This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zacharowski, K. Articles by Thiemermann, C. Search for Related Content PubMed PubMed Citation Articles by Zacharowski, K. Articles by Thiemermann, C. Related Collections Restenosis Animal models of human disease Ischemic biology - basic studies

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2276-2280.)
© 1999 American Heart Association, Inc.

Rapid Communications

Endotoxin Induces a Second Window of Protection in the Rat Heart as Determined by Using p-Nitro-Blue Tetrazolium Staining, Cardiac Troponin T Release, and Histology

Kai Zacharowski; Mike Otto; Gerd Hafner; Prabal K. Chatterjee; Christoph Thiemermann

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—Pretreatment of rats with small doses of lipopolysaccharide (LPS), eg, for 24 hours, attenuates the cardiac dysfunction caused by subsequent period of myocardial ischemia. This phenomenon of enhanced tolerance to an ischemic insult has been termed "second window of protection." Although the cardioprotective effects of LPS were first reported in 1989, it is still unclear whether the observed attenuation by LPS of the ischemia-induced cardiac dysfunction is indeed secondary to the protection of cardiac myocytes against ischemic cell injury and death. This study was designed to investigate the effects of "preconditioning" with LPS on cell injury caused by regional myocardial ischemia and reperfusion in the anesthetized rat. Thirty-five Wistar rats were subjected to 25 minutes occlusion of the left anterior descending coronary artery followed by 2 hours of reperfusion. Hemodynamic parameters were continuously recorded, and at the end of the experiments, infarct size (using p-nitro-blue tetrazolium staining), cardiac troponin T release, and histological markers of cell injury and death were determined. In rats pretreated with a bolus of saline (vehicle for LPS) 2 or 24 hours before left anterior descending coronary artery occlusion and reperfusion, the infarct size was 59±4% (2 hours saline-control, n=6) and 61±3% (24 hours saline-control, n=6), respectively. Pretreatment of animals with a bolus of LPS (1 mg/kg IP) 24 hours before the onset of myocardial ischemia and reperfusion reduced both infarct size (to 18±7%; P<0.05, n=6) as well as histological signs of cell injury. Pretreatment (24 hours, as above) of rats with LPS also reduced the release of cardiac troponin T from 58±13 ng/mL (saline-control) to 16±9 ng/mL. In contrast, pretreatment of rats with LPS (2 hours, as above) did not affect infarct size (56±8%, n=6), cardiac troponin T release, or the histological parameters of cell injury. These data provide the first conclusive evidence that pretreatment of rats with a bolus of LPS 24 hours before intervention reduces the cell injury and death caused by a subsequent period of myocardial ischemia and reperfusion.

Key Words: LPS • myocardial infarct size • myocardial ischemia • reperfusion • delayed preconditioning

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The second window of protection (SWOP) was originally described as enhanced tolerance to myocardial ischemia after exposure of the rabbit¹ or canine² heart to brief periods of myocardial ischemia (ischemic preconditioning, IPC). This SWOP appears to occur at 24 hours after IPC and is maintained for 72 hours. The SWOP against myocardial infarction has been observed in many species, eg, in the rabbit,³ dog,² pig,⁴ and rat.⁵ Several triggers are known to induce a SWOP, eg, brief repetitive cycles of coronary occlusion,¹ ventricular rapid pacing,⁶ stimulation of adenosine A₁ receptors,³ and administration of lipopolysaccharide (LPS)⁷ or monophosphoryl lipid A (MLA).⁸ Previously, the methods used to investigate SWOP involved the measurement of myocardial infarct size by using triphenyltetrazolium (TTC) macrochemical staining. In addition, SWOP enhances the resistance of the myocardium against the arrhythmias,^{6 9} the postischemic endothelial dysfunction,¹⁰ and the myocardial stunning^{11 12} caused by a subsequent period of ischemia-reperfusion. It is unclear, however, whether the SWOP caused by IPC (and other stimuli) is indeed due to a protection of myocardial cells against injury or death, as there is one report that demonstrates that SWOP leads to a reduction in infarct size as determined by TTC staining without reducing the histological signs of cell necrosis.¹³ Here, we used LPS as a trigger for SWOP and report that LPS causes a time-dependent reduction in infarct size in rats subjected to myocardial ischemia-reperfusion. To demonstrate that the observed "cardioprotective" effects of LPS were not an artifact of tetrazolium staining, we also investigated the effects of LPS on cardiac troponin T (cTnT) release and histological signs of tissue injury.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Myocardial Ischemia and Reperfusion in the Rat In Vivo
The technique used to produce coronary artery occlusion is identical to that described previously.¹⁴ Briefly, male Wistar rats (240 to 350 g, Tuck, Rayleigh, Essex, UK) were anesthetized using thiopentone sodium (120 mg/kg IP). The trachea was cannulated and artificial respiration was maintained using a Harvard ventilator with a frequency of 70 strokes/min, a tidal volume of 8 to 10 mL/kg, an inspiratory oxygen concentration of 30%, and a positive end-expiratory pressure of 1 to 2 mm Hg resulting in pCO₂ values of 36 to 44 mm Hg and pO₂ values over 150 mm Hg.¹⁴ Body temperature was maintained at 38±1°C. The right carotid artery was cannulated and connected to a pressure transducer to monitor mean arterial blood pressure (MAP) and heart rate (HR) continuously on a 4-channel Grass 7D polygraph recorder from which pressure rate index (PRI), a relative indicator of myocardial oxygen consumption,¹⁵ was calculated as the product of MAP and HR and expressed in mm Hg/(min · 10³). The right jugular vein was cannulated for the administration of drugs. The chest was opened by a left-side thoracotomy, the pericardium was incised, and an atraumatic needle and occluder were placed around the left anterior descending coronary artery (LAD). After completion of the surgical procedure, the animals were allowed to stabilize for 30 minutes before LAD ligation, which involved constriction of the occluder (time 0). This was associated with typical hemodynamic changes observed during myocardial ischemia, eg, fall in MAP. After 25 minutes of acute myocardial ischemia, the occluder was released allowing the reperfusion of the previously ischemic myocardium for 2 hours. After reocclusion of the LAD, Evans blue dye (1 mL of 2% wt/vol) was administered IV to determine between ischemic (area at risk) and nonischemic myocardium (area not at risk). Subsequently, the heart was cut into horizontal slices and then into small pieces. The area at risk (AR) was separated from the area not at risk and then incubated with p-nitro-blue tetrazolium (NBT, 0.5 mg/mL, 20 minutes at 37°C) to distinguish between ischemic and infarcted tissue, whereas the area not at risk was incubated with saline. The AR and infarct size were calculated after weighing the respective tissue samples and expressed as % of the AR.

Measurement of the Plasma Levels of Cardiac Troponin T in the Rat
At the end of the experiment, a blood sample (1 mL) was obtained from the carotid cannula and centrifuged to obtain plasma. The plasma supernatants were separated and stored at -20°C until assayed. The concentration of cardiac troponin T was determined using the STAT (Short TurnAround Time) immunoassay (Boehringer Mannheim) using an Elecsys System 2010.

Determination of the Degree of Myocardial Tissue Injury Using Light Microscopy
Biopsies of all sections of the heart (nonischemic, ischemic, and infarcted) were fixed in paraformaldehyde (4% wt/vol), embedded in paraffin, cut into 4-µm section, de-waxed, and stained with hematoxylin-eosin, Fuchsin, and Luxol-Fast-Blue.

Experimental Groups
Rats were randomly allocated into the following groups: (1) Sham operated controls (no occlusion of the LAD, n=3). (2) Injection of saline (1 mL/kg IP, n=6) 2 hours before 25 minutes LAD occlusion and 2 hours reperfusion. (3) Injection of saline (1 mL/kg IP, n=6) 24 hours before 25 minutes LAD occlusion and 2 hours reperfusion. (4) Injection of LPS (1 mg/kg IP, n=6) 24 hours before no occlusion of the LAD. (5) Injection of LPS (1 mg/kg IP, n=6) 2 hours before 25 minutes LAD occlusion and 2 hours reperfusion. (6) Injection of LPS (1 mg/kg IP, n=6) 24 hours before 25 minutes LAD occlusion and 2 hours reperfusion. The n-numbers in the above groups refer to rats, which survived until the end of the experiment. The number of rats that died in the individual groups were as follows: group 3, n=1; group 5, n=1.

Drugs and Materials
Unless otherwise stated, all compounds were obtained from Sigma Chemical Co. LPS was obtained from E. coli serotype 0.127:B8. Thiopentone sodium (Intraval) was obtained from May & Baker Ltd.

Statistical Analysis
Data are reported as mean±SEM of n observations. ANOVA with Bonferroni's test was used to compare groups. A P value of <0.05 was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The Cardioprotective Effects of LPS In Vivo
The mean values for the AR were similar in all animal groups studied and ranged from 46±2% to 56±1% (P>0.05, data not shown). In rats pretreated with saline (2 or 24 hours before ischemia), occlusion of the LAD (for 25 minutes) followed by reperfusion (for 2 hours) resulted in an infarct size of 59±4% (n=6) or 61±3% (n=6) of the AR, respectively. When compared with vehicle, administration of 1 mg/kg LPS 2 hours before coronary artery ligation did not cause a reduction in infarct size (56±8%, n=6), (P>0.05, Figure 1). When compared with vehicle, bolus injection of LPS (24 hours before ischemia) caused a significant reduction in infarct size of approximately 65% (P<0.05, Figure 1). Sham operation alone did not result in a significant degree of infarction in any of the animal groups studied (<3% of the AR).

View larger version (15K): [in this window] [in a new window]   Figure 1. Myocardial ischemia caused by occlusion (25 minutes) and reperfusion (2 hours) of the LAD in the anesthetized rat. Separate groups of animals were pretreated at different time points before experimental intervention with saline (2 hours, 2-con, n=6), saline (24 hours, 24-con, n=6), LPS (2 hours, 2-LPS, 1 mg/kg IP, n=6), or LPS (24 hours, 24-LPS, 1 mg/kg IP, n=6). In addition, sham operated rats (no LAD occlusion and reperfusion) were studied: sham-con (24 hours pretreatment with saline, n=3) and sham-LPS (24 hours pretreatment with LPS, n=6). Infarct size expressed as percentage of the area at risk caused by occlusion and reperfusion of the LAD. *P<0.05 when compared with control.

Hemodynamic Effects of LPS in Rats Subjected to Myocardial Ischemia and Reperfusion
Hemodynamic data, eg, MAP (mm Hg), HR (bpm), and PRI [mm Hg/(min · 10³)] measured during the course of the experiments were similar in all groups studied (P>0.05, data not shown). In sham-operated rats (no LAD occlusion), injection of vehicle (saline) did not cause any significant effects on MAP, HR, or PRI. In rats subjected to LAD occlusion and reperfusion that received either saline or LPS, mean values for MAP and PRI fell throughout the experiment (P>0.05, data not shown).

Effects of LPS on Plasma Levels of Cardiac Troponin T in the Rat
In rats that were subjected to the surgical procedure, but not to LAD occlusion (sham-operation), there was no significant increase in the plasma levels of the cardiac-specific marker cTnT (Figure 2). Pretreatment of rats with saline (2 or 24 hours) followed by ischemia-reperfusion of the LAD resulted in a significant increase in the plasma levels of cTnT (Figure 2). When compared with vehicle, pretreatment with LPS 24 hours before ischemia caused a significant reduction in the release of cTnT (P<0.05, Figure 2). LPS pretreatment 2 hours before ischemia did not reduce the cTnT release (P>0.05, Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 2. cTnT release in a model of myocardial ischemia (25 minutes) and reperfusion (2 hours) of the LAD in the anesthetized rat. Different groups of animals were pretreated at different time points before experimental intervention with saline (2 hours, 2-con, n=6), saline (24 hours, 24-con, n=6), LPS (2 hours, 2-LPS, 1 mg/kg IP, n=6), or LPS (24 hours, 24-LPS, 1 mg/kg IP, n=6). In addition, sham operated rats (no LAD occlusion and reperfusion) were studied: sham-con (24 hours pretreatment with saline, n=3) and sham-LPS (24 hours pretreatment with LPS, n=6). *P<0.05 when compared with control.

Effects of LPS on Histological Signs of Tissue Injury in the Myocardium of the Rat
Histological evaluation by light microscopy of biopsies of control hearts subjected to regional ischemia and reperfusion demonstrated the occurrence of complete coagulation necrosis. Cytoplasm of myocytes was deeply eosinophilic, which demonstrates a strong staining with Fuchsin as well as submaximal staining with Luxol-Fast Blue in the peripheral myocytes. In addition, there is an absence of nuclear structures. LPS pretreatment 2 hours before ischemia resulted in the same degree of tissue injury as described above. Rats pretreated with LPS 24 hours before ischemia had a significantly smaller infarct size. The infarcted tissue of these animals demonstrated the same typical signs of necrosis as described above, eg, cytoplasmic eosinophilia of cardiomyocytes, hyperemia of blood vessels, and extravasation of red blood cells, but less hemorrhage and accumulation of polymorphonucleocytes (PMN) in the border zone of the infarcted tissue (Figure 3, each group n=3 to 4).

View larger version (129K): [in this window] [in a new window]   Figure 3. Histological sections after hematoxylin-eosin staining of the area at risk of a rat heart subjected to myocardial ischemia and reperfusion. A, Depicted is a typical example of heart tissue from a rat pretreated with saline 24 hours before ischemia. This section demonstrates the occurrence of complete coagulation necrosis, deeply eosinophilic cytoplasm of myocytes, hyperemia of blood vessels, and an extravasation of red blood cells. Magnification, x120. B, Depicted is a section of A in a higher magnification (x 400), which demonstrates the accumulation of PMN in the border zone of the infarcted tissue. C, Depicted is a typical example of heart tissue from a rat pretreated with LPS 24 hours before ischemia, which demonstrates the same typical signs of necrosis as described in A but with less extravasation of red blood cells. D, Depicted is a section of C in a higher magnification (x500), which demonstrates a reduction in the number of PMN in the border zone of the infarcted tissue when compared with B.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The purpose of this study was to examine the effects of pretreatment with LPS, a well known trigger of the second window of protection,⁷ in a model of regional myocardial ischemia and reperfusion in the rat on (1) myocardial infarct size, (2) cTnT release, and (3) histological markers of tissue injury. In 1989 Brown and colleagues demonstrated for the first time⁷ that pretreatment of rats with LPS 24 hours before ischemia improved myocardial function in isolated, perfused hearts subjected to global myocardial ischemia and reperfusion. In the same study, hearts isolated from rats that were pretreated with LPS 1 hour before ischemia did not show enhanced resistance to ischemia-reperfusion injury. The authors suggested that SWOP produced by LPS was associated with and possibly due to an upregulation of catalase activity.⁷ Interestingly, compounds with less toxicity than LPS,¹⁶ such as MLA, also produce a significant reduction in myocardial infarct size in dogs.⁸ The methods used to investigate the SWOP triggered by LPS or MLA involved the measurement of myocardial infarct size by using TTC macrochemical staining. In addition, pretreatment of animals with LPS or MLA also reduced the number of ischemia-reperfusion arrhythmias⁶ and the degree of myocardial stunning¹¹ caused by ischemia-reperfusion. In this study, the reduction in infarct size caused by pretreatment of rats with LPS 24 hours before ischemia was determined by staining of the viable myocardium (within the AR) with the formazan dye NBT. This reduction in infarct size (as determined by NBT) is due to a reduction in myocardial tissue necrosis, as LPS also attenuated the increase in the plasma levels of cTnT caused by regional myocardial ischemia and reperfusion. There is good evidence that a rise in the plasma levels of cTnT is specific for myocardial tissue injury.¹⁷ Unlike plasma levels of creatine phosphokinase or lactate dehydrogenase, which are elevated in open-chest models of myocardial infarction due to the surgical procedure (Zacharowski and Thiemermann, unpublished data, 1998), the thoracotomy used here did not result in any detectable rise in the plasma levels of cTnT. Thus these data strongly support the conclusion that LPS does cause a significant reduction in myocardial infarct size. In addition, we have demonstrated for the first time that pretreatment of rats with LPS (1 mg/kg 24 hours before ischemia) does not lead to myocardial necrosis by itself, as determined by measurement of cTnT concentrations in the plasma. Previously, we have demonstrated that there is a significant increase in the levels of cTnT in the plasma within 3 hours after regional myocardial ischemia and reperfusion in the rat.¹⁴ In cases of acute myocardial infarction in humans, cTnT levels in serum rise approximately 3 to 4 hours after the occurrence of cardiac symptoms and can remain elevated for up to 14 days.¹⁸

It is interesting to speculate on the prospective mechanisms by which LPS causes a significant reduction in the degree of necrosis as demonstrated in this study. Recently the problems involved in using the tetrazolium staining have been discussed.¹³ Miki et al demonstrated a SWOP (infarct size reduction) using TTC, but these findings could not be confirmed using light microscopy.¹³ The same group also proposed that exogenously administered SOD may cause false-positive staining with tetrazolium¹⁹ and have suggested that endogenous upregulation of SOD caused by preconditioning may account for an artifactual limitation of myocardial injury. However, these results could not be confirmed by other groups.^{20 21} Clearly, in both intervention studies, and in all groups studied, there were no differences in body weight, heart weight, AR, or hemodynamic parameters such as mean MAP or HR, suggesting that the beneficial effects of LPS pretreatment (24 hours before ischemia) were not related to differences in the amount of myocardial tissue sampled nor to changes in myocardial oxygen demand. Therefore, we have also used histology as a tool to determine the degree of cell injury in the myocardium of rats, which were subjected to LAD occlusion and reperfusion. LPS caused a convincing reduction in myocardial infarct size and demonstrates the existence of SWOP.

Thus this study demonstrates, for the first time, that pretreatment with LPS 24 hours before ischemia reduces infarct size, cTnT release, and the signs of histological tissue injury in rats subjected to myocardial ischemia-reperfusion. These results imply that LPS induces a SWOP without interfering with the staining procedure. The mechanism(s) underlying in the cardioprotective effects afforded by LPS warrants further investigation.

	Acknowledgments

 
K.Z. is supported by the Deutsche Gesellschaft für Kardiologie- Herz- und Kreislaufforschung. C.T. is a Senior Fellow of the British Heart Foundation (BHF FS 96/018). P.K.C. is funded by the Joint Research Board of St. Bartholomew's Hospital, London (Grant XMLA).

Received April 19, 1999; accepted June 11, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation. 1993;88:1264–1272.[Abstract/Free Full Text]

2. Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res. 1993;72:1293–1299.[Abstract/Free Full Text]

3. Baxter GF, Marber MS, Patel VC, Yellon DM. Adenosine receptor involvement in a delayed phase of myocardial protection 24 hours after ischemic preconditioning. Circulation. 1994;90:2993–3000.[Abstract/Free Full Text]

4. Qiu Y, Tang XL, Park SW, Sun JZ, Kalya A, Bolli R. The early and late phases of ischemic preconditioning: A comparative analysis of their effects on infarct size, myocardial stunning, and arrhythmias in conscious pigs undergoing a 40-minute coronary occlusion. Circ Res. 1997;80:730–742.[Abstract/Free Full Text]

5. Yamashita N, Hoshida S, Taniguchi N, Kuzuya T, Hori M. A "second window of protection" occurs 24 h after ischemic preconditioning in the rat heart. J Mol Cell Cardiol. 1998;30:1181–1189.[Medline] [Order article via Infotrieve]

6. Vegh A, Papp JG, Parratt JR. Prevention by dexamethasone of the marked antiarrhythmic effects of preconditioning induced 20 h after rapid cardiac pacing. Br J Pharmacol. 1994;113:1081–1082.[Medline] [Order article via Infotrieve]

7. Brown JM, Grosso MA, Terada LS, Whitman GJ, Banerjee A, White CW, Harken AH, Repine JE. Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat hearts. Proc Natl Acad Sci U S A. 1989;86:2516–2520.[Abstract/Free Full Text]

8. Yao Z, Auchampach JA, Pieper GM, Gross GJ. Cardioprotective effects of monophosphoryl lipid A, a novel endotoxin analogue, in the dog. Cardiovasc Res. 1993;27:832–838.[Abstract/Free Full Text]

9. Yang XM, Baxter GF, Heads RJ, Yellon DM, Downey JM, Cohen MV. Infarct limitation of the second window of protection in a conscious rabbit model. Cardiovasc Res. 1996;31:777–783.[Medline] [Order article via Infotrieve]

10. Kaeffer N, Richard V, Thuillez C. Delayed coronary endothelial protection 24 hours after preconditioning: Role of free radicals. Circulation. 1997;96:2311–2316.[Abstract/Free Full Text]

11. Tang XL, Qiu Y, Park SW, Sun JZ, Kalya A, Bolli R. Time course of late preconditioning against myocardial stunning in conscious pigs. Circ Res. 1996;79:424–434.[Abstract/Free Full Text]

12. Sun JZ, Tang XL, Knowlton AA, Park SW, Qiu Y, Bolli R. Late preconditioning against myocardial stunning. An endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs. J Clin Invest. 1995;95:388–403.

13. Miki T, Swafford AN, Cohen MV, Downey JM. Second window of protection in conscious rabbits: Real or artifactual. J Mol Cell Cardiol. 1999;31:809–816.[Medline] [Order article via Infotrieve]

14. Zacharowski K, Olbrich A, Otto M, Hafner G, Thiemermann C. Effects of the prostanoid EP3-receptor agonists M&B 28767 and GR 63799X on infarct size caused by regional myocardial ischaemia in the anaesthetized rat. Br J Pharmacol. 1999;126:849–858.[Medline] [Order article via Infotrieve]

15. Baller D, Bretschneider HJ, Hellige G. A critical look at currently used indirect indices of myocardial oxygen consumption. Basic Res Cardiol. 1981;76:163–181.[Medline] [Order article via Infotrieve]

16. Ribi E. Beneficial modification of the endotoxin molecule. J Biol Response Mod. 1984;3:1–9.[Medline] [Order article via Infotrieve]

17. Adams JE III, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation. 1993;88:750–763.[Free Full Text]

18. Remppis A, Scheffold T, Karrer O, Zehelein J, Hamm C, Grunig E, Bode C, Kubler W, Katus HA. Assessment of reperfusion of the infarct zone after acute myocardial infarction by serial cardiac troponin T measurements in serum. Br Heart J. 1994;71:242–248.[Abstract/Free Full Text]

19. Shirato C, Miura T, Ooiwa H, Toyofuku T, Wilborn WH, Downey JM. Tetrazolium artifactually indicates superoxide dismutase-induced salvage in reperfused rabbit heart. J Mol Cell Cardiol. 1989;21:1187–1193.[Medline] [Order article via Infotrieve]

20. Tanaka M, Richard VJ, Murry CE, Jennings RB, Reimer KA. Superoxide dismutase plus catalase therapy delays neither cell death nor the loss of the TTC reaction in experimental myocardial infarction in dogs. J Mol Cell Cardiol. 1993;25:367–378.[Medline] [Order article via Infotrieve]

21. Holmbom B, Naslund U, Eriksson A, Virtanen I, Thornell LE. Comparison of triphenyltetrazolium chloride (TTC) staining versus detection of fibronectin in experimental myocardial infarction. Histochemistry. 1993;99:265–275.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				E. I. Chang, R. G. Bonillas, S. El-ftesi, E. I. Chang, D. J. Ceradini, I. N. Vial, D. A. Chan, J. Michaels V, and G. C. Gurtner Tissue engineering using autologous microcirculatory beds as vascularized bioscaffolds FASEB J, March 1, 2009; 23(3): 906 - 915. [Abstract] [Full Text] [PDF]

				W. Chao Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H1 - H12. [Abstract] [Full Text] [PDF]

				Y. Feng, H. Zhao, X. Xu, E. S. Buys, M. J. Raher, J. C. Bopassa, H. Thibault, M. Scherrer-Crosbie, U. Schmidt, and W. Chao Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1311 - H1318. [Abstract] [Full Text] [PDF]

				H. Stapel, S.-C. Kim, S. Osterkamp, P. Knuefermann, A. Hoeft, R. Meyer, C. Grohe, and G. Baumgarten Toll-like receptor 4 modulates myocardial ischaemia-reperfusion injury: Role of matrix metalloproteinases Eur J Heart Fail, November 1, 2006; 8(7): 665 - 672. [Abstract] [Full Text] [PDF]

				S. R. Bornstein, P. Zacharowski, R. R. Schumann, A. Barthel, N. Tran, C. Papewalis, V. Rettori, S. M. McCann, K. Schulze-Osthoff, W. A. Scherbaum, et al. Impaired adrenal stress response in Toll-like receptor 2-deficient mice PNAS, November 23, 2004; 101(47): 16695 - 16700. [Abstract] [Full Text] [PDF]

				J. T. Beranek Comments to the Editor Concerning the Paper Entitled "Effects of Endotoxin on Neutrophil-Mediated Ischemia/Reperfusion Injury in the Rat Heart In Vivo" by Lipton et al. Experimental Biology and Medicine, April 1, 2002; 227(4): 223 - 224. [Full Text] [PDF]

				K. Zacharowski, S. Frank, M. Otto, P. K. Chatterjee, S. Cuzzocrea, G. Hafner, J. Pfeilschifter, and C. Thiemermann Lipoteichoic Acid Induces Delayed Protection in the Rat Heart : A Comparison With Endotoxin Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1521 - 1528. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zacharowski, K. Articles by Thiemermann, C. Search for Related Content PubMed PubMed Citation Articles by Zacharowski, K. Articles by Thiemermann, C. Related Collections Restenosis Animal models of human disease Ischemic biology - basic studies