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Related Articles Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. Eur Respir J. 2007 May;29(5):834-60 Authors: An SS, Bai TR, Bates JH, Black JL, Brown RH, Brusasco V, Chitano P, Deng L, Dowell M, Eidelman DH, Fabry B, Fairbank NJ, Ford LE, Fredberg JJ, Gerthoffer WT, Gilbert SH, Gosens R, Gunst SJ, Halayko AJ, Ingram RH, Irvin CG, James AL, Janssen LJ, King GG, Knight DA, Lauzon AM, Lakser OJ, Ludwig MS, Lutchen KR, Maksym GN, Martin JG, Mauad T, McParland BE, Mijailovich SM, Mitchell HW, Mitchell RW, Mitzner W, Murphy TM, Paré PD, Pellegrino R, Sanderson MJ, Schellenberg RR, Seow CY, Silveira PS, Smith PG, Solway J, Stephens NL, Sterk PJ, Stewart AG, Tang DD, Tepper RS, Tran T, Wang L
Related Articles Chronic Asthma Induced Airway Remodeling is Prevented by the Toll-like Receptor 7/8 Ligand S28463. Am J Respir Crit Care Med. 2007 Mar 30; Authors: Camateros P, Tamaoka M, Hassan M, Marino R, Moisan J, Marion D, Guiot MC, Martin JG, Radzioch D RATIONALE: Allergic asthma is a heterogeneous disease whose pathology is a result of improper immune responses to innocuous antigens. We and others have previously shown that one of the Toll-like Receptor (TLR) 7/8 ligands, the synthetic compound S28463 (Resiquimod, R-848) is able to inhibit acute allergic asthma in mice. OBJECTIVES: Given that the efficiency of this pharmacological compound against the smooth muscle mass increase and goblet cell hyperplasia that are characteristic of chronic allergic asthma has not been previously assessed, we investigated the ability of this compound to prevent these aspects of chronic airway remodeling. METHODS: The impact of S28463 treatment was assessed in a Brown Norway rat model of chronic asthma by histological, morphometric and molecular techniques. MAIN RESULTS: We demonstrate that treatment with S28463 is able to prevent the development of goblet cell hyperplasia and increases in airway smooth muscle mass, and that this effect is at least partially mediated by inhibiting proliferation of goblet and smooth muscle cells, respectively. Furthermore, we show that the abrogation of airway remodeling is preceded by the inhibition of the inflammatory reaction normally occurring in response to allergen challenge in sensitized animals. This inhibition was associated with a reduction of both TH1 and TH2 cytokine protein expression in the lungs, demonstrating the potent anti-inflammatory effect of this pharmaceutical compound in the context of allergic reactions. CONCLUSION: Taken together, our results indicate great potential for the use of S28463 as an anti-inflammatory therapeutic agent for the management of chronic asthma.
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Related Articles Downregulation of a disintegrin and metalloproteinase 33 by IFN-gamma in human airway smooth muscle cells. J Allergy Clin Immunol. 2007 Jan;119(1):89-97 Authors: Ito I, Laporte JD, Fiset PO, Asai K, Yamauchi Y, Martin JG, Hamid Q BACKGROUND: A disintegrin and metalloproteinase 33 (ADAM33) has been identified as a susceptibility gene for asthma. ADAM33 is expressed in airway smooth muscle (ASM) cells and is suggested to play a role in the function of these cells. However, there is little information on the regulation of ADAM33. OBJECTIVE: To investigate whether ADAM33 is more highly expressed in ASM cells of patients with asthma than in those of normal subjects, and whether there is any inflammatory mediator (asthma-related cytokine/chemokine) that could modulate the expression of ADAM33 in ASM cells. METHOD: smRNA and protein expression of ADAM33 in bronchial biopsy specimens was investigated (in situ hybridization and immunohistochemistry). Effects of cytokines on expression of ADAM33 in cultured human ASM cells were evaluated by measuring mRNA (real-time RT-PCR) and protein (Western blotting). RESULTS: ADAM33 mRNA and protein in biopsied specimens were more highly expressed in ASM cells of patients with asthma than in cells of normal subjects. Cultured ASM cells expressed ADAM33 at both the mRNA and the protein levels. IFN-gamma reduced the mRNA expression dose-dependently and time-dependently, whereas IL-4 and IL-13 or chemokines did not affect the expression. The reduction by IFN-gamma was partially restored by U0126, inhibitor for mitogen-activated protein kinase kinase 1/2, suggesting a role for extracellular signal-regulated kinase pathway. Further studies using cycloheximide and actinomycin-D suggested that the downregulation was at the transcriptional level. CONCLUSION: The expression of ADAM33 by ASM cells is increased in patients with asthma, and its expression may be regulated by IFN-gamma. CLINICAL IMPLICATIONS: IFN-gamma might have a role in suppressing ADAM33 in ASM cells.
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