Roflumilast improves resolution of sepsis‐induced acute kidney injury by retarding late phase renal interstitial immune cells infiltration and leakage in urinary sediments

Abstract

Some evidence has demonstrated that both inflammation and immune cell dysregulation are coincident at late phase (post 24 h) of sepsis. The present study was designed to determine the pathological role of hyperinflammation and renal immune cells mobilization during late phase of sepsis induced acute kidney injury (S-AKI) and tests the pharmacological effects of PDE-4 inhibitor on these events. Sepsis was induced by cecal ligation puncture and renal function, oxidative-inflammatory stress biomarkers were assessed after 24 h. PDE-4 inhibitor was administered for 7 days prior to induction of S-AKI. Renal immune cells infiltration during sepsis was analyzed by H&E staining and papanicolaou staining method was used for detecting leukocytes and cast in urinary sediments, periodic acid schiff (PAS) staining was used for detection of brush border loss. AKI developed 24 h post sepsis insult as depicted by increase in serum creatinine, blood urea nitrogen (BUN), renal oxidative stress, and elevated inflammatory biomarkers levels. Moreover, septic rats displayed increased bacterial load, renal expression of phosphodiesterase-4B, 4D isoforms, enhanced vascular permeability, caspase-3 and myeloperoxidase activity, electrolyte imbalance, reduced Na + K + ATPase activity, declined cAMP levels, increased interstitial leukocyte infiltration, and leakage in urinary sediments along with histological alterations. Pre-treatment with roflumilast at high dose completely prevented the various AKI associated manifestations in septic rats. Renal hyper-inflammation and leukocyte infiltration was detected in late phase of S-AKI. Roflumilast pre-treatment resolved sepsis induced renal dysfunction and histological damage by suppressing late phase renal immune cells invasion and anti-inflammatory effects mediated by upregulation of renal cAMP levels.

Angiotensin aldosterone inhibitors improve survival and ameliorate kidney injury induced by sepsis through suppression of inflammation and apoptosis

“…The treated groups showed restoration of kidney function evident in a reduction in serum cys-c and a lower creatinine level in ramipril-treated group. In CLPtreated rats, marked and variable degrees of restoration of normal renal architecture was observed consistent with previous studies showing the effect of nephroprotective agents in sepsis [36].…”

Pathological role of the calcium‐sensing receptor in sepsis‐induced hypotensive shock: Therapeutic possibilities and unanswered questions

“…Wu et al (2015) carried out an experimental study in cecal ligation induced sepsis rat model to demonstrate the role of CaSR in promoting the cytokine release and T lymphocyte apoptosis. The cecal ligation and puncture (CLP) is a widely used sepsis model, which represents the features of human sepsis such as hypothermia, tachycardia, tachypnoea, and hypotensive shock (Gupta et al, 2022). In this study, the administration of calcimimetic NPS R‐568 enhanced CaSR expression on T cells, induced their apoptosis, increased vulnerability to tissue injury, and stimulated the production of TNF‐α and IL‐4 cytokines.…”

“…The functions of the vascular endothelial cells, including vasoregulation and maintenance of homeostasis, are compromised during sepsis, resulting in reduced perfusion and multiorgan failure (Gupta et al, 2022; Shankar‐Hari et al, 2016). Glycocalyx, an essential constituent of endothelial cell lining, apparently breaks down during sepsis due to release of various mediators, including hydrogen peroxide and superoxide, heparanase, and TNF‐α (Beurskens et al, 2020; Ince et al, 2016; Schmidt et al, 2012).…”

“…Wu et al (2015) carried out an experimental study in cecal ligation induced sepsis rat model to demonstrate the role of CaSR in promoting the cytokine release and T lymphocyte apoptosis. The cecal ligation and puncture (CLP) is a widely used sepsis model, which represents the features of human sepsis such as hypothermia, tachycardia, tachypnoea, and hypotensive shock (Gupta et al, 2022).…”