Assuntos
Anti-Inflamatórios/síntese química , Compostos de Epóxi/síntese química , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Isoprostanos/síntese química , Fosfatidilcolinas/síntese química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Interleucina-12/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Isoprostanos/química , Isoprostanos/farmacologia , Estrutura Molecular , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacologiaRESUMO
Isoprostanes comprise a class of membrane lipid metabolites produced during oxidative stress, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. They are widely recognized to evoke a variety of biological responses in airway and pulmonary vascular smooth muscle, lymphatics, and innervation. However, their effects on airway epithelium are largely unstudied. We examined the electrophysiological responses evoked by several different isoprostane species in bovine airway epithelium using the Ussing chamber technique. The E-ring isoprostanes 15-E(1t)-IsoP and 15-E(2t)-IsoP evoked a substantial increase in short-circuit current (I(SC)), whereas four different F-ring isomers were ineffective. 15-E(2t)-IsoP-evoked I(SC) was mimicked by the prostaglandin E(2)-selective prostanoid receptor (EP)-agonist prostaglandin E(2) but not by agonists of EP(1)/EP(3)-, FP-, or TP receptors (sulprostone, fluprostenol, and U46619, respectively). This response was significantly reduced by the EP(4)-receptor blocker GW627386 but not by blockers of other prostanoid receptors (ICI 192,605 [TP-selective], SC19220 [EP(1)-selective], AH6809 [DP/EP(1)/EP(2)-selective], and AL8810 [FP-selective]). 15-E(2t)-IsoP-evoked I(SC) was reduced by blockers of Cl(-) channels (niflumic acid and 5-nitro-2-(3-phenylpropylamino)-benzoic acid), of Na(+)/K(+)/2Cl(-) co-transport (furosemide and bumetanide), of adenylate cyclase (MDL 12,330A), or of guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but not by blockers of Na(+) conductances (amiloride). We conclude that 15-E(2t)-IsoP activates a transepithelial Cl(-) conductance in bovine airway epithelium through an EP(4) receptor coupled to adenylate cyclase and soluble guanylate cyclase.
Assuntos
Canais de Cloreto/metabolismo , Isoprostanos/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptores de Prostaglandina E/metabolismo , Mucosa Respiratória/metabolismo , Traqueia/metabolismo , Animais , Bovinos , Agonistas dos Canais de Cloreto , Condutividade Elétrica , Potenciais Evocados/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Isoprostanos/síntese química , Isoprostanos/química , Lipídeos de Membrana/metabolismo , Músculo Liso Vascular/inervação , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Estresse Oxidativo/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E Subtipo EP4 , Mucosa Respiratória/inervação , Mucosa Respiratória/patologia , Técnicas de Cultura de Tecidos , Traqueia/inervação , Traqueia/patologiaRESUMO
A stereoselective Julia-Lythgoe olefination followed by an efficient 1,3-allylic transposition of the C-9 hydroxyl group of compound 13 has allowed the first total synthesis of J(2) isoprostane (1), a recently discovered member of the growing isoprostane family. This elusive compound opens up numerous new avenues for the molecular biology of cyclopentenone prostaglandins which are endowed of intriguing biological effects such as antitumor, antiinflammatory, and antiviral activities. In principle, our approach is flexible enough to allow an easy synthesis of other isoprostanes of the J family following the same methodology.
Assuntos
Isoprostanos/síntese química , Prostaglandina D2/análogos & derivados , Prostaglandina D2/síntese química , Indicadores e Reagentes , Isoprostanos/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A stereoselective Julia-Lythgoe olefination has allowed the first total synthesis of A(2) isoprostane (1), a recently discovered member of the growing isoprostane family. This elusive compound opens up numerous new avenues for the molecular biology of cyclopentenone prostaglandins, which are endowed of intriguing biological effects such as antitumor, antiinflammatory, and antiviral activities.