Toll-Like Receptor (TLR) Response Tolerance: A Key Physiological "Damage Limitation" Effect and an Important Potential Opportunity for Therapy
ABSTRACT Endotoxin tolerance is a well known phenomenon, described both in vivo and in vitro, in which repeated exposure to endotoxin results in a diminished response, usually characterised as a reduction in pro-inflammatory cytokine release. The mechanisms responsible for endotoxin tolerance have become clear in recent years as our understanding of the pathways through which endotoxin mediates its effects has increased. The principal cell surface receptor for the lipopolysaccharide (LPS) component of endotoxin is Toll-Like Receptor 4 (TLR-4), a member of a highly conserved family of receptors specific for highly conserved bacterial and viral components which play key roles in the early inflammatory response to pathogens. As our understanding of the part played by TLR-4 signalling in endotoxin has increased, so it has become clear that response tolerance occurs to other TLR ligands in addition to LPS/endotoxin. Clinically, endotoxin/TLR response tolerance is thought to play an important part in susceptibility to reinfection in patients treated for severe sepsis. Whilst this may have developed as a protective evolutionary mechanism to prevent death caused by overwhelming cytokine release in sepsis, in the modern era of antibiotics, vasopressors and organ support, undoing this downregulation or "re-booting" the immune system may be a useful therapeutic target in the post-septic patient. This should, however, be approached with caution as it is possible that endotoxin/TLR response tolerance is also a physiological regulatory mechanism in areas normally exposed to bacterial-derived TLR-ligands such as the gut and liver.
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ABSTRACT: A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection.International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 04/2011; 29(6):551-63. DOI:10.1016/j.ijdevneu.2011.04.004 · 2.92 Impact Factor
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ABSTRACT: The adverse respiratory effects of agricultural dust inhalation are mediated in part by endotoxin, a constituent of gram-negative bacterial cell walls. This study quantified personal work-shift exposures to inhalable dust, endotoxin, and its reactive 3-hydroxy fatty acid (3-OHFA) constituents among workers in grain elevators, cattle feedlots, dairies, and on corn farms. Exposures were compared with post-work-shift nasal lavage fluid inflammation markers and respiratory symptoms. Breathing-zone personal air monitoring was performed over one work shift to quantify inhalable dust (Institute of Medicine samplers), endotoxin (recombinant factor C [rFC] assay), and 3-OHFA (gas chromatography/mass spectrometry). Post-shift nasal lavage fluids were assayed for polymorphonuclear neutrophils (PMN), myeloperoxidase (MPO), interleukin 8 (IL-8), albumin, and eosinophilic cation protein (ECP) concentrations. The geometric mean (GSD) of endotoxin exposure (rFC assay) among the 125 male participants was 888 +/- (6.5) EU/m(3), and 93% exceeded the proposed exposure limit (50 EU/m(3)). Mean PMN, MPO, albumin, and ECP levels were two- to threefold higher among workers in the upper quartile of 3-OHFA exposure compared to the lowest exposure quartile. Even numbered 3-OHFA were most strongly associated with nasal inflammation. Symptom prevalence was not elevated among exposed workers, possibly due to endotoxin tolerance or a healthy worker effect in this population. This is the first study to evaluate the relationship between endotoxin's 3-OHFA constituents in agricultural dust and nasal airway inflammation. More research is needed to characterize the extent to which these agents contribute to respiratory disease among agricultural workers.Journal of Toxicology and Environmental Health Part A 01/2010; 73(1):5-22. DOI:10.1080/15287390903248604 · 1.83 Impact Factor
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ABSTRACT: We investigated, whether the Toll-like receptors (TLRs)-2/6-agonist fibroblast-stimulating lipopeptide-1 (FSL-1), like the TLR-4 agonist lipopolysaccharide (LPS), induces a state of tolerance. We further tested the influence of repeated pre-treatment with FSL-1 on the animals' responsiveness to LPS. Abdominal temperature was recorded in unrestrained guinea-pigs with intra-abdominally implanted radiotransmitters. Circulating concentrations of tumour necrosis factor (TNF) and interleukin-6 (IL-6) were measured with specific bioassays. We tested the effects of intra-arterial (i.a.) or intraperitoneal (i.p.) injections of 100 microg kg(-1) FSL-1, repeated five times at intervals of 3 days. The animals' responses to i.a. or i.p. injections of 10 microg kg(-1) LPS were determined another 3 days later and compared to those of naïve guinea-pigs. The FSL-1-induced TNF peak was significantly attenuated starting with the third i.a. administration, while fever was unimpaired and the IL-6-peak just tended to decrease. Fever and IL-6 in response to i.a. injections of LPS were identical in both groups, while circulating TNF was higher in naïve compared to FSL-1 pre-treated animals. The effects of repeated i.p. injections of FSL-1 were more pronounced resulting in attenuation of fever as well as circulating TNF and IL-6, the strongest reduction observed after the third stimulation with FSL-1. Repeated i.p. pre-treatment with FSL-1 induced hyporesponsiveness to i.p. administration of LPS compared to naïve animals with regard to fever and especially with regard to LPS-induced formation of cytokines. There is a development of tolerance to FSL-1 and cross-tolerance between FSL-1 and LPS depending on the route of administration of the respective TLR-2/6 and TLR-4 agonists.Acta Physiologica 04/2009; 197(1):35-45. DOI:10.1111/j.1748-1716.2009.01989.x · 4.25 Impact Factor