bq-123 and Pneumonia

The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Colitis; Endothelin A Receptor Antagonists; Granulocytes; Inflammation; Mice; Mice, Inbred BALB C; Myeloid-Derived Suppressor Cells; Peptides, Cyclic; Pneumonia; T-Lymphocytes

The participation of endothelins (ETs) in a model of neutrophil-dependent lung injury induced by intrabronchial instillation of rabbit antibodies to ovalbumin followed by i.v. injection of the antigens (Arthus reaction) was investigated. Hemorrhagic lesions were evaluated by measuring the extravasations of hemoglobin in lung parenchyma. From 5 min to 24 h after the Arthus reaction (AR), endothelin (ir-ET) levels in bronchoalveolar lavage fluid (BALF) and in plasma were measured by radioimmunoassay. BALF levels of ir-ET were not different between control and AR animals for the first 90 min after the antigen challenge but increased from 2 to 24 h after induction of AR. ET levels in the plasma did not change from the respective controls over the same 24 h period. Increased ir-ET in BALF was not affected by pretreatment with L-NAME (30 mg/kg, i.v.). A PAF antagonist (BN52021; 5 and 10 mg/kg, i.v.) increased ET content in BALF and decreased the intensity of the AR. Thiorphan (2 mg/kg, i.v.) inhibited the AR-induced hemorrhagic lesions in lungs. An ET(A) receptor antagonist, BQ-123 (1 mg/kg, i.v.) potentiated, whereas the ET(B) antagonist, BQ-788 (1 mg/kg, i.v.) inhibited the lung hemorrhage. It is concluded that ETs are released during and play a role in the lung AR.

Topics: Animals; Antigen-Antibody Complex; Arthus Reaction; Bronchoalveolar Lavage Fluid; Diterpenes; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelins; Fibrinolytic Agents; Ginkgolides; Hemoglobins; Hemorrhage; Lactones; Lung Diseases; Male; Neutrophils; Oligopeptides; Ovalbumin; Peptides, Cyclic; Piperidines; Pneumonia; Rats; Rats, Wistar

In this study, we have examined the effect of endothelin (ET) receptor antagonists on lung granulocyte inflammation after antigen challenge in sensitized mice. The antagonists used were BQ-123, an ETA antagonist, BQ-788, an ETB antagonist, and SB209670, an ET(A&B) antagonist. Thirty minutes prior exposure to aerosolized ovalbumin, ET antagonists (50 pmol/mouse) were administered directly into the lungs of sensitized Balb/c mice via the intranasal route. BQ-123 and SB209670 significantly decreased eosinophil number in the bronchoalveolar lavage fluid by 47 and 68%, respectively. Both compounds also inhibited neutrophil infiltration into the lungs. In contrast, BQ-788 did not affect granulocyte infiltration. A similar inhibition of lung eosinophilia was also obtained with an anti-ET antibody applied via the intranasal route. BQ-123 and SB209670, but not BQ-788, significantly increased the production of interferon-gamma (Th1 cytokine) from purified lung Thy1.2+ cells without affecting interleukin-4 and interleukin-5 (Th2 cytokines) secretion. Furthermore, neutralizing antibody against interferon-gamma prevented the inhibitory effect of the ETA antagonist. Taken together, these results suggest an important pathophysiologic role for ET in the development of lung inflammation in asthma and highlight the potential of ET antagonists for the treatment of the disease.

Topics: Administration, Intranasal; Aerosols; Animals; Antibodies, Monoclonal; Antigens; Bronchoalveolar Lavage Fluid; Cell Movement; Endothelin Receptor Antagonists; Endothelins; Granulocytes; Interferon-gamma; Interleukin-4; Interleukin-5; Lung; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Ovalbumin; Peptides, Cyclic; Piperidines; Pneumonia