While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.
Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. However, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” the study’s authors wrote. Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
According to Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. N-acetyl Cystine (NAC) is the only approved treatment for this condition.
While CRP is a signpost for inflammation following tissue injury, a study from 2020 and one from 2018 suggest that the protein regulates complement activation and may affect immune cell responses. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.
Li and his colleagues also studied the mechanisms of CRP’s action in the laboratory and in mice with Fcy receptor 2B knockouts to further understand the role of CRP. These receptors may be modulators of immune cell responses according to the research. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice.
Researchers also examined the expression of CRP in the liver of mutants that lack complement-mediated interactions. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.
Injecting 300 mg/kg Acetaminophen for 24 hours resulted in liver injury in wild-type mice. The cause was higher levels of circulating levels of aspartate transaminases (ALT) and alanine (ALT) as well massive necrosis (hepatocytes) The researchers noted that these manifestations were exacerbated significantly in CRP mice that were knocked out.
Injecting human CRP intravenously to mice suffering from liver damage caused by drugs protected the mice from the defects caused by mice knocking out CRP. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.
The researchers also examined mechanisms that protect CRP in the initial stages of liver damage caused by drugs. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury.
Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Instead, they explained that CRP might work through factor H that is recruited by CRP to regulate complement activation, which can inhibit overactivation of complement on injured liver cells. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation, which is mediated through neutrophils’ C3a-dependent functions.
Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.
The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. Human CRP, however, in this study was still highly effective at this point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.
The study was supported by the National Natural Science Foundation of China. The researchers did not report any conflicts of interest with any pharmaceutical companies.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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