Table 1.
In vivo studies on the role of TLRs in Ischemia / Reperfusion (I/R) Injury and Hemorrhagic Shock / Resuscitation (HS/R)
| Publication | Model | Findings |
|---|---|---|
| DeMaria J Trauma 1993 | Systemic HS/R | TLR4 deficient mice had lower levels of TNF-α and improved five day survival and survival time compared to TLR4 competent mice exposed to HS/R. |
| Pellicane J Surg Res 1994 | Systemic HS/R | TLR4 deficiency was associated with reduced TNF-α and faster return of lactate levels to baseline following HS/R. |
| Frink Mol Immunol 2007 | Trauma HS/R | Laparotomy and HS/R in TLR4 deficient mice showed attenuated levels of chemokines in plasma, lung tissue and Kupffer cell supernatants, and reduced lung neutrophil infiltration compared to TLR4 competent controls. |
| Prince J Am Coll Surg 2006 | Liver in HS/R | HS/R induced elevation in serum ALT, IL-6 and IL-10 were attenuated in TLR4 deficient mice, as were hepatic NF-κB activation and hepatic TNF-α, IL-10, and iNOS mRNA levels. |
| TLR2 deficient and CD14 deficient mice were not protected against HS/R induced liver injury or systemic inflammation. | ||
| Meng Am J Physiol Regul Integr Comp Physiol 2005 | Myocardium in HS | HS without resuscitation resulted in increased plasma and myocardial TNF-α and depressed myocardial contractility, which were both attenuated in TLR4 deficient mice. |
| Barsness Am J Physiol Regul Integr Comp Physiol 2004 | Lung in HS | Hemorrhage-induced lung injury was associated with lower levels of TNF-α, less neutrophil accumulation, and reduced protein permeability in TLR4 deficient mice. |
| Chen Shock 2008 | Lung HS/R | TLR4 deficiency was associated with reduced acute lung injury as evidenced by lower levels of IL-10, myeloperoxidase, and HO-1, and lower p38 MAPK activation, in response to HS/R. |
| Wu Hepatobiliary Pancreat Dis Int 2004 | Liver I/R | TLR4 deficient mice had lower systemic levels of AST and TNF-α, as well as lower hepatic TNF-α mRNA and myeloperoxidase after hepatic I/R compared to TLR4 competent mice. |
| Zhai J Immunol 2004 | Liver I/R | TLR4 deficient but not TLR2 deficient mice were protected against liver I/R injury as assessed by liver function, histology, and local cytokine / chemokine production. |
| Hepatocellular damage from I/R mediated by TLR4 required IRF3 but not MyD88 signaling. | ||
| Shen Am J Transplant 2005 | Liver I/R | TLR4 deficient mice had reduced I/R injury by liver function, histology, neutrophil infiltration, and TNF-α production compared to TLR2 deficient or wild type mice. |
| TLR4 deficiency was associated with increased HO-1 production, and tin protoporphyrin-mediated HO-1 inhibition removed protection against I/R induced hepatic damage in TLR4 deficiency. | ||
| Tsung J Exp Med 2005 | Liver I/R | TLR4 deficient mice had reduced damage in hepatic I/R, and neutralizing antibody to HMGB1 failed to protect TLR4 deficient mice from hepatic I/R injury but did protect TLR4 competent mice. In wild type mice, administration of recombinant HMGB1 worsened I/R injury. |
| Tsung J Immunol 2005 | Liver I/R | Chimeric wild type mice bearing TLR4 mutant hemopoietic cells and TLR4 mutant mice transplanted with their own bone marrow were protected against hepatic I/R injury, but TLR4 mutant mice transplanted with wild type bone marrow exhibited injury from I/R. Additionally, depletion of phagocytes reduced injury in wild type mice but did not afford additional protection to TLR4 mutant mice. |
| Tsung J Leukoc Biol 2007 | Liver I/R | Increasing DC numbers worsened I/R injury in wild type mice but not TLR4 deficient mice. |
| Tsung J Exp Med 2007 | Liver I/R | Hypoxia-induced HMGB1 release by hepatocytes was mediated by TLR4 dependent ROS production and downstream CaMK signaling. Antioxidant treatment or CaMK inhibition in vivo both reduced hepatic I/R injury in wild type mice but not TLR4 deficient mice. |
| Shishido Circulation 2003 | Cardiac I/R | TLR2 deficient mice had improved survival compared to wild type mice in response to myocardial infarction. They had reduced TFG-β1 and collagen type 1 mRNA, and reduced myocardial fibrosis in the non-infarct area accompanied by higher fractional shortening. Left ventricular dimensions at end diastole were smaller in TLR2 deficiency after injury. |
| Oyama Circulation 2004 | Cardiac I/R | TLR4 deficient mice had smaller infarcts, less neutrophil infiltration, fewer lipid peroxides, and less complement deposition in the myocardium following I/R compared to wild type mice. Systemic IL-12 and INF-γ levels were lower in TLR4 deficient mice after I/R. |
| Kaczorowski Transplantation 2007 | Cardiac I/R | A cardiac cold I/R model performed by transplantation of hearts between TLR4 deficient and wild type mice showed intermediate levels of serum IL-6 and MCP-1, and intragraft TNF- α, IL-6, IL-1β and ICAM-1 mRNA levels were found in TLR4 deficient to wild type or wild type to TLR4 deficient transplants, compared with low levels for TLR4 deficient to TLR4 deficient mice and high levels for wild type to wild type transplantation. |
| Kim BMC Physiol 2007 | Cardiac I/R | TLR4 deficiency was associated with reduced infarct size and inflammatory cytokines, but also reduced left ventricular developed pressure, and echocardiography showed no functional difference from wild type. |
| Hua J Immunol 2007 | Cardiac I/R | Protection against myocardial I/R in TLR4 deficient mice was abrogated by use of pharmacological inhibitors of PI3k. |
| Favre Arterioscler Thromb Vasc Biol 2007 | Cardiac I/R | TLR2 deficient mice had smaller infarct size, reduced reperfusion-associated production of ROS, and reduced leukocyte infiltration. |
| Chimeric studies showed a role for both parenchymal and myeloid cells in protection against I/R induced coronary endothelial dysfunction. | ||
| Shimamato Ann Thorac Surg 2006 | Lung I/R | TLR4 deficiency reduces vascular permeability, lung MPO, and leukocyte accumulation in broncho-alveolar lavage fluid, associated with reduced pro-inflammatory cytokine levels following lung I/R. |
| Leemans J Clin Invest 2005 | Renal I/R | TLR2 deficient mice had reduced levels of local cytokines and chemokines, leukocytes, and renal injury and dysfunction from I/R compared to wild type mice. |
| Chimeric studies showed that TLR2 expression on parenchymal cells was necessary for induction of inflammation from I/R. | ||
| Shigeoka J Immunol 2007 | Renal I/R | TLR2 deficient mice were better protected from ischemic renal injury than MyD88 deficient mice. There was no significant difference between TRIF deficient and wild type mice in response to ischemic injury. |
| Wu J Clin Invest 2007 | Renal I/R | TLR4 deficient and MyD88 deficient mice were protected against renal I/R injury as seen by less tubular dysfunction or damage, reduced proinflammatory cytokines / chemokines, and less neutrophil and macrophage accumulation. |
| Chimeric studies showed that TLR4 on parenchymal cells mediated kidney damage in I/R. | ||
| Pulskens PLoS ONE 2008 | Renal I/R | TLR4 deficiency was associated with lower levels of chemokines, fewer infiltrating granulocytes, less renal damage, and better preserved renal function. |
| Chimeric studies indicated that both epithelial and leukocyte TLR4 contribute to I/R injury. | ||
| MyD88 and TRIF deficient mice had similar inflammation and renal dysfunction as wild type mice. | ||
| Tang Proc Natl Acad Sci USA 2007 | Brain I/R | TLR2 and TLR4 deficiency were associated with reduced I/R induced brain damage and neurological deficit. |
| TLR2 and TLR4 expression were increased in wild type neurons in cortical I/R injury. | ||
| Ziegler Biochem Biophys Res Commun 2007 | Brain I/R | TLR2 deficient mice had reduced cerebral infarct size. |
| In wild type mice, TLR2 was the most significantly upregulated TLR compared to TLR4 and TLR9 in postischemic mouse brains, and TLR2-related genes were induced. | ||
| Lehnardt J Neuroimmunol 2007 | Brain I/R | TLR2 deficient mice had decreased injury after focal cerebral ischemia compared to wild type mice. |
| Wild type mice had upregulated expression of TLR2 mRNA after I/R, and TLR2 protein was found in lesion-associated microglia. | ||
| Cao Biochem Biophys Res Commun 2007 | Brain I/R | TLR4 deficient mice had reduced cerebral infarct size and neurological impairment after I/R, and lower TNF-α and IL-6 levels than TLR4 competent mice. |
| Caso Circulation 2007 | Brain I/R | TLR4 deficient mice had smaller infarct volumes and better outcomes in neurological and behavioral tests and their TLR4 competent counterparts. |
| Levels of IRF-1, iNOS, COX2, INF-β, malondialdehyde, and MMP-9 were also lower in TLR4 deficient mice after I/R. | ||
| Hua J Neuroimmunol 2007 | Brain I/R | TLR4 deficiency was associated with lower levels of NF-κB activity, Akt and GSK3β phosphorylation, cytokine expression and neuronal death / apoptosis in response to I/R. |
| Kilic Neurobiol Dis 2008 | Brain I/R | TLR4 deficiency was associated with reduced brain injury from I/R but increased densities of myeloperoxidase positive neutrophils and Iba1 positive microglial cells. Decreased levels of phosphorylated MAPKs ERK1/2, JNK, and p38, as well as decreased iNOS levels, were found in neurons from TLR4 deficient mice exposed to I/R. |
| Aprahamian Pediatr Crit Care Med 2008 | Gut I/R | TLR2 deficient mice had increased intestinal injury scores by histology, and elevated levels of INF-γ, IL-4, and IL-6 mRNA but not TNF-α mRNA in response to I/R compared to wild type mice. |
| Cavassani JEM 2008 | Gut I/R | TLR3 deficient mice had increased chemokine / cytokine levels and neutrophil infiltration following gut I/R, and in vivo TLR3 antibody in wild type mice attenuated tissue injury from I/R. |
| In TLR3 deficient mice, levels of TNF-α and chemokines returned to baseline quickly after the initial rise due to I/R, and TLR3 deficient mice were then protected from the lethal effects of sustained inflammation. | ||
| Khandoga Shock 2008 | Cremasteric muscle I/R | TLR 2 and TLR4 deficiency reduced I/R induced vascular leakage. |
| I/R induced leukocyte transmigration was attenuated in TLR2 deficiency, but I/R induced leukocyte adhesion was not affected by TLR2 or TLR4 deficiency. |