Soluble guanylyl cyclase is reduced in airway smooth muscle cells from a murine model of allergic asthma 英文参考文献.docVIP

ORIGINALARTICLE SolubleGuanylylCyclaseIsReducedinAirwaySmooth MuscleCellsFromaMurineModelofAllergicAsthma FabiolaPlaceres-Uray,PhD,RamonaGonza′lez deAlfonzo,PhD, ItalaLippodeBecemberg,MD,PhD,andMarceloJ.Alfonzo,MD,PhD reactivity.Theseelementstogetherareresponsibleforrevers- Abstract:Airwayremodelingplaysanimportantroleinthedevel- ibleobstructionoftheairwaysandtheclinicalexpressionof opmentofairwayhyperresponsivenessinasthma.Muscarinicago- asthma. 1–3 nistssuchascarbamylcholineincreasedcyclicGMP(cGMP)levels in bovine tracheal smooth muscle strips, via stimulation of NO- sensitive soluble guanylylcyclase (NO-sGC), which is an enzyme highlyexpressedinthelungs.cGMPproduction,byactivationofa NO-sGC, may contribute to airway smooth muscle relaxation. To determine whether the bronchoconstriction observed in asthma is accompanied by changes in this NO-sGC activity, we used a well-established murine model, ovalbumin-airway smooth muscle cells(OVA-ASMCs)ofallergicasthmatoevaluatesuchhypothesis. Histologic studies of trachea specimens showed the existence of in?ammation,hyperplasiaandtissueremodelinginOVA-ASMCs. Interestingly,culturedOVA-ASMCsshowedlowerGCbasalactiv- ity than CONTROL-ASMCs. Also, we found that both OVA- ASMCs and CONTROL cells exposed to carbamylcholine and sodium nitroprusside and combinations of both drugs increased cGMP levels, which were inhibited by 1H-[1,2,4]oxadiazolo[4,3-] quinoxalin-1-one.AlltheexperimentalevidencesuggeststhatNO-sGC activity is reduced in isolated ASMCss from experimental asthma murinemodel. This chronic in?ammatory process leads to structural changes in the bronchial wall, involving hypertrophy and hyperplasiaofsmoothmusclecellsofairways(ASMCs) 2–5 as describedabove.TheroleofASMCsinairwayremodelingis supportedbyincreasedmusclemassinthebronchialtree.In thisregard,therehavebeennumerousmorphometricstudies totestsuchanincreaseinmusclemassandtotrytoestablish thepathophysiologicmechanism,eitherhyperplasia(increase in cell number) or hy