The effects of specıfıc and non-specıfıc phosphodıesterase ınhıbıtors and n-acetylcysteıne on oxıdatıve stress and remote organ ınjury ın two hıt trauma model

Abstract

BACKGROUND: Sepsis is a systemic inflammatory response to infection and is one of the leading causes of morbidity and mortality. The second hit after trauma causes increased inflammatory response and multiple organ failure (MOF). The infection which develops after burn injury is a suitable model for a two-hit trauma study. Sepsis causes the release of biochemical mediators, such as Free Oxygen Radicals (FORs), which may lead to lipid peroxidation, which may play a key role in multiple organ failure. In this study, we aimed to investigate the effects of phosphodiesterase (PDE) inhibitors (sildenafil, milrinone, pentoxifylline) and N-acetylcysteine (NAS) on oxidative stress and organ damage in two-hit models. METHODS: In this experimental study, peritonitis was created by cecal ligation and puncture (CLP) method in 40 rats, 72 hours after creating a 30% scalding injury. Rats were divided into five groups of eight rats each as follows: Group I: No treatment; Group II: 10/mg/ kg/day dosage of intraperitoneal (i.p) sildenafil treatment was applied for 72 hours after CLP; Group III: 1/mg/kg/day dosage of i.p milrinone treatment was applied for 72 hours after CLP; Group IV: 150/mg/kg/day dosage of i.p NAS treatment was applied for 72 hours after CLP; Group V: 50/mg/kg/day dosage of i.p pentoxifylline treatment was applied for 72 hours after CLP. All rats were sacrificed on the seventh day of this study. Malondialdehyde (MDA), Glutathione Peroxidase (GPx), Superoxide Dismutase (SOD), catalase, Tumor Necrotic Factor-alpha (TNF-α) levels, and tissue (lung, kidney) and serum samples were taken for histopathological study. RESULTS: When compared to the control group, the tissue damage score was found to be lower in all treatment groups. Sildenafil, milrinone and NAS groups had higher kidney GPx levels compared to the control group. Milrinone and pentoxifylline were higher in the lung tissue compared to the SOD control group. TNFα levels were lower in pentoxifylline and milrinone groups compared to the control group. CONCLUSION: This experimental study has shown that PDE inhibitors and NAS have a decreasing effect on oxidative stress and distant organ damage in the two-hit model. Further clinical and experimental studies are needed on this subject.

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

“…Olprinone also reduced the lung, liver, renal, and pancreatic injury, diminished lung and intestine MPO activity, immunohistochemical staining for nitrotyrosine, inducible NO synthase, PAR, TNFα and IL-1β in the tissue sections obtained from zymosaninjected mice, and prevented systemic toxicity, loss in body weight, and mortality [139]. In CLP-induced sepsis in rats, milrinone elevated antioxidant enzymes and reduced pathological score in the lung and kidney [68].…”

“…Pentoxifylline-suppressed production of pro-inflammatory cytokines in the intestine was observed in rats with LPS-induced sepsis, too [65]. Similarly, pentoxifylline decreased local and systemic inflammation, reduced mortality [66,67] and increased levels of antioxidant enzymes in the lung and kidney [68] in rat models of LPS-induced endotoxemia or cecal ligation and puncture (CLP)-induced sepsis, respectively. Favorable effects of pentoxifylline were also demonstrated in models of direct ALI where pentoxifylline prevented an increase in TNFα, protein concentration, and counts of alveolar macrophages in BALF in meconium-injured piglets [69], and reduced histological signs of lung injury and inflammation, diminished oxidative stress, and upregulated markers of wound repair in nitrogen mustard-induced rat model of ALI [70].…”

Agentes inibidores da fosfodiesterase no tratamento da sepse e choque séptico

“…Nesse modelo, os animais são submetidos a um trauma inicial, geralmente uma queimadura de terceiro grau por contato com água em temperatura próxima a 100°C. Posteriormente, o segundo trauma é estabelecido por CLP ou injeção de LPS, gerando a uma resposta inflamatória sistêmica exagerada com maior chance de desenvolver falência múltipla de órgãos (Özer, Topal & Sem, 2020;Paterson et al, 2003).…”

“…A pentoxifilina, por outro lado, em um estudo mais recente mostrou diminuir os scores de dano tecidual por meio da histopatologia do pulmão e rim de ratos submetidos a um modelo de "two-hit trauma" (Özer, Topal & Sem, 2020). Nos estudos pré-clínicos, a aminofilina demonstra diminuir a pressão arterial média (PAM) dos animais, o que pode ser prejudicial em situações de sepse, em que a hipotensão já é um efeito presente.…”

“…Os iPDE-3, como amrinona, milrinona e oprinona e inibidores inespecíficos, como a pentoxifilina e teofilina, foram pioneiros nas pesquisas préclínicas e clínicas do manejo da sepse (Németh et al, 1997;Schimidt et al, 2000a;Miyakawa et al, 2004). Nos últimos anos, foram realizados estudos em modelos animais com o inibidor da PDE-5 sildenafil (Kovalski et al, 2017;Özer, Topal & Sem, 2020) e iPDE-4 como rolipram e roflumilaste (Sims et al, 2017;Lu et al, 2020;Xu et al, 2020). Devido as recentes descobertas, e visto que a sepse e o choque representam um problema de saúde de alta incidência e difícil manejo, o objetivo desse trabalho foi relatar o uso de inibidores da fosfodiesterase nas condições de sepse observando as metodologias empregas, desfechos dos estudos e perspectivas futuras.…”