Mast cell stabilization with ketotifen decreases il-13 and cgrp in the ascitic fluid of rats with microsurgical cholestasis

Ascites is one of the most severe complications of cirrhosis with portal hypertension. Since mast cells by type 2 immunity could be involved in the production of portal hypertensive ascites, we are studying the effectiveness of Ketotifen administration, a mast cell stabilizer, to modulate the production of interleukin-13, a type-2 associated cytokine, as well as calcitonin gene-related peptide (CGRP), one important regulator of its production, in the ascitic fluid of microsurgical extrahepatic cholestatic rats. The increased IL-13 and CGRP release in the ascitic fluid of the rats with obstructive cholestasis and its significant reduction after both, prophylactic plus therapeutic and delayed therapeutic oral administration of Ketotifen, allows for proposing that mast cells could play an important role in the etiopathogeny of portal hypertensive ascites

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Airway fibroblasts in asthma manifest an invasive phenotype.

RATIONALE: Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-ß1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-ß1 and MMPs. OBJECTIVES: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-ß1 and MMPs in asthma compared with normal controls. METHODS: Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-ß1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels. MEASUREMENTS AND MAIN RESULTS: IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-ß1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects. CONCLUSIONS: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-ß1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.

IL-13 receptor isoforms: breaking through the complexity.

Interleukin (IL)-13 is an immunoregulatory cytokine secreted predominantly by activated T-helper type 2 (Th2) cells, and it has been identified as crucial in developing allergic inflammatory responses. Its diverse functions are mediated by a complex receptor system including IL-4 receptor alpha (IL-4Ralpha; CD124) and two other cognate cell surface proteins, IL-13Ralpha1 (CD213a1) and IL-13Ralpha2 (CD213a2). IL-13Ralpha1 forms a heterodimer with IL-4Ralpha that is a signaling IL-13 receptor. In contrast, IL-13Ralpha2 has been thought to be a decoy receptor due to its short cytoplasmic tail. IL-13Ralpha2 exists on the cell membrane, intracellularly, and in soluble form. Recent reports revealed that membrane IL-13Ralpha2 may have some signaling capabilities, and soluble IL-13Ralpha2 is a critical endogenous modulator for IL-13 responses. The receptor has more complicated functions than a simple decoy receptor. In this review, we describe the isoforms of IL-13Ralpha2 and discuss newly revealed functions of IL-13Ralpha2.

Increased hyperoxia-induced mortality and acute lung injury in IL-13 null mice.

IL-13 is a critical effector at sites of Th2 inflammation and remodeling. As a result, anti-IL-13-based therapies are being actively developed to treat a variety of diseases and disorders. However, the beneficial effects of endogenous IL-13 in the normal and diseased lung have not been adequately defined. We hypothesized that endogenous IL-13 is an important regulator of oxidant-induced lung injury and inflammation. To test this hypothesis, we compared the effects of 100% O(2) in mice with wild-type and null IL-13 loci. In this study, we demonstrate that hyperoxia significantly augments the expression of the components of the IL-13R, IL-13Ralpha1, and IL-4Ralpha. We also demonstrate that, in the absence of IL-13, hyperoxia-induced tissue inflammation is decreased. In contrast, in the IL-13 null mice, DNA injury, cell death, caspase expression, and activation and mortality are augmented. Interestingly, the levels of the cytoprotective cytokines vascular endothelial cell growth factor, IL-6, and IL-11 were decreased in the bronchoalveolar lavage fluid. These studies demonstrate that the expression of the IL-13R is augmented and that the endogenous IL-13-IL-13R pathway contributes to the induction of inflammation and the inhibition of injury in hyperoxic acute lung injury.