Is there a therapeutic window for pentoxifylline after the onset of acute pancreatitis?

Abstract

PURPOSE:To investigate the effects of pentoxifylline (PTX) in experimental acute pancreatitis (AP) starting drug administration after the induction of the disease. METHODS: One hundred male Wistar rats were submitted to taurocholate-induced AP and divided into three groups: Group Sham: sham-operated rats, Group Saline: AP plus saline solution, and Group PTX: AP plus PTX. Saline solution and PTX were administered 1 hour after induction of AP. At 3 hours after AP induction, peritoneal levels of tumor necrosis factor (TNF)-α, and serum levels of interleukin (IL)-6 and IL-10 levels were assayed by Enzyme-Linked Immunosorbent Assay (ELISA). Determinations of lung myeloperoxidase activity (MPO), histological analysis of lung and pancreas, and mortality study were performed. RESULTS: PTX administration 1 hour after induction of AP caused a significant decrease in peritoneal levels of TNF-α and in serum levels of IL-6 and IL-10 when compared to the saline group. There were no differences in lung MPO activity between the two groups with AP. A decrease in mortality was observed in the PTX treatment compared to the saline group. CONCLUSIONS: Administration of PTX after the onset of AP decreased the systemic levels of proinflammatory cytokines, raising the possibility that there is an early therapeutic window for PTX after the initiation of AP. Key words: Acute Pancreatitis; Pentoxifylline; Inflammation; Cytokines; Systemic Inflammatory Response RESUMO OBJETIVO: Investigar os efeitos da pentoxifilina (PTX) na pancreatite aguda (PA) experimental administrando a droga após a indução da doença. MÉTODOS: Cem ratos machos Wistar foram submetidos à indução da PA através da infusão de taurocolato de sódio e divididos em três grupos: Grupo Sham: sham-operated ratos, Grupo Salina: AP e solução salina, e Grupo PTX: AP e PTX. Solução salina e PTX foram administradas 1 hora após a indução da PA. Três horas após indução da PA os níveis de fator de necrose tumoral (TNF)-α no líquido peritoneal e os níveis séricos de interleucina (IL)-6 e IL-10 foram analisados pelo método de Enzima Imunoensaio (ELISA). A atividade da mieloperoxidase (MPO) foi analisada no pulmão e foram realizadas análises histológicas do pulmão e pâncreas, além do estudo da mortalidade. RESULTADOS: A administração de PTX 1 hora após a indução da PA reduziu significativamente os níveis de TNF-α peritoneal e os níveis séricos de IL-6 e IL-10 quando comparado ao grupo salina. Redução na mortalidade foi observado após o tratamento com PTX comparado ao grupo salina. CONCLUSÃO: A administração de PTX após a indução da PA diminuiu os níveis sistêmicos de citocinas pró-inflamatórias, sugerindo a possibilidade de que existe uma janela terapêutica para PTX após o início do PA.

Pentoxifylline decreases glycemia levels and TNF-alpha, iNOS and COX-2 expressions in diabetic rat pancreas

“…Evidences (Coelho et al 2012) indicate that the administration of PTX, after the onset of acute pancreatitis, decreased levels of pro-inflammatory cytokines.Other studies have shown that PTX exerts a protective effect in animal models of diabetes (Stosic-Grujicic et al 2001a; Stosic-Grujicic et al 2001b). These authors showed that the administration of PTX to diabetic animals reduced the production of inflammatory mediators and prevented the development of hyperglycemia.…”

Apigenin Exerts Anti-inflammatory Effects in an Experimental Model of Acute Pancreatitis by Down-regulating TNF-α

“…TNF-α, IL-1, IL-6, IL-8, PAF) and anti-inflammatory cytokines (i.e.IL-2, IL-10, IL-11) (13,37,38). In the evolution of acute pancreatitis TNF-α plays a prominent role (14,39). TNF-α has long been considered one of the initial triggers of the inflammatory cascade since it stimulates synthesis and release of multiple cytokines (40,41).…”

“…These events lead to additional pro-and antiinflammatory cytokine production via transcriptional factors like NF-ĸB, and their release (13). This cytokine release not only increases capillary permeability in the pancreatic microcirculation, but also provokes pancreatic necrosis due to thrombosis and haemorrhage within the pancreatic tissue (14,15). In turn, local and systemic hyper-production of proinflammatory cytokines like, tumor necrosis factor alpha (TNF-α), interleukins, nitric oxide, complement system components, platelet activating factor, free radicals and other macrophage and neutrophil secretory products takes place (16).…”

Effects of intravenous administration of pentoxifylline in pancreatic ischaemia–reperfusion injury

“…have demonstrated that the use of pentoxifylline reduces I–R injury in the liver and contributes to hepatic cytoprotection by increasing and decreasing, respectively, liver tissue levels of prostaglandin E2 and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). Recently, pentoxifylline has been shown to be able to attenuate local and systemic inflammatory responses, as well as reduce pancreatic infection and mortality rates in experimental acute pancreatitis …”