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Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β. In the current study, we examine the contribution of TGF-β activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-β expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFβRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-β activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-β.

Aiitract Some new pyridazinone derivatives(3) were synthesized through addition of antipyrin to 8aroylacrylic acids (1)followcdbycyclization of the adducts. Reactions of 3 with ethyl bromoaetak, benzenesulfonyl chloride, benzoyl chloride and POCI, give N-substituted products and monochlorosubstituted pyridazines (4). respectively. The reactions of the latter with thiourea give unexpected dithio-derivativesq5). which react with phenylhydrazine to give pyrazolopyridazino pyridazine derivatives (6).Reactions of 2 with NH,OH in ethanol and pyridine afford oxime and oxazinone derivatives 7 and 8, respectively. The antibacterial activities of several compounds were screened.Recent publications'-* dealing with the synthesis and antibacterial screening of PYridainones revealed that some of these compounds exhibited activities against gram positive and gram negative bacteria, yeast and fungi. This prompted us to synthesize a new series of pyridazinones to screen their antibacterial activities. The syntheses of various compounds (2-8) are outlined in Scheme 1. Thus, the reaction of 4-ChlOrO or 2,4-dimethyl p-benzoylacrylic acids (la and lb), with antipyrin gave /3-aroyl-a-(4-antipyrinyl)-propionic acids (2a and 2b) respectively.Reactions of the acids (2a, 2b) with hydrazine hydrate or phenylhydrazine yielded 6-aryl-4-(4'-antipyrinyl)-2,3,4,5-tetrahydropyridazin-3-ones (3a, 3b) and the 2,6-diaryl4(4'-anti-pyriny1)-2,3,4,5-tetrahydropyridazin-3-one(&). Reactions of 3a and 3b with ethyl bromoacetate, benzenesulfonyl chloride and benzoylchloride gave N-substituted products (3d-3g). Structure of 3e was further established by its reaction with benzylamine t o give amide 3b.On the previous papera it was reported that reactions of pyridazinone derivatives and POCI, gave chloropyridazine derivatives by substitution of the hydroxyl group of enol with chlorine. However, treatment of 3a and 3b with POCI, by substitution together with dehydrogenation gave 4a and 4b, respectively. The phenomenon of dehydrogenation is not strange since it has been obscrved in the reactions of pyridazhones with P , S , ' and Grignard reagents.5 Reaction of 4b with hydrazine hydrate and bemylamine in boiling ethanol gave the 4 3-substituted derivatives 4c and 4d, respectively. Surprisingly in reactions of 4a and 4b with thiourea to prepare thiuronium salt or monothio compounds, dithio compounds (5a and 5b) instead of the expected compounds were isolated as the sole products.The reactions possibly take place according to the mechanism described in Scheme 2.Alternatively, reactions of pyridazinone derivatives 3a and 3b with P,S, in dry xylene gives the same compounds 5a and 5b . rn, ArH + pyridazine proton), 2.38 (6H, s, 2 x CH,), 2.36 (6H, s, 2 x CH,) ppm. m/z: 404 Reaction of P,S, with 3a or 3b toform 5a or 5b A solution of 3a (0.01 mol, or 3b). Pas, (0.02 mol) and dry xylene (50 mL) was refluxed for 6 h. The reaction mixture was filtered while hot and concentrated. The crude product separated on cooling was crystallized from ethanol to give 50 (or 3).Reac...

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