Renal effects of treatment with a TLR4-inhibitor in conscious septic sheep

Fenhammar, Johan; Rundgren, Mats; Hultenby, Kjell; Forestier, Jakob; Taavo, Micael; Kenne, Ellinor; Weitzberg, Eddie; Eriksson, S.; Özenci, Volkan; Wernerson, Annika; Frithiof, Robert

doi:10.1186/preaccept-1770070480124389

Cited by 14 publications

(33 citation statements)

References 34 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…, Fenhammar et al . ). Stimulated leucocytes may both participate in eradicating invading pathogens as well as causing collateral damage to renal tissues.…”

Section: Leucocyte Infiltration Tlr4 and Si‐akimentioning

confidence: 97%

“…In a follow‐up study Fenhammar et al . () demonstrated that TAK‐242 reversed a pronounced decline in urine output and GFR, when used as intravenous treatment twelve hours into ovine hyperdynamic E. coli sepsis. This was associated with reduced endothelial swelling in the glomeruli, but compared to sham‐treated animals, there were no differences with regard to blood pressure, RBF or renal microcirculation, suggesting that hemodynamic factors were not pivotal for the SI‐AKI to develop.…”

Section: Targeting Tlr4 In Experimental Models Of Si‐akimentioning

confidence: 99%

“…Glomerular endothelial swelling and diminished glomerular endothelial fenestrae were noted in mice subjected to LPS or TNF‐α as well as in sheep subjected to live E. coli infusion (Fenhammar et al . , Xu et al . ).…”

Section: Renal Endothelial Effects Of Tlr4 Activationmentioning

confidence: 99%

See 2 more Smart Citations

Physiological aspects of Toll‐like receptor 4 activation in sepsis‐induced acute kidney injury

2016

View full text Add to dashboard Cite

Sepsis‐induced acute kidney injury (SI‐AKI) is common and associated with high mortality. Survivors are at increased risk of chronic kidney disease. The precise mechanism underlying SI‐AKI is unknown, and no curative treatment exists. Toll‐like receptor 4 (TLR4) activates the innate immune system in response to exogenous microbial products. The result is an inflammatory reaction aimed at clearing a potential infection. However, the consequence may also be organ dysfunction as the immune response can cause collateral damage to host tissue. The purpose of this review is to describe the basis for how ligand binding to TLR4 has the potential to cause renal dysfunction and the mechanisms by which this may take place in gram‐negative sepsis. In addition, we highlight areas for future research that can further our knowledge of the pathogenesis of SI‐AKI in relation to TLR4 activation. TLR4 is expressed in the kidney. Activation of TLR4 causes cytokine and chemokine release as well as renal leucocyte infiltration. It also results in endothelial and tubular dysfunction in addition to altered renal metabolism and circulation. From a physiological standpoint, inhibiting TLR4 in large animal experimental SI‐AKI significantly improves renal function. Thus, current evidence indicates that TLR4 has the ability to mediate SI‐AKI by a number of mechanisms. The strong experimental evidence supporting a role of TLR4 in the pathogenesis of SI‐AKI in combination with the availability of pharmacological tools to target TLR4 warrants future human studies.

show abstract

“…, Fenhammar et al . ). Stimulated leucocytes may both participate in eradicating invading pathogens as well as causing collateral damage to renal tissues.…”

Section: Leucocyte Infiltration Tlr4 and Si‐akimentioning

confidence: 97%

Section: Targeting Tlr4 In Experimental Models Of Si‐akimentioning

confidence: 99%

See 1 more Smart Citation

Physiological aspects of Toll‐like receptor 4 activation in sepsis‐induced acute kidney injury

2016

View full text Add to dashboard Cite

show abstract

“…Surgery was performed aseptically and under general anesthesia as previously described [17]. Anesthesia was induced by an intravenous injection of sodium thiopental (15 mg/kg) in 0.9% saline.…”

Section: Methodsmentioning

confidence: 99%

The novel nitric oxide donor PDNO attenuates ovine ischemia-reperfusion induced renal failure

Nilsson

Sandin

Gustafsson

et al. 2017

ICMx

Self Cite

View full text Add to dashboard Cite

BackgroundRenal ischemia-reperfusion injury is a common cause of acute kidney injury in intensive care and surgery. Recently, novel organic mononitrites of 1,2-propanediol (PDNO) were synthesized and shown to rapidly and controllably deploy nitric oxide in the circulation when administered intravenously. We hypothesized that intravenous infusion of PDNO during renal ischemia reperfusion would improve post-ischemic renal function and microcirculation.MethodsSixteen sheep were anesthetized, mechanically ventilated, and surgically instrumented. The left renal artery was clamped for 90 min, and the effects of ischemia were studied for a total of 8 h. Fifteen minutes prior to the release of the clamp, intravenous infusions of PDNO (n = 8) or vehicle (1,2 propanediol + inorganic nitrite, n = 8) were initiated (180 nmol/kg/min for 30 min, thereafter 60 nmol/kg/min for the remainder of the experiment).ResultsRenal artery blood flow, cortical and medullary perfusion, and diuresis and creatinine clearance decreased in the left kidney post ischemia. However, in the sheep treated with PDNO, diuresis and creatinine clearance in the left kidney were significantly higher post ischemia compared to vehicle-treated animals (1.7 ± 0.5 vs 0.7 ± 0.3 ml/kg/h, p = 0.04 and 7.5 ± 2.1 vs 1.7 ± 0.6 ml/min, p = 0.02, respectively). Left renal medullary perfusion and oxygen uptake were higher in the PDNO group (73 ± 9 vs 37 ± 5% of baseline, p = 0.004 and 2.6 ± 0.4 vs 1.6 ± 0.3 ml/min, p = 0.02, respectively). PDNO significantly increased renal oxygen consumption and reduced the oxygen utilization for sodium reabsorption (p = 0.03 for both). Mean arterial blood pressure was significantly reduced by PDNO (83 ± 3 vs 94 ± 3 mmHg, p = 0.02) but was still within normal limits. Total renal blood flow was not affected, and there were no signs of increased blood methemoglobin concentrations or tachyphylaxis.ConclusionsThe novel nitric oxide donor PDNO improved renal function after ischemia. PDNO also prevented the persistent reduction in medullary perfusion during reperfusion and improved renal oxygen utilization without severe side effects.

show abstract

“…Other studies to decrease pro‐inflammatory cytokine release via inhibition of signalling have targeted the Toll‐like receptor itself. Several studies have been documenting the anti‐inflammatory ability of a novel small molecule known as TAK‐242, which is a TLR4 inhibitor . Two novel compounds known as C34 and C35 have also been demonstrated to be inhibitors of TLR4 by direct binding.…”

Section: Novel Drug Targetsmentioning

confidence: 99%

Current and novel anti-inflammatory drug targets for inhibition of cytokines and leucocyte recruitment in rheumatic diseases

Szollosi

Manzoor

Aquilato

et al. 2017

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives Many studies of disease state mechanisms reveal that unbridled inflammation is to blame for many of the symptoms associated with autoimmune diseases such as Crohn’s and Rheumatoid Arthritis (RA). While therapies aimed at decreasing levels of pro‐inflammatory cytokines exist, some have failed clinically or have extensive adverse effects. The aim of this review is to discuss common drug targets for anti‐inflammatory therapies as well as explore potential mechanisms of action for new therapies. Various studies done on novel mechanisms targeting pro‐inflammatory cytokine release as well as leukocyte chemotaxis have been researched for discussion here. Both of these contribute to tissue injury and patient symptoms in inflammatory and autoimmune disease states. Key findings While many current drug targets suppress inflammation via the receptor, research aimed at identifying new compounds and signaling mechanisms is ongoing to identify new targets within pro‐inflammatory signaling pathways, or specific immune cell types. Conclusions While glucocorticoids and monoclonal antibodies have shown to be efficacious, some patients have encountered mixed results. Biologic therapies also come with a high price tag Thus, novel compounds with new immune drug targets are ideal for patients whose therapies have not been successful.

show abstract

Renal effects of treatment with a TLR4-inhibitor in conscious septic sheep

Cited by 14 publications

References 34 publications

Physiological aspects of Toll‐like receptor 4 activation in sepsis‐induced acute kidney injury

Physiological aspects of Toll‐like receptor 4 activation in sepsis‐induced acute kidney injury

The novel nitric oxide donor PDNO attenuates ovine ischemia-reperfusion induced renal failure

Current and novel anti-inflammatory drug targets for inhibition of cytokines and leucocyte recruitment in rheumatic diseases

Contact Info

Product

Resources

About