Skeletal muscle atrophy is a common complication in survivors of sepsis, which affects the respiratory and motor functions of patients, thus severely impacting their quality of life and long-term survival. Although several advances have been made in investigations on the pathogenetic mechanism of sepsis-induced skeletal muscle atrophy, the underlying mechanisms remain unclear. Findings from recent studies suggest that the nucleotide-binding and oligomerisation domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a regulator of inflammation, may be crucial in the development of skeletal muscle atrophy. NLRP3 inhibitors contribute to the inhibition of catabolic processes, skeletal muscle atrophy and cachexia-induced inflammation. Here, we review the mechanisms by which NLRP3 mediates these responses and analyse how NLRP3 affects muscle wasting during inflammation.

Acute lung injury (ALI) has been known to be a devastating form of respiratory infection and an important contributor to mortality in intensive care, due to its lacking of effective treatment. Inflammation, oxidative stress, and pyroptosis are associated with multiple kinds of inflammatory diseases such as ALI. It is commonly accepted that Gly‐Pro‐Ala (GPA) peptide regulates oxidative stress and pyroptosis in different kinds of inflammatory diseases. Our study is aimed at exploring the regulatory function and protective effects of GPA peptides on ALI. In the current study, the cecal ligation and puncture (CLP) technique was used to evoke sepsis in mice, and GPA peptide was administered intraperitoneally with different concentrations (50, 100, and 150 mg/kg) after CLP. Histopathological changes and the ratio of wet‐to‐dry in lung were recorded and analyzed. We also investigated the level of oxidative stress, inflammation, and pyroptosis. Results showed that GPA peptide significantly ameliorated CLP‐stimulated lung tissue injury, impeded proinflammatory cytokine release, and reduced inflammatory cell infiltration. Additionally, GPA peptide suppressed oxidative stress and caspase‐1‐dependent pyroptosis in alveolar macrophages. Furthermore, our study showed that the GPA peptide prevents alveolar macrophage from undergoing pyroptosis by attenuating ROS. In conclusion, results demonstrated that GPA peptide has protective effects in CLP‐stimulated ALI by inhibiting oxidative stress as well as pyroptosis of alveolar macrophage.

Intestinal barrier dysfunction is associated with the occurrence and development of sepsis. Further, aerobic glycolysis plays an essential role in inflammation and cell death. This study is aimed at investigating the protective effect and mechanism of PFKFB3 inhibition on intestinal barrier dysfunction in sepsis mice. Sepsis mouse models were established by cecal ligation and puncture (CLP) in wild‐type mice and Gsdmd^-/- mice. The results showed that the expression of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) in the small intestines was significantly upregulated in sepsis. 3‐(3‐Pyridinyl)‐1‐(4‐pyridinyl)‐2‐propen‐1‐one (3PO), the specific inhibitor of PFKFB3, and Gsdmd gene knockout significantly inhibited the inflammatory response and cell death caused by sepsis, thus alleviating intestinal damage and barrier dysfunction. 3PO was also shown to significantly inhibit oxidative stress and NLRP3/caspase‐1/GSDMD‐dependent cell pyroptosis in the small intestines. The in vitro studies revealed that 3PO reduced NLRP3/caspase‐1/GSDMD‐dependent cell pyroptosis by inhibiting ROS. Taken together, our results suggest that PFKFB3 is involved in inflammation, oxidative stress, and pyroptosis during sepsis and enhances intestinal damage, which may provide important clues about the potential targets to be exploited in this highly lethal disease.

Sepsis is described as an immune response disorder of the host to infection in which microorganisms play a non-negligible role. Most survivors of sepsis experience ICU-acquired weakness, also known as septic myopathy, characterized by skeletal muscle atrophy, weakness, and irreparable damage/regenerated or dysfunctional. The mechanism of sepsis-induced myopathy is currently unclear. It has been believed that this state is triggered by circulating pathogens and their related harmful factors, leading to impaired muscle metabolism. Sepsis and its resulting alterations in the intestinal microbiota are associated with sepsis-related organ dysfunction, including skeletal muscle wasting. There are also some studies on interventions targeting the flora, including fecal microbiota transplants, the addition of dietary fiber and probiotics in enteral feeding products, etc., aiming to improve sepsis-related myopathy. In this review, we critically assess the potential mechanisms and therapeutic prospects of intestinal flora in the development of septic myopathy.