Abstract
Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor β (TGFβ), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1+ cells. The interleukin-1β (IL-1β) levels were increased in the subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-α (TNF-α), IL-10, and IL-4 mRNA expression were increased in the kidney of BSA-challenged post-septic mice, and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult such as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.
Highlights
Sepsis is a life-threatening condition caused by a systemic inflammatory response to infection, resulting in multisystem organ failure and death [1]
By considering that inflammation is one of the major components of organ dysfunctions in sepsis, we previously investigated whether a second-hit challenge exacerbates inflammation and tissue injury using a subclinical acute kidney injury model
Based on our previous data, sepsis-surviving mice already presented tubulointerstitial injury at days 7 and 14, which was aggravated after bovine serum albumin (BSA) challenge [16]
Summary
Sepsis is a life-threatening condition caused by a systemic inflammatory response to infection, resulting in multisystem organ failure and death [1]. This cytokine storm induces endothelial and microvascular dysfunction, tissue damage, and apoptosis, being closely associated with multiple organ failure [2]. Prevention, early recognition of at-risk patients, and efficient supportive care have all contributed to a decline in short-term mortality among septic patients [3,4,5,6]; long-term adverse outcomes are still evident after sepsis with impaired immune response in vital organs [7,8]. One in five sepsis survivors is rehospitalized due to infections or other acquired comorbidities [9]. In this regard, acute kidney injury (AKI) is reported in 50% of sepsis patients with an ICU mortality rate of
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