Heartfelt sepsis: microvascular injury due to genomic storm

Abstract

Sepsis is one of the ten leading causes of death in developed and developing countries. In the United States, sepsis mortality approaches that of acute myocardial infarction and exceeds deaths from stroke. Neonates and the elderly are the most vulner-able patients, with these groups suffering from the highest sepsis mortality. In both groups, many survivors respectively display serious developmental disabilities and cognitive decline. The National Institute of Health/National Heart, Lung, and Blood Institute Panel redefined sepsis as a "severe endothelial dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure." Microvas-cular endothelial injury in sepsis due to microbial inflammation encompasses small blood vessels (< 100 μm in diameter). While the lungs remain the principal organ of interest due to sepsis-associated acute respiratory distress syndrome, "septic heart" or "septic cardiomyopathy" accelerates sepsis' transition to potentially lethal septic shock. This review analyses both new advances in understanding the septic mechanism and possible resolutions of sepsis. The concept of a "genomic storm," caused by microbes triggering florid production of inflammatory mediators, is based on septic reprogramming of the human genome. This genomic storm leads to microvascular endothelial injury, persistent hypotension, and organ failure. While very early control of sepsis-causing bacterial, fungal and viral infections remains crucial for the treatment of sepsis, supportive measures are likewise necessary to maintain blood pressure, respiration, and kidney function. New evidence indicates that preadmission b-blockers may reduce sepsis-associated mortality. The fundamental role of nuclear signalling in the progres-sion and resolution of sepsis was established with a new class of cell-penetrating nuclear transport modifiers (NTMs). NTMs target the translocation of proinflammatory and metabolic transcription factors to the cell's nucleus while also enhancing bacterial clearance in experimental polymicrobial sepsis models. The result is a 700-fold reduction in the bacterial burden of the lungs and improvement of sepsis-associated thrombocytopaenia and blood markers of endothelial injury. When added to anti-microbial therapy, NTM has increased survival from 30% to 55%, when compared to antimicrobial therapy alone. Yet, the prevention of sepsis remains the most rational and beneficial path. Anti-pneumococcal vaccination has reduced the incidence of pneumonia and sepsis caused by increasingly antibiotic-resistant Streptococcus pneumoniae in all age groups. Similarly, the incidence of meningococcal sepsis known as "purpura fulminans" has been reduced by a recently approved vaccine thereby preventing hearing loss, neurologic damage, and limb amputations in young survivors of septic outbreaks. We urgently need further preventive, diagnostic, and therapeutic measures as the tide of sepsis rises in the ...

Risk factors for postoperative sepsis-induced cardiomyopathy in patients undergoing general thoracic surgery: a single center experience

“…Few studies have reviewed the clinical data of SICM after general thoracic surgery. Therefore, our study set out to determine the incidence of SICM among Sepsis is a hyperdynamic process characterized by an increase in cardiac output and low systemic vascular resistance (7)(8)(9). Septic shock is a type of sepsis that manifests with unstable hemodynamics and abnormal metabolism (10,11), for which the mortality rate exceeds 40%.…”

Current Status of Septic Cardiomyopathy: Basic Science and Clinical Progress

“…In MyD88-dependent pathway, MyD88 binds IRAK4, IRAK1, and/or IRAK2, and promotes their binding to TRAF6, then leads to the activation of TAK1 by TRAF6. After a series of activations/reactions, this eventually leads to nuclear translocation of NF-κB, which activates the expression of various inflammatory genes (called gene storms), causing host dysfunction and multiple organ dysfunction (Hawiger, 2018). In MyD88 independent pathways, such as Trif-dependent pathways, Trif interacts with TRAF3 to activate TBK1 and IKKi, and then cause the phosphorylation of IRF3.…”

“…Some studies suggested that the pathogenesis of sepsis is the damage of micro-vessels caused by "Genomic Storm" (Hawiger, 2018). Bacteria, fungi, infectious agents and viral nucleic acids bind to TLRs, causing the activation of stress response transcription factors (SRTFs), such as NF-κB, and activated protein 1 (AP-1), which in turn activate multiple genes encoding pro-inflammatory cytokines and chemokines, leading to septic shock and multiple organ dysfunction (Hawiger, 2018). Based on this observation, gene therapy for sepsis and SCM has been proposed.…”

“…Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated immune response to an infection (Singer et al, 2016) and has become one of the top ten leading causes of death in developed and developing countries (Hawiger, 2018), with a mortality rate as high as 30% (Morin et al, 2015). Septic shock is defined as hypotension with lactic acid >2 mmol/L after adequate fluid resuscitation (Singer et al, 2016) and its death rate can be as high as 50% (Lu et al, 2019).…”

YiQiFuMai Lyophilized Injection Attenuates Sepsis-Induced Acute Lung Injury via TLR4/Src/VE-cadherin/p120-catenin Signaling Pathway

“…The leakage of in ammatory cells into the alveolar cavity is mainly associated by the destruction of the pulmonary microvascular endothelial barrier function, which plays an important role in ALI caused by sepsis [35]. The degree of lung vascular permeability was examined by EB dye.…”