratory System; Transcription Factors