1 The aim of the present study was to investigate the e ects of bradykinin and [des-Arg 9 ]-bradykinin and their relaxant mechanisms in the mouse isolated trachea. 2 In the resting tracheal preparations with intact epithelium, bradykinin and [des-Arg 9 ]-bradykinin (each drug, 0.01 ± 10 mM) induced neither contraction nor relaxation. In contrast, bradykinin (0.01 ± 10 mM) induced concentration-dependent relaxation when the tracheal preparations were precontracted with methacholine (1 mM). 5 Prostaglandin E 2 (PGE 2 , 0.01 ± 33 mM) caused concentration-dependent relaxation of the tracheal preparations precontracted with methacholine. Indomethacin (1 mM) and ODQ (10 mM) exerted no inhibitory e ects on the relaxation induced by PGE 2 . 6 The NO-donor, sodium nitroprusside (SNP; 0.01 ± 100 mM) also caused concentration-dependent relaxation of the tracheal preparations precontracted with methacholine. ODQ (0.1 ± 1 mM) concentration-dependently inhibited the relaxation induced by SNP. 7 These data demonstrate that bradykinin and [des-Arg 9 ]-bradykinin relax the mouse trachea precontracted with methacholine by the activation of bradykinin B 2 -receptors and B 1 -receptors, respectively. The stimulation of bradykinin receptors induces activation of the cyclo-oxygenase pathway, leading to the production of relaxing prostaglandins. The NO pathway is not involved in the bradykinininduced relaxation. The relaxation caused by NO-donors in the mouse trachea is likely to be mediated via activation of soluble guanylate cyclase.

A murine model of food allergy based on sensitization via epicutaneous exposure to allergen without immunostimulatory adjuvants was developed. Effective production of MMCP-1 together with specific IgE and IgG1 suggests a breakdown in oral tolerance to the allergen. Intragastric challenges were accompanied by mast cell-dependent immunopathological changes and diarrhea.

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The low densities of secretin and CCK cells in IBS-diarrhea patients may cause a functional pancreatic insufficiency as well as inadequate gall emptying, as these hormones stimulate pancreatic bicarbonate and enzyme secretion and CCK stimulates as well gall bladder contraction. Low densities of secretin, GIP, and somatostatin cells in IBS patients might result in a high secretion of gastric acid, as secretin, GIP, and somatostatin inhibit gastric acid secretion.

Inflammasomes are intracellular protein platforms, which, upon activation, produce the highly proinflammatory cytokines interleukin (IL)-1β and IL-18. Heme, hemin and their degradation products possess significant immunomodulatory functions. Here, we studied whether hemin regulates inflammasome function in macrophages. Both hemin and its derivative, cobalt protoporphyrin (CoPP), significantly reduced IL-1β secretion by cultured human primary macrophages, the human monocytic leukemia cell line and also mouse bone marrow-derived and peritoneal macrophages. Intraperitoneal administration of CoPP to mice prior to urate crystal-induced peritonitis alleviated IL-1β secretion to the peritoneal cavity. In cultured macrophages, hemin and CoPP inhibited NLRP3 inflammasome assembly by reducing the amount of intracellular apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). The reduction of ASC was associated with enhanced autophagosome formation and autophagic flux. Inhibition of autophagy prevented the CoPP-induced depletion of ASC, implying that the depletion was caused by increased autophagy. Our data indicate that hemin functions as an endogenous negative regulator of the NLRP3 inflammasome. The inhibition is mediated via enhanced autophagy that results in increased degradation of ASC. This regulatory mechanism may provide a novel approach for the treatment of inflammasome-related diseases.