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PubMed1988

The effects of endotoxin on platelet-activating factor synthesis in cultured rat glomerular mesangial cells.

Platelet-activating factor (PAF), a potent vasoactive phospholipid, may contribute to acute renal failure and septic shock accompanying endotoxemia. Rat glomerular mesangial cells in culture synthesize PAF and contract after the addition of PAF. We thus investigated the potential of mesangial cells to respond to Escherichia coli lipopolysaccharide endotoxin with enhanced PAF synthesis in vitro. The mesangial cells were incubated with [3H]acetate, substrate for lyso-PAF: acetyl-CoA acetyltransferase, and endotoxin at different concentrations for various periods of time at 37 degrees C. Lipids were extracted and PAF was isolated by thin-layer chromatography. Endotoxin stimulated PAF generation in a time- and dose-related manner. Whereas most of the PAF was associated with the cells, endotoxin more than doubled the amount of PAF released into the extracellular medium as compared to control. Furthermore, the PAF-like material obtained from endotoxin-stimulated mesangial cells irreversibly aggregated washed rabbit platelets. This effect was lost after alkaline methanolysis and was totally blocked by L-652,731, a specific PAF-receptor antagonist. Finally, the PAF-like material exerted a hypotensive effect, which was abolished by L-652,731, when infused intravenously into healthy rats. These data indicate that rat glomerular mesangial cells have the ability to synthesize PAF in response to endotoxin. This suggests that PAF, so generated within the glomerulus, may contribute to acute decrements of glomerular filtration rate in endotoxemia.

Acetates↗
PubMed1990

Quantitative determination of endotoxins on surgical gloves.

The amount of endotoxin on surgical gloves was investigated by the limulus chromogenic substrate method. Heavy endotoxin contamination was observed on the outside of certain surgical gloves sold in Sweden. Given an endotoxin absorption of 10% to the patients, one of the types of gloves studied would cause fever, chills, headache and muscle pain. The amount of endotoxin on the gloves could be minimized by rinsing in endotoxin-free water. We conclude that the manufacturing process of latex gloves should be checked microbiologically for Gram-negative bacteria before sterilization. Alternatively, the amount of endotoxin should be checked on the product by the limulus ameobocyte lysate test before release.

Endotoxins↗
PubMed1983

A pathophysiological role of endogenous prostacyclin in endotoxin induced increase in lung vascular permeability in dogs.

Escherichia coli endotoxin (1 mg/kg) infusion over 30 min into anesthetized artificially ventilated dogs caused a biphasic response: an early phase of pulmonary hypertension and a late phase of increased lung vascular permeability. During an early phase, PG F2 alpha, Tx A2 (as Tx B2) and prostacyclin (as 6-keto-PG F1 alpha) concentrations increased in plasma or right duct lymph of dogs. During a late phase, the concentrations of PG F2 alpha and Tx A2 decreased to near the base-line values, while the concentration of prostacyclin remained elevated. Administrations of PG synthetase inhibitors 45 min prior to endotoxin inhibited the increase in concentration of prostacyclin following the infusion of endotoxin and potentiated the increase in lung vascular permeability at the beginning of the late phase. Continuous infusion of prostacyclin (20 ng/kg/min) starting one hour before endotoxin for 5 hour periods prevented the increase in lung vascular permeability induced by endotoxin. Based on these results, we could conclude that endogenous prostacyclin might play an important role in preserving cell integrity of lungs and counteract the deleterious effects of endotoxin.

Animals↗
PubMed1995

B/PI-derived synthetic peptides: synergistic effects in tethered bactericidal and endotoxin neutralizing peptides.

Human neutrophil bactericidal protein (B/PI) is known for its ability to kill bacteria and to neutralize the action of endotoxin. Short linear peptides derived from residues 80-109 have been synthesized and their bactericidal and endotoxin neutralizing activities have been assayed. A series of 'walk-through' decapeptides, overlapping 3 to 4 residues, indicates that endotoxin neutralizing and partial bactericidal activities can be localized within the N- and C-terminal portions, respectively, of the 80-109 sequence. Bactericidal activity toward Pseudomonas aeruginosa was localized in central peptides of the walk-through series and greatest in peptide 90-99. By using longer peptides, residues 86-104 and 82-108, both bactericidal and endotoxin neutralizing activities are significantly enhanced. Bactericidal activity of peptide 82-108 is now only 6-fold less than that of parent B/PI and 9-fold more potent than peptide 86-104. The 82-108 peptide was 7-fold more active at endotoxin neutralization than 86-104 but showed less enhanced activity, being approx. 470-times less active than B/PI. Cyclized 82-108 peptide retained bactericidal activity but did not improve in capacity to neutralize endotoxin.

Amino Acid Sequence↗
PubMed1992

Are plasma endotoxin levels related to burn size and prognosis?

Plasma endotoxin concentrations were determined in 42 patients with burns covering more than 20 per cent of the body surface area, using the endotoxin-specific Endospecy assay and treatment of plasma by a new method developed by ourselves. The normal endotoxin level was 9.8 pg/ml or less. In the early period after injury when no infection was present, very few patients had an endotoxin level above 9.8 pg/ml and endotoxin levels did not correlate with the area of the burns or with prognosis. However, later in the clinical course, endotoxin levels were correlated significantly with the burned area and with the prognosis.

Adolescent↗
PubMed1985

The effect of endotoxin on bleomycin-induced lung fibrosis in the rat.

Bleomycin is a commonly used antineoplastic agent which produces dose- and time-dependent pneumonitis and fibrosis in humans. The mechanism of bleomycin-induced lung injury is uncertain. However, current data shows that bleomycin can generate reactive oxygen species such as superoxide and hydroxyl radicals. We therefore investigated whether intraperitoneal (i.p.) injection of endotoxin, a protectant for hyperoxia, could modulate the biochemical and morphological estimates of bleomycin-induced lung fibrosis in rats. However, pretreatment with multiple i.p. injections of endotoxin, combined with intratracheal bleomycin instillation, resulted in increased lung collagen content compared to bleomycin treatment alone and controls. Furthermore, morphological estimates of the severity of lung lesions present in the endotoxin-bleomycin treatment group were increased when compared with saline and endotoxin control lung lesions. These data indicate, in the current study design, that endotoxin did not reduce, but instead increased the severity of bleomycin-induced pulmonary fibrosis in rats. The mechanism for this increase in fibrosis may be the result of pre-existing endotoxin-induced cell injury.

Animals↗
PubMed1994

Lazaroid pretreatment preserves gas exchange in endotoxin-treated dogs.

PURPOSE: The lazaroids are a new class of potent free-radical scavengers. We tested whether U-74389G, a lazaroid, could attenuate some of the adverse cardiopulmonary effects of sepsis. METHODS: Dogs were randomized to receive either 10 mg/kg U-74389G (n = 10), or a saline control (n = 11). After baseline measurements of hemodynamics and gas exchange, they were then randomized to receive either 0.2 mg/kg endotoxin or a saline infusion. Measurements of hemodynamics and gas exchange were repeated. The study was concluded 70 minutes after endotoxin infusion and the lungs were then removed for histologic evaluation. RESULTS: In endotoxin-treated control animals, PO2 decreased (278 +/- 123 mm Hg to 67 +/- 13 mm Hg, P < .05) and intrapulmonary shunt increased (12.9% +/- 1.1% to 28.2% +/- 11.4%, P < .05) after endotoxin. Pretreatment with U-74389G attenuated the decrease in PO2 (476 +/- 61 mm Hg to 226 +/- 143) and the increase in intrapulmonary shunt (12.6% +/- 6.1% to 14.3% +/- 6.8%) observed after endotoxin. The extent of lung injury and systemic hemodynamics were similar between control or U-74389G-treated dogs. CONCLUSIONS: A free-radical-scavenger can attenuate the gas exchange defect commonly associated with endotoxin but it does not improve the derangement of systemic hemodynamics.

Analysis of Variance↗
PubMedDate not supplied

Protective effects of BAY U 3405, a thromboxane A2 receptor antagonist, in endotoxin shock.

The present study was designed to investigate the effects of BAY U 3405, a new thromboxane A2 (TxA2) receptor antagonist, in endotoxin shock. Endotoxin shock (ES) was induced in male rats by an i.v. injection of Salmonella enteritidis lipopolysaccharide (LPS; 20 mg kg-1). LPS administration caused animal death (survival = 0%, 48 h after endotoxin challenge), systemic hypotension, depressed phagocytosis and increased blood levels of TNF-alpha, TxB2 and 6-keto-PGF1 alpha, reduced white blood cell (WBC) count (ES = 5.9 +/- 1 x 10(3) mm-3; CTRL = 13.4 +/- 5 x 10(3) mm-3) and enhanced myeloperoxidase (MPO) activity, studied as a quantitative means for assessing leukocyte accumulation, in the ileum (ES = 0.24 +/- 0.7 U g-1 fresh tissue; CTRL = 0.13 +/- 0.04 U g-1 fresh tissue), in the heart (ES = 0.41 +/- 0.1 U g-1 fresh tissue; CTRL = 0.16 +/- 0.08 U g-1 fresh tissue) and in the lung (ES = 0.68 +/- 0.11 U g-1 fresh tissue; CTRL = 0.19 +/- 0.05 U g-1 fresh tissue). Furthermore, endotoxin administration produced characteristic damage of the gastric mucosa consisting of haemmorrhagic infiltrates. BAY U 3405 (30 mg kg-1 i.v., 30 min before endotoxin challenge) increased survival rate (45% survival rate 48 h after endotoxin challenge), reduced hypotension, decreased TNF-alpha levels in serum, enhanced phagocytic activity (ES = 25.6 +/- 1.9%, BAY U 3405 = 45.9 +/- 0.4%, P < 0.001) and lowered MPO activity in the ileum (0.14 +/- 0.05 U g-1 fresh tissue), in the heart (0.18 +/- 0.08 U g-1 fresh tissue) and in the lung (0.44 +/- 0.09 U g-1 fresh tissue). Finally, the gastric alterations were significantly reduced in rats pretreated with BAY U 3405. These data suggest that this thromboxane receptor antagonist might be a useful drug in shock conditions.

Analysis of Variance↗
PubMed2004

Endotoxin exposure in early life alters the development of anxiety-like behaviour in the Fischer 344 rat.

Previous research in the rat has demonstrated that neonatal exposure to bacterial endotoxin alters the level of anxiety-like behaviour displayed in adulthood. Currently, however, little is known about the emergence and development of this type of behaviour. Given the ability of neonatal endotoxin exposure to alter neural substrates involved in regulating anxiety, we tested the hypothesis that it may also alter the developmental trajectory of anxiety-like behaviour in the rat. Male Fischer 344 neonatal rats were treated with endotoxin (0.05 mg/kg lipopolysaccharide from Salmonella enteriditis) or vehicle on postnatal days 3 and 5. Age related changes in anxiety-like behaviour were subsequently investigated using the elevated plus maze apparatus at three developmental time points; adolescence (43 days), adulthood (80 days) and senescence (400 days). Neonatal endotoxin exposure was found to significantly increase circulating levels of corticosterone on postnatal days 3 and 5 at 4 h postadministration (P < 0.05). Additionally, endotoxin exposure was found to markedly alter anxiety-like behaviour in adulthood and senescence (P < 0.05). Specifically, adult and senescent endotoxin treated animals displayed significantly more anxiety-like behaviour than vehicle treated controls. Interestingly no significant differences in anxiety-like behaviour were observed between treatment groups during adolescence. These findings highlight the importance of the early life microbial environment in the development of emotional behaviour and suggests that neonatal infection may be an important predictor of susceptibility to anxiety related disorders in adult life.

Aging↗
PubMed2004

Endotoxin unmasks the role of gap junctions in the liver.

Gap junctions are thought to be necessary for proper tissue function. However, no clear hepatic phenotype has been described in patients lacking connexin 32 (Cx32), the principal gap junction in liver. To determine the physiological role of Cx32 in liver, we compared the response of wild type and Cx32-deficient mice to endotoxin, since this stress increases serum levels of hormones that bind to receptors that are asymmetrically distributed across the hepatic lobule. In hepatocyte couplets isolated from wild type mice, most hepatocytes could transfer microinjected dye to their neighbor even after treatment with endotoxin. Dye transfer was not observed in Cx32-deficient couplets. Treatment of hepatocyte couplets from wild type mice with vasopressin induced calcium (Ca(2+)) waves that crossed the couplets in a concentration-dependent fashion, but the delay in transmission was markedly prolonged at all concentrations in Cx32-deficient couplets. Expression of the vasopressin receptor and the inositol 1,4,5-trisphosphate receptor was not decreased by endotoxin or in Cx32-deficient couplets. Finally, endotoxin caused transient hypoglycemia and cholestasis in wild type animals, but hypoglycemia was slightly prolonged and cholestasis was much worse in Cx32-deficient mice treated with endotoxin. The hepatic response to endotoxin is markedly impaired in the absence of Cx32. Thus, an important role of gap junctions in the liver is to assure integrated and uniform tissue response in times of stress.

Animals↗
PubMed2005

Comparison of the rabbit pyrogen test and Limulus amoebocyte lysate (LAL) assay for endotoxin in hepatitis B vaccines and the effect of aluminum hydroxide.

The rabbit pyrogen test and Limulus amoebocyte lysate (LAL) assay have been used to detect endotoxins in vaccines, but interactions between the endotoxins and proteins or aluminum hydroxide can interfere with the results. Currently, the rabbit pyrogen test is used to detect endotoxin in hepatitis B (HB) vaccines even though the HB surface protein, the active ingredient, is over-expressed in and purified from eukaryotic cells which lack endotoxin. Therefore, we examined the possibility of replacing the animal tests with the more efficient LAL test. To this end, we determined whether the aluminum hydroxide in the HB vaccines affects the rabbit pyrogen test and the LAL assay. HB vaccines and HB protein solutions spiked with lipopolysaccharide (LPS) produced almost the same dose-dependent temperature rise in rabbits, indicating that the aluminum hydroxide in the HB vaccine does not interfere with the pyrogenic response in rabbit. In contrast, a spike recovery study showed that aluminum hydroxide interfered with the LAL clot and kinetic assays; however, the LAL clot assay was effective at detecting endotoxin without loss of LAL activity after serial dilution of the samples. Furthermore, there was good correlation in the LAL clot assay between the amount of LPS added and the amount recovered. However, both turbidimetric and chromogenic kinetic assays displayed no correlation between the LPS amount added and recovered. Our results suggest that the LAL clot assay is sensitive and reliable when samples are properly prepared, and can be used to replace the rabbit pyrogen test for the detection of endotoxin in HB vaccines.

Aluminum Hydroxide↗
PubMed2005

An electrokinetic study on a synthetic adsorbent of crystalline calcium silicate hydrate and its mechanism of endotoxin removal.

A synthetic, disposable adsorbent of crystalline calcium silicate hydrate, LRA product by Advanced Minerals Corp., has been found highly effective for endotoxin removal from aqueous solutions. Endotoxin removal by this adsorbent is greatly enhanced by the addition of an electrolyte, such as NaCl or Tris-HCl. The electrophoretic method has been used to study the mechanism of endotoxin adsorption. In many cases, adding the electrolyte increases the magnitude of negative zeta potential of the adsorbent in water, while endotoxin adsorption reduces the magnitude. It is hypothesized that ion-exchange between monovalent cations from the aqueous phase and Ca2+ ions near the surface of the adsorbent shift zeta potential of the adsorbent to the more negative direction. It is further hypothesized that endotoxins form cationic species through binding between its phosphate groups and Ca2+ ions dissolved from the adsorbent. The adsorption of endotoxins in the form of cationic species is enhanced by the increased negative zeta potential of the adsorbent when an electrolyte is added.

Adsorption↗
PubMed2004

Effect of pioglitazone on endotoxin-induced decreases in hepatic drug-metabolizing enzyme activity and expression of CYP3A2 and CYP2C11.

It has been reported that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands ameliorate the expression of inducible nitric oxide synthase (iNOS) by endotoxin. In the present study, we investigated the effect of pioglitazone, a potent PPAR-gamma ligand, on the endotoxin-induced reduction of hepatic drug-metabolizing enzyme activity and on the down-regulation of the expression of hepatic cytochrome P450 (CYP) 3A2 and CYP2C11 proteins in rats. Endotoxin (1 mg/kg) significantly decreased hepatic drug-metabolizing enzyme activity in vivo, as represented by the systemic clearance of antipyrine and protein levels of CYP3A2 and CYP2C11 24 h after intraperitoneal injection. Pretreatment with pioglitazone (10 mg/kg, 4 times at 10-min intervals) significantly protected the endotoxin-induced decreases in the systemic clearance of antipyrine and protein levels of CYP3A2, but not CYP2C11, with no biochemical and histopathological changes in the liver. Pioglitazone alone had no effect on the systemic clearance of antipyrine and protein levels of CYP3A2 or CYP2C11. Pioglitazone significantly protected endotoxin-induced overexpression of iNOS in the liver, but not the overproduction of nitric oxide (NO) in plasma. It is unlikely that the protective effect of pioglitazone against endotoxin-induced decreases in the hepatic drug-metabolizing enzyme activity and protein levels of CYP3A2 in the liver is due to the inhibition of the overproduction of NO.

Animals↗
PubMed2006

Anti-endotoxin hyperimmune globulin attenuates portal cytokinaemia, phagocytic cell priming, and acute lung injury after lower limb ischaemia-reperfusion injury.

OBJECTIVES: Acute limb ischaemia is a common and often lethal clinical event. Reperfusion of an ischaemic limb has been shown to induce a remote gut injury associated with transmigration of endotoxin into the portal and systemic circulation, which in turn has been implicated in the conversion of the sterile inflammatory response to a sepsis syndrome, after lower torso ischaemia-reperfusion injury. This study tests the hypothesis that an anti-endotoxin hyperimmune globulin attenuates ischaemia-reperfusion (I/R) associated sepsis syndrome. DESIGN: Prospective, randomised placebo controlled trial, animal experiment. MATERIALS AND METHODS: Experimental porcine model, bilateral hind limb I/R injury, randomised to receive anti-endotoxin hyperimmune globulin or placebo. RESULTS: Bilateral hind limb I/R injury significantly increased intestinal mucosal acidosis, portal endotoxaemia, plasma cytokine (TNF-alpha, IL-6, IL-8) concentrations, circulating phagocytic cell priming and pulmonary leukosequestration, oedema, and capillary-alveolar protein leak. Conversely, pigs treated with anti-endotoxin hyperimmune globulin (IgG) 20mg/kg at onset of reperfusion had significantly reduced portal endotoxaemia, early circulating phagocytic cell priming, plasma cytokinaemia and attenuation of acute lung injury. CONCLUSIONS: Endotoxin translocation across a hyperpermeable gut barrier, phagocytic cell priming and cytokinaemia are key events of limb I/R injury induced systemic inflammation and acute lung injury. This study shows that an anti-endotoxin hyperimmune globulin attenuates portal endotoxaemia, which may reduce early phagocytic cell activation, cytokinaemia and ultimately acute lung injury.

Animals↗
PubMed2006

A pilot study to assess residential endotoxin and blood IgE in a group of pregnant women from Trujillo, Peru.

OBJECTIVE: This November 2003 pilot study investigates the correlation between serum IgE and residential endotoxin levels from a group of 18 pregnant women living in Trujillo, Peru, and investigates the impact of the demographic and lifestyle factors of this group on the IgE and endotoxin levels measured. METHODS: Serum samples were collected from 19 subjects and analyzed for IgE. Dust samples were collected from the mattresses of 18 subjects and measured for endotoxin levels. A questionnaire was used to obtain demographic, socioeconomic, and lifestyle information for each subject. RESULTS: Geometric means for IgE and endotoxin were 246.8 (GSD=4.3, n=19) IU/mL and 66.5 EU/mg (GSD=1.7, n=18), respectively. Log-transformed IgE and endotoxin were not correlated (R2=0.02; p=0.60). CONCLUSIONS: Residential endotoxin and serum IgE were not correlated in this group. Potential selection bias and sample size are major limitations of the study. However, 74% (14/19) of the subjects in this study had an IgE over 100 IU/mL, a level generally considered elevated.

Adolescent↗
PubMed2005

Ischemic and endotoxin pre-conditioning reduce lung reperfusion injury-induced surfactant alterations.

BACKGROUND: Pulmonary ischemia/reperfusion injury represents a common clinical phenomenon after lung transplantation, pulmonary embolism, and cardiac surgery with extracorporeal circulation. We investigated the influence of ischemic and endotoxin pre-conditioning on gas exchange and surfactant properties in a canine model of ischemia/reperfusion injury. METHODS: Twenty-six foxhounds underwent 3 hours of warm ischemia of the left lung, followed by 8 hours of reperfusion. Ischemic pre-conditioning was performed for either 5 minutes (IPC-5) or by 2 10-minute ischemic periods (IPC-10), before ischemia. For endotoxin pre-conditioning, dogs were pre-treated by a daily intravenous application of increasing amounts of endotoxin for 6 days. No pre-conditioning was performed in the controls. Bronchoalveolar lavage was performed before ischemia/reperfusion injury (baseline) and after the 8-hour reperfusion period in the non-injured right and in the reperfused left lung. Bronchoalveolar lavage fluids were analyzed for the phospholipid-protein ratio, the content of large surfactant aggregates, the phospholipid and neutral lipid profile, the surfactant protein (SP) content, and for biophysical activity. RESULTS: Severe surfactant alterations were observed in the ischemia/reperfusion-injured left lung, with increased protein concentrations and depressed concentrations of large surface aggregates, SP-B, dipalmitoylated phosphatidylcholine, and phosphatidylglycerol. Endotoxin pre-conditioning and IPC-5 were both capable of greatly preventing the ischemia/reperfusion injury-related deterioration of surfactant properties. IPC-10 exerted no effects. Endotoxin pre-conditioning and IPC-5, but not IPC-10, also prevented loss of gas exchange. CONCLUSIONS: Ischemic and endotoxin pre-conditioning may protect against impairment of gas exchange in ischemia/reperfusion injury by restoring physiological surfactant properties.

Animals↗
PubMed2004

Inhalation of low-dose endotoxin favors local T(H)2 response and primes airway phagocytes in vivo.

BACKGROUND: We previously reported that inhalation of 5 mug of endotoxin (30,000 endotoxin units [EU]) induced airway neutrophilia and decreased phagocytosis by airway monocytes, macrophages, and neutrophils. Conversely, we recently reported that very low doses of endotoxin, which are not associated with neutrophil influx, enhance response to allergen in the nasal and bronchial airway. OBJECTIVE: We sought to determine whether endotoxin (0-10,000 EU) at doses that do not induce airway neutrophilia prime airway phagocyte function, alter expression of relevant cell-surface receptors (membrane-bound CD14 [mCD14] and CD11b/CR3), and cause induction of a T(H)2 cytokine profile in the airway. METHODS: Thirteen nonallergic healthy volunteers were challenged on separate occasions with escalating doses of Clinical Center Reference Endotoxin (CCRE; 0, 2500, 5000, and 10,000 EU), with 9 volunteers completing the entire dose range. Sputum cells and fluid-phase components were recovered 6 hours after challenge. Sputum inflammatory cells were analyzed by means of flow cytometry for mCD14 and CD11b expression and immune function (phagocytosis of IgG-opsonized zymosan particles). RESULTS: At all doses of CCRE, there was no increase in airway neutrophils relative to that caused by saline. However, inhalation of 10,000 EU enhanced phagocytosis (monocytes and macrophages), upregulated expression of CD11b and mCD14 (monocytes and neutrophils), and increased IL-13 levels, whereas IFN-gamma levels were significantly decreased. CONCLUSION: The 10,000-EU dose of CCRE is subthreshold for inducing airway neutrophilia but primes phagocyte function and cell-surface receptor expression in the presence of increased IL-13 and decreased IFN-gamma levels. We speculate that low-dose endotoxin challenge skews airway inflammation in a T(H)2 direction in vivo .

Administration, Inhalation↗
PubMed2026

Acyloxyacyl Hydrolase-Mediated Lipopolysaccharide Inactivation Limits Macrophage Endotoxin Tolerance and Promotes Inflammation and Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis, a chronic liver disease, is characterized by persistent low-grade inflammation, partially driven by gut-derived lipopolysaccharide. Although repeated lipopolysaccharide exposure can induce endotoxin tolerance in innate immune cells, its role in chronic liver diseases remains unclear. Acyloxyacyl hydrolase is an endogenous enzyme that inactivates lipopolysaccharide, potentially modulating this process. We aimed to investigate how acyloxyacyl hydrolase regulates endotoxin tolerance in Kupffer cells and how this affects hepatic inflammation and fibrosis during metabolic dysfunction-associated steatohepatitis progression. METHODS: Acyloxyacyl hydrolase-deficient mice and wild-type controls were subjected to multiple dietary metabolic dysfunction-associated steatohepatitis models. Inflammatory responses, fibrosis, and transcriptomic changes in liver tissues and isolated Kupffer cells were analyzed. Endotoxin tolerance was modulated through &#x3b2;-glucan administration or lipopolysaccharide preconditioning. Lipopolysaccharide bioactivity was assessed using Toll-like receptor 4-reporter cell assays. RESULTS: Lipopolysaccharide-preconditioned Kupffer cells exhibited reduced proinflammatory cytokine production and transcriptional suppression of inflammatory pathways, indicating tolerance. Despite slight elevation of plasma lipopolysaccharide levels in metabolic dysfunction-associated steatohepatitis, upregulation of hepatic acyloxyacyl hydrolase positively correlated with disease severity, suggesting enhanced lipopolysaccharide inactivation but impaired establishment of tolerance. In contrast, acyloxyacyl hydrolase-deficient Kupffer cells displayed reinforced endotoxin tolerance, leading to diminished hepatic inflammation and fibrosis. Reversal of tolerance using &#x3b2;-glucan reactivated inflammatory and fibrogenic responses in acyloxyacyl hydrolase-deficient mice, whereas tolerance induction by low-dose lipopolysaccharide preconditioning mitigated metabolic dysfunction-associated steatohepatitis pathology, supporting the protective role of macrophage tolerance in chronic liver injury. CONCLUSIONS: Endotoxin tolerance in Kupffer cells represents a protective mechanism against chronic liver inflammation and fibrosis. Acyloxyacyl hydrolase regulates this state by limiting bioactive lipopolysaccharide, thereby modulating the establishment of endotoxin tolerance and downstream inflammatory and fibrotic responses. Enhancing macrophage tolerance by utilizing lipopolysaccharide may offer a novel therapeutic avenue to control the progression of metabolic dysfunction-associated steatohepatitis.

AOAH↗