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 up-regulation of renal cAMP levels.