Bacterial Endotoxins and Clinical Diseases

Release Date:

2014-09-10

Over the past decade, research in the medical and healthcare fields has demonstrated that bacterial endotoxins have emerged as pathogenic factors underlying a wide range of complications in patients. Because the production of bacterial endotoxins in the bloodstream exhibits no regional variation, the primary cause is dysbiosis and translocation of intestinal microbiota triggered by traumatic or burn injuries, or by other infections such as influenza virus infection. Following the lysis of exogenous or enteric Gram-negative bacteria, their cell walls are hydrolyzed, releasing substantial amounts of bacterial endotoxin. These endotoxins can enter the circulation via exudates, leading to “endotoxemia” and eliciting a cascade of pathological and physiological responses, including fever or pyrogenic reactions, the release of vasoactive mediators, and ultimately microcirculatory dysfunction or multiorgan failure.
　　Endotoxemia is closely linked to bacterial infections. Although the mechanisms by which infection triggers sepsis and multiple organ dysfunction syndrome remain incompletely understood, bacterial endotoxin is generally considered to promote their onset and progression. Extensive research has demonstrated that endotoxin exerts broad and complex biological effects; the dysregulated inflammatory response, immune dysfunction, hypermetabolic state, and multiorgan damage observed in the pathogenesis of sepsis and multiple organ dysfunction syndrome can all be directly or indirectly initiated by endotoxin. At present, routine clinical microbiological “bacterial culture” methods are often unable to detect pathogens, posing significant challenges to diagnosis. Consequently, the lack of timely diagnosis and treatment for endotoxemia results in a steadily increasing mortality rate.
　　A substantial body of literature in clinical medical research has demonstrated that endotoxemia can precipitate a cascade of pathophysiological changes, triggering febrile responses in the organism and promoting the release of vasoactive substances, thereby leading to microcirculatory dysfunction. Its pathophysiological tendencies include leukopenia and thrombocytopenia, an increased bleeding diathesis, and direct or indirect hepatotoxicity, as well as disturbances in carbohydrate metabolism and alterations in enzymatic and protein metabolic pathways. Further progression of endotoxemia may culminate in septic shock, disseminated intravascular coagulation, severe acute respiratory syndrome (SARS), systemic inflammatory response syndrome (SIRS), or multiple organ dysfunction syndrome (MODS), ultimately resulting in mortality.
　　According to reports, the incidence of endotoxemia varies across different conditions as follows: acute hepatitis, 37–64%; fulminant hepatitis, 58–100%; hepatitis C, 61.54%; cholelithiasis with acute obstructive suppurative infection, 85%; burns, 85%; sepsis, 70%; acute pancreatitis, 90%; skin and soft‑tissue infections, 70–81.1%; intraabdominal infections, 72–84%; urinary tract infections, 70–80% (including nephritis); cancer, 70%; pulmonary infections and multiple organ dysfunction syndrome, up to 100%; and common cold, 100%. Relevant studies indicate that more than 500,000 patients develop endotoxemia annually, with approximately 40–50% of them succumbing to the condition due to delayed diagnosis and inadequate treatment. Research suggests that influenza virus and atypical pneumonia may result in death from “acute endotoxin poisoning”; pathological examinations of fatal cases of atypical pneumonia reveal clear evidence of organ damage attributable to endotoxemia.
　　Examples of the associations between common endotoxins and clinical diseases are presented below:
　　 I. Intestinal Endotoxemia
　　Studies have shown that following severe burns, aerobic bacteria, anaerobic bacteria, and fungi can all enter the mesenteric lymph nodes, liver, spleen, kidneys, or bloodstream via the intestinal tract. Endotoxin, a constituent of the outer membrane of Gram-negative bacteria and its principal toxic component, is released during bacterial proliferation and lysis; it often accompanies these organisms. Notably, after severe trauma, since bacteria can gain access through the gut, the intestine—often referred to as an “endotoxin reservoir”—should facilitate even easier translocation of endotoxins (with molecular weights of 3,000–5,000). Using radioactive labeling, researchers introduced radiolabeled endotoxin into the intestinal lumen at doses that did not affect healthy animals and tracked its distribution in vivo. Results demonstrated that, within 15 minutes post‑burn, endotoxin levels in the portal vein began to rise, peaking between 3 and 6 hours; moreover, portal venous endotoxin concentrations frequently exceeded those in the vena cava, supporting the hypothesis that endotoxin originates in the gut. Further, electron microscopic autoradiography revealed that, by 6 hours post‑injury, endotoxin particles could be detected in hepatic Kupffer cells and hepatocytes. Subsequently, experimental intestinal lymph fistulas were established, with continuous collection of intestinal lymph for endotoxin quantification, confirming that intestinal lymphatic circulation represents another critical route for the entry of gut‑derived endotoxin. Clinically, this finding not only helps explain the longstanding clinical conundrum of sepsis without an obvious source of infection but also underscores the importance of early recognition and intervention for certain types of shock that are resistant to fluid resuscitation; the translocation of gut microbiota and endotoxin may serve as a “trigger” for multiple organ dysfunction syndrome.
　　The human intestinal tract is the body’s largest reservoir of microorganisms and a major repository of endotoxins. While it performs essential functions such as digesting and absorbing nutrients, it also maintains a robust defensive barrier against harmful microbes and their byproducts. Even when small amounts of endotoxins occasionally translocate, the gut-associated lymphoid tissue and hepatic Kupffer cells possess sufficient capacity to neutralize them, thereby contributing to the development of immune tolerance. However, upon exposure to severe stressors, the resulting changes can be profound.
　　Long ago, clinicians observed that severe burns and traumatic brain injury could be complicated by gastric and duodenal ulcers, bleeding, or perforation; this condition was then referred to as Cushing’s ulcer. However, clinical attention has traditionally focused on the upper gastrointestinal tract, while the lower gastrointestinal tract harbors a more insidious threat: endogenous infection—namely, the translocation of bacteria and endotoxins. The key to the development of such endogenous infections lies in the impairment of intestinal barrier function.
　　Experimental studies have demonstrated that intravenous administration of endotoxin can induce shivering followed by high fever; at higher doses, the body temperature may fall below normal before death. Endotoxin elicits widespread vasoconstriction of arterioles and venules, which is subsequently succeeded by vasodilation, leading to plasma leakage and substantial blood stasis within the microcirculation. This results in a reduction of effective circulating volume, a decline in arterial pressure, and the development of endotoxic shock.
　　Endotoxemia manifests in the blood profile as leukocytosis or leukopenia, marked thrombocytopenia, and coagulation dysfunction, potentially leading to disseminated intravascular coagulation (DIC).
　　Moderate levels of endotoxin can induce hyperglycemia, which is subsequently followed by hypoglycemia, accompanied by marked hepatic glycogen depletion. Endotoxemia may also manifest as altered consciousness and psychiatric disturbances.
　　The clinical manifestations described above closely resemble those of Gram-negative bacterial sepsis. This similarity arises, on the one hand, from the frequent coexistence of endotoxemia and Gram-negative bacteremia, and, on the other hand, because endotoxin is the principal virulence factor of Gram-negative bacteria. The pathogenic effects of endotoxin are not solely due to its intrinsic toxicity; more importantly, it triggers the release of multiple inflammatory mediators by various cell types, including monocytes/macrophages, vascular endothelial cells, and neutrophils. Furthermore, endotoxin can modulate the complement and fibrinolytic systems, underscoring that its primary actions are indirect. The specific diagnostic marker for endotoxemia is the quantitative measurement of endotoxin in blood, which demands highly precise reagents, meticulous assay procedures, and effective mitigation of interference from blood components in the Limulus Amebocyte Lysate (LAL) test. It was only in 2010 that China approved the first commercially available assays for this purpose; even today, such testing remains underutilized in clinical practice, including at major hospitals both domestically and internationally. Consequently, while many clinicians have a theoretical understanding of endotoxin, they often lack data‑driven evidence to inform their clinical decisions, leading to a limited perception confined largely to positive blood cultures. Numerous studies have demonstrated that, following severe trauma or major surgery, quantitative assessment of blood endotoxin frequently reveals varying degrees of endotoxemia, with the gut serving as the predominant source. Similarly, endogenous endotoxemia is commonly observed in patients with severe hepatitis. In summary, routine quantitative endotoxin monitoring would reveal that endotoxemia is remarkably prevalent among critically ill patients.
　　 II. Post-Burn Multiple Organ Dysfunction Syndrome
　　Severe burns can disrupt the body’s mechanical barriers—both on the skin and within body cavities—and leave extensive areas of necrotic tissue, creating an ideal environment for the invasion of bacteria and other microorganisms. Coupled with suppression of host immune function, infection becomes the most common complication following severe burns. Clinical data from both domestic and international sources indicate that infection is the leading cause of mortality in patients with extensive burns, with systemic infections posing the greatest threat to survival. Over the past two decades, research has demonstrated a close association between endotoxemia and bacterial infection, establishing endotoxin as one of the key pathogenic factors in burn‑related infections. Indeed, in burn‑induced sepsis, endotoxin often acts synergistically with bacteria, coexisting with them in the same infectious focus. Although the precise mechanisms by which infection triggers sepsis and multiple organ dysfunction syndrome remain incompletely understood, it is generally accepted that bacterial endotoxin plays a promoting role in their onset and progression. Extensive studies have shown that endotoxin exerts highly diverse and complex biological effects; the uncontrolled inflammatory response, immune dysregulation, hypermetabolic state, and multiorgan dysfunction observed in the pathogenesis of sepsis and multiple organ dysfunction syndrome can all be directly or indirectly initiated by endotoxin.
　　Does endotoxemia occur after burns, and what is its clinical significance? In an effort to detect evidence of endotoxin in the blood of burn patients who develop severe infection, Cardis et al. first reported the incidence and clinical implications of endotoxemia following severe burns using the limulus amebocyte lysate assay. They concluded that, in the early phase after extensive burns, enterogenic endotoxemia may arise and exert a measurable influence on post‑burn mortality. Subsequently, another study examined 35 burn patients; based on the extent of the burn injury and integrating clinical findings, limulus testing, ancillary investigations, and autopsy results, the clinical manifestations of burn‑associated endotoxemia were classified into five categories. With the exception of Type I, which represents isolated signs of endotoxemia, the remaining four types correspond to advanced stages of endotoxin‑induced shock—namely, respiratory failure, disseminated intravascular coagulation, cerebral edema, fatty degeneration of the myocardium and liver, and septic shock. These early studies have had a significant impact on our understanding of endotoxemia in the context of burn injury.
　　With the continuous advancement of production technologies for limulus amebocyte lysate reagents in China and the steady improvement in product quality, these reagents have increasingly been applied to research on the early diagnosis of clinical infectious diseases. Yu Qing and colleagues used the limulus assay to measure plasma endotoxin levels in five burn patients; the results showed that, following Gram-negative bacterial infection of the burn wounds, varying degrees of endotoxin could be detected in the plasma, leading to endotoxemia of differing severity. The persistent detection of elevated endotoxin levels in the plasma of patients with Gram-negative sepsis constitutes a warning sign, indicating a high risk of progression to fatal endotoxic shock. These findings suggest that the limulus assay holds practical value for the rapid diagnosis of endotoxemia and for prognostic assessment.
　　 III. Sources of Endotoxemia
　　Previously, it was widely believed that post‑burn endotoxemia originated from the burn wound or from the systemic circulation, resulting from the massive release of endotoxin following Gram‑negative bacterial infection. However, as research into gut‑derived infections in surgery has advanced, a new perspective has emerged regarding the mechanisms underlying post‑burn endotoxemia. In the early phase of extensive burns, plasma endotoxin levels rise markedly, often accompanied by overt sepsis symptoms, even when the burn wound shows no evidence of significant bacterial proliferation or when blood cultures remain sterile. These observations suggest that, in the early stages after burn injury, endotoxemia is not primarily driven by the wound; rather, excessive translocation of gut‑derived endotoxin into the bloodstream may represent the principal source. Dobke et al. provided clear evidence that circulating endotoxin concentrations peak between 7 and 12 hours post‑injury, with a second peak occurring on day 4. The authors concluded that this early surge in endotoxin originates predominantly from the gut and is unrelated to wound‑borne bacteria. Subsequent re‑elevation of endotoxin levels, they proposed, might be associated with wound‑related sepsis. Additional data further support these findings: in five patients with burn surface areas exceeding 60%, limulus amebocyte lysate assays were positive within one day of injury, and all developed multiple organ dysfunction syndrome between days 1 and 4, despite the absence of any identifiable infectious foci. Collectively, these clinical studies underscore that gut‑derived endotoxemia can occur in the early phase of burn injury, and that intestinal endotoxin and bacterial translocation may constitute critical contributors to sepsis and multiorgan failure.
　　It has now been demonstrated that, in rats subjected to severe hemorrhagic shock for as little as 30 minutes, one-third of the animals already develop gut-derived endotoxemia; by 2 hours post‑shock, the positivity rate rises to 87.5%, with approximately half of the animals also exhibiting bacteremia. Experimental data show that endotoxin cleared from the circulation is rapidly distributed into tissue macrophages in organs such as the liver, lungs, and kidneys. Following metabolism and transport by these macrophages, endotoxin and its metabolic products can be progressively excreted via the biliary system. Using a phenol–water extraction method to isolate endotoxin eliminated from the bile of rats with endotoxemia, it was found to retain highly potent lethal activity in mice. This indicates that, although circulating endotoxin is swiftly removed by the monocyte/macrophage system, endotoxin that enters tissues may still maintain significant biological activity. Extensive animal studies have shown that severe burns are frequently accompanied by a shock phase of varying severity. Under conditions of traumatic stress, the tight junctions between intestinal epithelial cells are often disrupted, compromising the mesenteric barrier and markedly increasing intestinal mucosal permeability. Consequently, accumulated endotoxin within the gut can translocate into the systemic circulation, leading to endotoxemia; meanwhile, circulating endotoxin further promotes the continued entry of endotoxin and bacteria into the bloodstream, creating a vicious cycle. Therefore, in the management of burn‑induced shock, in addition to fluid resuscitation, it is essential to counteract early endotoxemia in order to mitigate or reduce secondary injury to the host.
　　 IV. Intestinal Bacterial Translocation
　　As early as the 1950s, Fine proposed that the translocation of intestinal bacteria and endotoxins constitutes a critical factor in the progression of hemorrhagic shock toward an irreversible state. The human gut harbors a vast bacterial population, which, through bacterial proliferation and lysis, generates substantial amounts of endotoxin. Consequently, the intestine is often referred to as the body’s largest “endotoxin reservoir.”
　　Under normal conditions, the intestine serves as a barrier, preventing endotoxins within the gut from entering the bloodstream. ① The mechanical barrier comprises an intact and tightly organized tissue structure, including the continuous intestinal mucosa and tight junctions between mucosal epithelial cells; ② The chemical barrier consists of physiologically secreted substances in the gastrointestinal tract that inhibit, degrade, and neutralize endotoxins, such as gastric acid, bile, lysozyme, proteolytic enzymes, and the mucin secreted by goblet cells, which helps lubricate the intestinal lumen and non-specifically bind endotoxins to form fecal matter; ③ The luminal microbiota comprises over 400 bacterial species, with 95% being anaerobic. Under normal circumstances, their abundance and distribution remain relatively stable, with microbial populations both antagonizing and depending on one another; ④ The immune barrier: the intestine itself is a major immune organ of the human body. Peyer’s patches in the intestinal mucosa generate large numbers of lymphocytes, while intestinal plasma cells produce secretory IgA, which neutralizes endotoxins.
　　Weakening of the intestinal barrier function can lead to bacterial translocation (BT) and gut‑origin septic states. BT refers to the passage of intestinal microorganisms and their products, including endotoxins, across the intact intestinal epithelium into the systemic circulation. The most common translocating organisms are Escherichia coli, Klebsiella species, and Pseudomonas spp., whereas anaerobic bacteria rarely undergo translocation; this is determined by the bacteria’s intrinsic adhesion and invasiveness. Following extracorporeal circulation, the occurrence of BT plays a critical role in the development of systemic inflammatory responses, bacteremia, and sepsis.
　　After intestinal endotoxins cross the intestinal barrier, they enter the systemic circulation via several major routes: the portal venous pathway, the lymphatic pathway, and, in rare cases, direct translocation across the intestinal wall into the peritoneal cavity. Studies have shown that 60 minutes after cardiac resuscitation, there is a significant difference in endotoxin levels between the right atrium and the portal vein, with portal venous endotoxin concentrations markedly higher than those in the vena cava; thus, the portal venous route may be the primary pathway for endotoxin entry into the body.
　　 V. Decline in the Function of the Hepatic Reticuloendothelial System
　　The liver is the primary organ for clearing endotoxins from the body and serves as a critical barrier that prevents gut-derived endotoxins from entering the systemic circulation. Studies have shown that intravenous administration of endotoxin to humans, rats, or rabbits is predominantly cleared by the liver. When radioactively labeled endotoxin was infused into the intestinal lumen of burned rats, it was found that, after entering the bloodstream via the gut, the endotoxin was not only taken up by mononuclear phagocytes but also rapidly internalized into hepatocytes, where it preferentially localized to mitochondria, ultimately being eliminated through the biliary system. The hepatic mononuclear phagocytes exert their phagocytic function primarily via the LPS–lipopolysaccharide-binding protein (LBP)–CD14 pathway; concurrently, the reticuloendothelial system (RES) is activated, accelerating the clearance of endotoxin and its associated mediators. The RES pathway represents an important mechanism for the host’s defense against endotoxins.
　　Following cardiopulmonary bypass, hypoxia and stress lead to impaired phagocyte function and hepatocyte dysfunction, reducing the liver’s capacity to detoxify endotoxin and allowing it to enter the systemic circulation. Once absorbed into the bloodstream, endotoxin further exacerbates damage to intestinal epithelial cells and the endothelial cells of intestinal microvessels, thereby perpetuating a vicious cycle.
　　 VI. Effects of Endotoxemia on Systemic Organs
　　The injurious effects of endotoxin stem primarily from two mechanisms: 1) direct cytotoxicity, whereby endotoxin binds to tissue cells, directly causing cellular damage and impairing organ function; and 2) indirect injury, in which endotoxin activates platelets, neutrophils, monocytes, macrophages, lymphocytes, endothelial cells, as well as the complement and coagulation systems, leading to the excessive secretion and release of endogenous mediators and pro-inflammatory cytokines, which in turn inflict damage on parenchymal cells. Among these, the liver and lungs exhibit the most pronounced pathological changes, followed by the intestine, kidneys, heart, and brain.
　　The extent of parenchymal cell injury induced by endotoxin is dose‑dependent; however, differences in dosage are reflected only in the course of the disease. A low dose of endotoxin can elicit typical pathological changes, yet these are self‑limiting; by contrast, a high dose produces similar histopathological alterations, but with a prolonged clinical course, and the resulting parenchymal cell damage is often irreversible.
　　 (1) Pulmonary Injury
　　The pulmonary injury induced by endotoxin resembles ARDS, characterized primarily by diffuse damage to endothelial and alveolar epithelial cells, interstitial edema, focal intraalveolar hemorrhage, and the formation of hyaline membranes. A series of in vivo and in vitro experiments—both direct and indirect—have demonstrated that endotoxin can directly injure endothelial cells. Within 30 minutes after endotoxin stimulation, endothelial cell contraction, cytoplasmic membrane blebbing, disruption of intercellular junctions, formation of intercellular clefts, and increased microvascular permeability can already be observed. These changes occur prior to the plasma peak of inflammatory cytokines and the upregulation of adhesion molecules. Meanwhile, endotoxin can activate macrophages, prompting the release of large amounts of pro-inflammatory mediators, recruiting neutrophils, and amplifying the inflammatory response, thereby leading to acute lung injury (ALI).
　　 (II) Liver Injury
　　The mechanisms by which endotoxin directly damages hepatocytes are as follows: 1. After hepatocytes encounter a certain amount of lipid A, lipid A is transported to the inner mitochondrial membrane, where it binds to specific receptors, inhibiting ATP synthase and NADH dehydrogenase, thereby impeding energy production and blocking electron transport in the respiratory chain. Insufficient reduction of oxygen molecules generates reactive oxygen species that damage cellular membranes, leading to hepatocyte necrosis; 2. By activating phospholipase A2 or triggering lipid peroxidation in the mitochondrial membranes of hepatocytes, endotoxin elevates free radical levels, contributing to hepatocellular injury; 3. It suppresses the activity of Na⁺‑K⁺‑ATPase on the canalicular membrane, reducing ATP availability and impairing the active uptake, metabolism, and secretion of bile acids by parenchymal hepatocytes, thus disrupting canalicular excretion and resulting in intrahepatic cholestasis. The mechanisms by which endotoxin indirectly injures the liver include: 1. Stimulating the release of inflammatory cytokines, thereby damaging hepatocytes; 2. Inducing microcirculatory disturbances in the liver and reducing hepatic blood flow, leading to tissue ischemia; 3. Promoting the release of vasoconstrictive substances from blood components or tissue cells, causing portal hypertension; 4. Inhibiting bile salt synthesis and hindering the adsorption of enteric endotoxins; 5. Activating the complement system via alternative pathways, damaging hepatic sinusoidal endothelial cells and compromising lymphocyte function.
　　 (3) Cardiac Injury
　　Endotoxin can stimulate the organism to produce inflammatory cytokines such as TNF‑α, IL‑1β, and IL‑6, as well as nitric oxide (NO), which in turn damage the heart; moreover, the endotoxin itself can directly injure cardiac tissue. The cardiotoxic effects of endotoxin are independent of coronary blood flow and oxygen delivery.
　　In endotoxemia, the myocardial vasculature and capillaries exhibit dilation, hyperemia, hemorrhage, diapedesis, and inflammatory cell infiltration, with these changes most pronounced 12 hours after the onset of endotoxemia. Mild cellular injury or apoptosis of vascular endothelial cells and parenchymal cells is observed even in the early stages of endotoxemia. Endotoxin induces loss of mitochondrial cristae in cardiomyocytes, accompanied by vacuolar degeneration and fragmentation of cardiac fibers. Perinuclear and interstitial edema, mitochondrial swelling or degeneration, as well as endothelial cell edema and numerous pinocytic vesicles are also evident.
　　Endotoxins can inhibit lipoprotein lipase (LPL), the rate-limiting enzyme in triglyceride (TG) metabolism, thereby impairing myocardial energy uptake and utilization. Myocardial oxidation of ketone bodies is reduced, leading to their intracellular accumulation and increased lipid deposition.
　　Endotoxin also exerts effects on hemodynamics. Following endotoxin administration in experimental animals, mean arterial pressure (MAP) decreased markedly, falling by approximately 44 mmHg within 1 hour and showing no significant recovery by 4 hours. Mean pulmonary artery pressure (MPAP) increased substantially, while pulmonary capillary wedge pressure (PCWP) was moderately elevated. Systemic vascular resistance (SVR) declined significantly, reaching half its baseline level, whereas pulmonary vascular resistance (PVR) was elevated. Cardiac output (CO) rose sharply 1 hour after endotoxin injection, then declined slightly but remained above normal. Endotoxin reduced cardiac index (CI), stroke index (SI), left ventricular work index (LVSWI), and right ventricular work index (RVSVI). Furthermore, endotoxin stimulated the release of plasma catecholamines; however, the vasculature’s responsiveness to these vasoconstrictor agents was markedly diminished, thereby failing to ameliorate the hemodynamic disturbances.
　　Endotoxin activates leukocytes, thereby affecting coronary microcirculation. At low doses, endotoxin has little impact on normal coronary arterial flow (CAF) because it does not disrupt the coronary arteries’ autoregulatory mechanisms. However, in the presence of coronary atherosclerosis, endotoxin can increase CAF.
　　 (4) Renal Injury
　　Lipid A in endotoxin potently constricts arteries, stimulates the sympathetic nervous system, and enhances the release of catecholamines. In endotoxemia, renal vascular resistance increases markedly, leading to reductions in renal blood flow, glomerular filtration rate, and the filtration fraction. Concurrently, endotoxin stimulates the synthesis of thromboxane A2 and the production of other cyclooxygenase‑derived vasoconstrictors, further exacerbating renal ischemia.
　　In endotoxemia, the body mounts a cascade of pro-inflammatory and anti-inflammatory responses, releasing large quantities of cytokines and inflammatory mediators. Concurrently, the circulating renin–angiotensin system (RAS) is activated, inducing vasoconstriction and impairing microcirculation, which can further exacerbate tissue ischemia and hypoxia; in severe cases, this may lead to renal failure.
　　 (5) Intestinal Injury
　　The intestine serves as a source of endotoxins; however, endotoxins can also impair intestinal structure and function. Following intraperitoneal injection of endotoxin in rats, the early manifestations include congestion and edema of the intestinal mucosa and submucosa, along with shrinkage of intestinal epithelial cells and widening of intercellular spaces. Consequently, clinical monitoring of endotoxemia is essential.
　　In recent years, both domestically and internationally, there has been a reported trend of increasing G‑negative bacterial infections; consequently, rapid diagnosis of sepsis and endotoxemia caused by these organisms has received growing attention. However, conventional bacteriological testing is time‑consuming, and the widespread use of antibiotics has further reduced culture‑positive rates. Moreover, an increasing number of studies have demonstrated that endotoxemia can occur in the absence of bacteremia, under conditions such as dysfunction of the reticuloendothelial system, intestinal mucosal injury, localized infection with Gram‑negative bacteria, or contamination of injectable medications, intravenous fluids, and blood products with substantial amounts of endotoxin.
　　Some clinical studies have demonstrated a close association between endotoxin levels and disease progression, severity, and prognosis in patients. Markus et al. found that lower concentrations of anti‑endotoxin core antibodies were associated with longer durations of respiratory support following cardiac surgery. These findings suggest that plasma endotoxin levels and related biomarkers may serve as effective early warning indicators. Consequently, timely detection and continuous monitoring of dynamic changes in endotoxin concentrations in bodily fluids are of great importance for disease diagnosis, clinical management, and prognosis assessment. Given the multifaceted deleterious effects of endotoxin on the host, higher endotoxin levels correlate with more pronounced adverse outcomes; thus, endotoxin levels can also function as an indicator of perioperative safety in extracorporeal circulation–based cardiac surgery.
　　 VII. Other Matters
　　The mechanisms of endotoxin action are highly complex, and its clinical management is particularly challenging. These mechanisms encompass a wide array of fundamental issues—such as infection, inflammation, immunity, and tissue injury—and are closely linked to pathophysiological changes across multiple systems and organs. Extensive evidence demonstrates that endotoxemia is a common complication in critically ill patients in both internal medicine and surgery, frequently precipitating sepsis and multiple organ dysfunction syndrome, and constituting one of the leading causes of mortality in this population. As endotoxin represents a novel research topic of shared interest across basic sciences, clinical disciplines, and preventive medicine, advancing our understanding and investigation of it can foster interdisciplinary integration and development. Consequently, research on the early diagnosis and prevention of endotoxemia is a critical challenge that modern medicine urgently needs to address; accordingly, studies on the detection of bacterial endotoxins in clinical blood samples undoubtedly hold significant theoretical value and practical clinical relevance.

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