Pretreatment of carprofen impaired initiation of inflammatory- and overlapping resolution response and promoted cardiorenal syndrome in heart failure

Abstract

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used to control pain, inflammation, and limit the cardinal signs of injury in humans. However, prolonged use of NSAIDs increases the risk of heart attack (myocardial infarction; MI) and the subsequent risk of heart and renal failure. The molecular and cellular mechanism of action for this adverse effect, particularly along the cardiorenal network, is incomplete. To define the mechanism, carprofen (CAP), an NSAID was administered at the dose of 5 mg/kg to C57BL/6 male mice for two weeks. After last dose of CAP treatment mice were subjected to permanent occlusion of coronary artery that induces irreversible cardiac remodeling while maintaining naive and MI-controls. After MI, cardiac pathology and dysfunction were confirmed, along with additional measurements of kidney function, histology, and injury markers, such as plasma creatinine. CAP treatment increased plasma creatinine levels and subsequently, myocardial structural disorganization increased. Kidney neutrophil gelatinase associated lipocalin (NGAL) and protein expression were increased post-MI. After two weeks CAP treatment, the expression of pyrogenic pro-inflammatory cytokines TNF-α and IL-1β were increased compared to non-CAP treated mice, indicative of amplified inflammatory response. There was also evidence that renal injury of both the post-CAP treatment controls and post-CAP MI were much greater than the non-CAP treated naïve controls, as serum creatinine and NGAL levels were elevated along with obvious structural impairment of the glomerulus. Therefore, CAP treatment tampers with the acute inflammatory response that promotes cardiorenal syndrome and non-resolving inflammation post-MI in acute heart failure.

Carcinogenesis: Failure of resolution of inflammation?

“…However, NSAIDs can down-regulate pro-tumorigenic cytokines but also generate toxic side effects and may be immunosuppressive resulting in increased risk for infections. Pre-treatment of the NSAID carprofen impaired initiation of inflammatory- and overlapping resolution response and promoted cardiorenal syndrome and heart failure ( Krishnan et al, 2019 ). The classic cyclooxygenase inhibitors, celecoxib and indomethacin, that block thromboxanes and prostanoids do not inhibit production of the clot-driven SPM cluster ( Norris & Serhan, 2018 ).…”

Role of polyunsaturated fatty acids in ischemic stroke – A perspective of specialized pro-resolving mediators

“…In addition, co-medication like cancer drugs or pain-killers could also influence the effect of inflammatory responses. For example, in a mouse model of acute heart failure, prolonged treatment with non-steroidal anti-inflammatory drug carprofen could exaggerate acute inflammation and hinder inflammation resolution, thus resulting in worse cardiorenal syndrome [177].…”

Subcutaneous and orally self-administered high-dose carprofen in male and female mice: pharmacokinetics, tolerability and impact on cage-side pain indicators

“…Currently, only few reports on side effects are available for mice, but indicate that carprofen might be associated with an increased risk of gastrointestinal ulceration (10). After cardiac injury, increased inflammation reaction and disordered immune reaction under carprofen treatment are described (11,12). Consequently, there is a need to investigate and describe side effects in a structured manner.…”