The pathogenesis and potential therapeutic targets in sepsis

Abstract

Sepsis is defined as “a life‐threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection.” At present, sepsis continues to pose a grave healthcare concern worldwide. Despite the use of supportive measures in treating traditional sepsis, such as intravenous fluids, vasoactive substances, and oxygen plus antibiotics to eradicate harmful pathogens, there is an ongoing increase in both the morbidity and mortality associated with sepsis during clinical interventions. Therefore, it is urgent to design specific pharmacologic agents for the treatment of sepsis and convert them into a novel targeted treatment strategy. Herein, we provide an overview of the molecular mechanisms that may be involved in sepsis, such as the inflammatory response, immune dysfunction, complement deactivation, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we highlight important targets involved in sepsis‐related regulatory mechanisms, including GSDMD, HMGB1, STING, and SQSTM1, among others. We summarize the latest advancements in potential therapeutic drugs that specifically target these signaling pathways and paramount targets, covering both preclinical studies and clinical trials. In addition, this review provides a detailed description of the crosstalk and function between signaling pathways and vital targets, which provides more opportunities for the clinical development of new treatments for sepsis.

Suppressing the Substance P-NK1R Signalling Protects Mice against Sepsis-Associated Acute Inflammatory Injury and Ferroptosis in the Liver and Lungs

“…The pathogenesis of dysregulated acute inflammatory reaction in sepsis involves many mechanisms [ 3 , 36 ]. As an immune-derived cell death, ferroptosis is also closely associated with the dysregulation of host acute inflammatory responses under various pathological conditions [ 12 , 24 , 25 ].…”

“…Sepsis, a major international health challenge, refers to a life-threatening pathological condition characterised by organ impairment induced by a dysregulated immune system [ 1 , 2 ]. The physiopathology by which the dysregulations of acute inflammatory response and associated organ injury occur in sepsis is yet to be investigated in depth [ 3 ].…”

The gasdermin family: emerging therapeutic targets in diseases

“… 331 – 335 The etiology of sepsis is multifaceted and involves numerous aspects of the interaction between the invading microorganism and the host, including persistent excessive inflammation and immunosuppression, as well as an inability to restore homeostasis. 336 – 341 Inflammatory imbalance is the most critical basis underlying the pathogenesis of sepsis, persisting throughout the progression of the disease. GSDMD is a critical regulator of pro-inflammatory cytokine secretion by immune cells, and recent evidence suggests a pivotal modulatory role for GSDMD in the pathogenesis of sepsis.…”

Evaluation of the efficacy of silymarin and dexmedetomidine on kidney and lung tissue in the treatment of sepsis in rats with cecal perforation

“…However, although there are studies showing that steroid treatment reduces mortality in sepsis, its effects on long-term mortality are controversial (15,16). Therefore, the effectiveness of novel drugs is being investigated in experimental and clinical studies (17)(18)(19)(20)(21).…”