RESUMO
OBJECTIVE AND DESIGN: This work explored the role of inhibition of cyclooxygenases (COXs) in modulating the inflammatory response triggered by acute kidney injury. MATERIAL: C57Bl/6 mice were used. TREATMENT: Animals were treated or not with indomethacin (IMT) prior to injury (days -1 and 0). METHODS: Animals were subjected to 45 min of renal pedicle occlusion and sacrificed at 24 h after reperfusion. Serum creatinine and blood urea nitrogen, reactive oxygen species (ROS), kidney myeloperoxidase (MPO) activity, and prostaglandin E2 (PGE(2)) levels were analyzed. Tumor necrosis factor (TNF)-alpha, t-bet, interleukin (IL)-10, IL-1beta, heme oxygenase (HO)-1, and prostaglandin E synthase (PGES) messenger RNA (mRNA) were studied. Cytokines were quantified in serum. RESULTS: IMT-treated animals presented better renal function with less acute tubular necrosis and reduced ROS and MPO production. Moreover, the treatment was associated with lower expression of TNF-alpha, PGE(2), PGES, and t-bet and upregulation of HO-1 and IL-10. This profile was mirrored in serum, where inhibition of COXs significantly decreased interferon (IFN)-gamma, TNF-alpha, and IL-12 p70 and upregulated IL-10. CONCLUSIONS: COXs seem to play an important role in renal ischemia and reperfusion injury, involving the secretion of pro-inflammatory cytokines, activation of neutrophils, and ROS production. Inhibition of COX pathway is intrinsically involved with cytoprotection.
Assuntos
Injúria Renal Aguda/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Indometacina/farmacologia , Inflamação/metabolismo , Animais , Citocinas/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interleucina-10/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismoRESUMO
BACKGROUND: Chronic heart failure (CHF) has a high morbidity and mortality. Chronic kidney disease (CKD) has consistently been found to be an independent risk factor for unfavorable cardiovascular (CV) outcomes. Early intervention on CKD reduces the progression of CHF, hospitalizations and mortality, yet there are very few studies about CKD as a risk factor in the early stages of CHF. The aims of our study were to assess the prevalence and the prognostic importance of CKD in patients with systolic CHF stages B and C. METHODS: This is a prospective cohort study, dealing with prognostic markers for CV endpoints in patients with systolic CHF (ejection fraction Assuntos
Assistência Ambulatorial
, Insuficiência Cardíaca/etiologia
, Insuficiência Cardíaca/terapia
, Falência Renal Crônica/complicações
, Falência Renal Crônica/terapia
, Idoso
, Assistência Ambulatorial/tendências
, Estudos de Coortes
, Feminino
, Seguimentos
, Insuficiência Cardíaca/mortalidade
, Humanos
, Falência Renal Crônica/mortalidade
, Masculino
, Pessoa de Meia-Idade
, Estudos Prospectivos
, Fatores de Risco
, Resultado do Tratamento
RESUMO
Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients. Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Furthermore, blockade of COX 1 and 2 has been associated with organ improvement after ischemic damage. The aim of this study was to evaluate the role of COX 1 and 2 in the development of fibrosis by performing a COX 1 and 2 blockade immediately before IRI. We subjected C57Bl/6 male mice to 60 min of unilateral renal pedicle occlusion. Prior to surgery mice were either treated with indomethacin (IMT) at days -1 and 0 or were untreated. Blood and kidney samples were collected 6 wks after IRI. Kidney samples were analyzed by real-time reverse transcription-polymerase chain reaction for expression of transforming growth factor beta (TGF-beta), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, IL-10, heme oxygenase 1 (HO-1), vimentin, connective-tissue growth factor (CTGF), collagen I, and bone morphogenic protein 7 (BMP-7). To assess tissue fibrosis we performed morphometric analyses and Sirius red staining. We also performed immunohistochemical analysis of anti-actin smooth muscle. Renal function did not significantly differ between groups. Animals pretreated with IMT showed significantly less interstitial fibrosis than nontreated animals. Gene transcript analyses showed decreased expression of TGF-beta, MCP-1, TNF-alpha, IL-1-beta, vimentin, collagen I, CTGF, and IL-10 mRNA (all P < 0.05). Moreover, HO-1 mRNA was increased in animals pretreated with IMT (P < 0.05). Conversely, IMT treatment decreased osteopontin expression and enhanced BMP-7 expression, although these levels did not reach statistical significance when compared with control expression levels. The blockade of COX 1 and 2 resulted in less tissue fibrosis, which was associated with a decrease in proinflammatory cytokines and enhancement of the protective cellular response.
Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Rim/irrigação sanguínea , Rim/patologia , Traumatismo por Reperfusão/metabolismo , Animais , Proteína Morfogenética Óssea 7/genética , Quimiocina CCL2/genética , Colágeno Tipo I/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Fibrose , Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Imuno-Histoquímica , Indometacina/farmacologia , Interleucina-10/genética , Interleucina-1beta/genética , Rim/metabolismo , Testes de Função Renal , Masculino , Camundongos , Osteopontina/genética , Traumatismo por Reperfusão/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/genética , Vimentina/genéticaRESUMO
Ischemia-reperfusion injury (IRI) is a common event in organ transplantation, being implicated as a potential contributor for the development of chronic allograft nephropathy. There are new evidences showing a tissue inflammatory response following renal IRI. Cyclooxygenases (COX) 1 and 2 can be detected in tissue submitted to IRI and may have impact on organ function outcome. We evaluated the role of COX inhibition on the renal tissue damage that follows IRI. Mice were submitted to 45 min of renal pedicle ligature and allowed to reperfuse for 24, 48, 72 and 120 h. Blood and kidney samples were collected at reperfusion times. mRNA was extracted from the kidney samples to amplify COX-1, COX-2 and beta-actin genes. Animals were pretreated with indomethacin or rofecoxib before the surgery. Indomethacin treatment induced a better renal function (serum urea) when compared to control animals at 24, 48 and 72 h (219+/-54.5 vs. 338+/-51 mg/dl; 106+/-51 vs. 326+/-86 mg/dl; 94+/-14 vs. 138+/-38 mg/dl, respectively). Surprisingly, rofecoxib use was associated with even better renal improvement following IR. Animals treated with the later drug showed lower urea values at 24 h post reperfusion compared to indomethacin-treated animals (128+/-33 vs. 219+/-54.5 mg/dl, P<0.05). Blockade of COX-1 and -2 resulted in a decrease of tubular necrosis. mRNA COX-2 was up-regulated post IRI and considerable inhibited after indomethacin or rofecoxib treatment. Our data show COX-1/-2 participates in the inflammatory tissue response to IR injury and its inhibition is associated with an improvement in renal function.