Experimental TLR4 inhibition improves intestinal microcirculation in endotoxemic rats

Soltow, Marieke; Zimmermann, Katrin; Pavlović, Dragan; Johnston, Brent; Lehmann, Christian

doi:10.1016/j.mvr.2015.06.004

Cited by 4 publications

(5 citation statements)

References 39 publications

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“…The length of the lipid chains of lipid A mimetics appeared crucial for TLR4 activation, leading to the discovery of CRX-526: a lipid A mimetic that is itself unable to induce inflammatory signalling in vitro and in vivo [ 108 ]. CRX-526 reduced pro-inflammatory effects in in vitro and in vivo studies in disease models of IBD [ 109 ], diabetic nephropathy [ 110 ], and gram-negative sepsis [ 111 ], but has not progressed into clinical trials.…”

Section: Inhibition Of the Md2 Co-receptormentioning

confidence: 99%

Inhibition of TLR4 signalling to dampen joint inflammation in osteoarthritis

Bartels,

van Lent,

van der Kraan

et al. 2023

Rheumatology

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Local and systemic low-grade inflammation, mainly involving the innate immune system, plays an important role in the development of OA. A receptor playing a key role in initiation of this inflammation is the pattern-recognition receptor Toll-like receptor 4 (TLR4). In the joint, various ligands for TLR4, many of which are damage-associated molecular patterns (DAMPs), are present that can activate TLR4 signalling. This leads to the production of pro-inflammatory and catabolic mediators that cause joint damage. In this narrative review, we will first discuss the involvement of TLR4 ligands and signalling in OA. Furthermore, we will provide an overview of methods for inhibit, TLR4 signalling by RNA interference, neutralizing anti-TLR4 antibodies, small molecules and inhibitors targeting the TLR4 co-receptor MD2. Finally, we will focus on possible applications and challenges of these strategies in the dampening of inflammation in OA.

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Section: Inhibition Of the Md2 Co-receptormentioning

confidence: 99%

Inhibition of TLR4 signalling to dampen joint inflammation in osteoarthritis

Bartels,

van Lent,

van der Kraan

et al. 2023

Rheumatology

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“…A total of 108 articles were identified. After reviewing the titles and abstracts, which was followed by assessing the full text, 50 articles [40][41][42][43][44][45][46][47][48][49][50][51][52][53] were included (Figure 1), and most of them were animal studies. These studies reported pathogenesis, including endothelial dysfunction, leukocyte recruitment and adhesion, microthrombus formation, microcirculation hypoperfusion, and redistribution of intestinal wall blood flow.…”

Section: Resultsmentioning

confidence: 99%

“…[41] Selective inhibition of adenosine triphosphate (ATP)-sensitive potassium (K ATP ) channels in vasodilatory shock by continuous infusion of glipizide could partially restore vasomotor tone in endotoxemic rats and improve systemic hemodynamics in septic rats. [42] Tetrahydrobiopterinl, [22] toll-like receptor World J Emerg Med, Vol 13, No 3, 2022 4 (TLR4) antagonist, [43] and desmopressin [44] have an effect on improving the intestinal microcirculation. There are individual reports of vasopressin V1A receptors, [45,46] physostigmine, [47] and dehydroepiandrosterone combined with orthovanadate, [48] showing that they could improve microcirculation.…”

Section: Other Treatmentsmentioning

confidence: 99%

Intestinal microcirculation dysfunction in sepsis: pathophysiology, clinical monitoring, and therapeutic interventions

Tang¹

2022

World J Emerg Med

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BACKGROUND: Intestinal microcirculation dysfunction is an important factor that causes poor prognosis in sepsis patients and is an important pathophysiological basis for the occurrence and development of sepsis.DATA RESOURCES: PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched from inception to August 1, 2021. The search was limited to the English language only. Two reviewers independently identified studies related to intestinal microcirculation dysfunction in sepsis. Exclusion criteria were duplicate articles according to multiple search criteria.RESULTS: Fifty articles were included, and most of them were animal studies. These studies reported pathogenesis, including endothelial dysfunction, leukocyte recruitment and adhesion, microthrombus formation, microcirculation hypoperfusion, and redistribution of intestinal wall blood flow. The monitoring methods of intestinal microcirculation were also diverse, including handheld microscopes, intravital microscopy (IVM), laser Doppler blood flow instruments, laser speckle contrast imaging, tissue refl ectance spectrophotometry, biochemical markers of intestinal ischemia, and histopathological examination. In view of the related pathogenesis of intestinal microcirculation disorder in sepsis, existing studies also have diff erent opinions on its treatment.CONCLUSIONS: Limited by monitoring, there are few clinical studies on intestinal microcirculation dysfunction in sepsis. Related research mainly focuses on basic research, but some progress has also been made. Therefore, this review may provide a reference for future research on intestinal microcirculation dysfunction in sepsis.

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“…TLR4 levels are increased in IBS patients, which suggests some degree of immune dysfunction is occurring [123]. TLR4 activation has also been shown to impair the intestinal microcirculation in experimental models of endotoxemia, acute pancreatitis and NEC [51,124,125]. As assessed with IVM, TLR4 blockade can attenuate changes in functional capillary density in the microcirculation of endotoxemic rats [124].…”

Section: Irritable Bowel Syndromementioning

confidence: 99%

“…TLR4 activation has also been shown to impair the intestinal microcirculation in experimental models of endotoxemia, acute pancreatitis and NEC [51,124,125]. As assessed with IVM, TLR4 blockade can attenuate changes in functional capillary density in the microcirculation of endotoxemic rats [124]. While the role of inflammation in IBS requires further investigation, current evidence suggests that anti-inflammatory therapies may have some utility.…”

Section: Irritable Bowel Syndromementioning

confidence: 99%

Imaging of the Intestinal Microcirculation during Acute and Chronic Inflammation

Dickson

Malitan

Lehmann

2020

Biology

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Because of its unique microvascular anatomy, the intestine is particularly vulnerable to microcirculatory disturbances. During inflammation, pathological changes in blood flow, vessel integrity and capillary density result in impaired tissue oxygenation. In severe cases, these changes can progress to multiorgan failure and possibly death. Microcirculation may be evaluated in superficial tissues in patients using video microscopy devices, but these techniques do not allow the assessment of intestinal microcirculation. The gold standard for the experimental evaluation of intestinal microcirculation is intravital microscopy, a technique that allows for the in vivo examination of many pathophysiological processes including leukocyte-endothelial interactions and capillary blood flow. This review provides an overview of changes in the intestinal microcirculation in various acute and chronic inflammatory conditions. Acute conditions discussed include local infections, severe acute pancreatitis, necrotizing enterocolitis and sepsis. Inflammatory bowel disease and irritable bowel syndrome are included as examples of chronic conditions of the intestine.

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Experimental TLR4 inhibition improves intestinal microcirculation in endotoxemic rats

Cited by 4 publications

References 39 publications

Inhibition of TLR4 signalling to dampen joint inflammation in osteoarthritis

Inhibition of TLR4 signalling to dampen joint inflammation in osteoarthritis

Intestinal microcirculation dysfunction in sepsis: pathophysiology, clinical monitoring, and therapeutic interventions

Imaging of the Intestinal Microcirculation during Acute and Chronic Inflammation

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