Immunoneutralization of Endogenous Aminoprocalcitonin Attenuates Sepsis-Induced Acute Lung Injury and Mortality in Rats

Abstract

Acute lung injury (ALI) secondary to sepsis is a complex syndrome associated with high morbidity and mortality. We report that aminoprocalcitonin (NPCT), an endogenous peptide derived from the prohormone procalcitonin, plays a critical role in the development of ALI during severe sepsis and is a suggested risk factor for sepsis morbidity and mortality. Lethal sepsis was induced in rats by cecal ligation and puncture (CLP). Two hours after CLP, an i.p. injection of 200 μg/kg of anti-rat NPCT antibody was followed by continuous infusion of anti-NPCT (16 μg per hour) via a minipump for 18 hours. Samples were harvested 20 hours after CLP. High expressions of the CALCA gene, procalcitonin, and NPCT were detected in the lung tissue of rats with severe sepsis. Immunoneutralization of NPCT decreased pulmonary levels of CALCA, procalcitonin, and NPCT; reduced lung inflammation and injury, neutrophil infiltration, and bacterial invasion; and improved survival in sepsis. Anti-NPCT treatment also suppressed sepsis-induced inflammatory cytokine expression, cytoplasmic degradation of the inhibitor of NF-κB, IκBα, and nuclear NF-κB translocation in lung tissues. Therapeutic benefits of anti-NPCT were also associated with increased pulmonary levels of the anti-inflammatory cytokine IL-10. These data support a pathogenic role for NPCT in sepsis and suggest NPCT as a potential new target for clinical prevention and treatment of ALI in severe sepsis.

New Insights into Sepsis Therapy Using Sepia Officinalis

“…It is therefore considered a gold standard tool for testing the success of CLP as a sepsis model, and for studying the efficacy of both SOBT and SOP extracts as novel antiseptic agents. In conjunction with the reports of Liu et al ( 13 ) and Tavares et al ( 27 ), data from the present investigation showed significantly increased PCT levels following CLP in rats. The increment of PCT in septic rats may be due to a continuous bulk-flow constitutive pathway, in which only limited conversion to mature calcitonin occurs ( 28 ).…”

Interleukin‐33 contributes to ILC2 activation and early inflammation‐associated lung injury during abdominal sepsis

“…Sepsis is defined as infection with organ dysfunction and is a leading cause of mortality in Intensive Care Units worldwide . The ultimate cause of death is due to secondary development of life‐threatening organ dysfunction, which is thought to result, in part, from a dysregulated inflammatory response . The lung is one of the most vulnerable organs during sepsis .…”

“…The ultimate cause of death is due to secondary development of life‐threatening organ dysfunction, which is thought to result, in part, from a dysregulated inflammatory response . The lung is one of the most vulnerable organs during sepsis . and acute lung injury develops early during the course of sepsis and is associated with high morbidity and increased mortality .…”

Serum Procalcitonin Correlates with Renal Function in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure

“…Elevated serum PCT was found to be associated with a higher mortality rate in a septic model [15], while immunoneutralization of PCT protected rats from lethal endotoxemia [6,16]. Thus, elevated serum PCT levels were associated with the progression of sepsis.…”

“…Serum PCT rapidly increases in animal models after exposure to bacterial components and cytokines such as lipopolysaccharides (LPS), tumor necrosis factor-α (TNF-α), and IL-6 [18], and our previous study proved that hepatic macrophages are the cell source of hepatic PCT in acute liver failure [19]. The inhibition of PCT expression reduces the cytokine storm and rescues a mouse sepsis model [6,16]. Systemic inflammation and immune system dysregulation are thought to integrate with the main physiopathological pathway involved in the natural history of HBV-ACLF [14].…”