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Biomedical subjects

L H Michael

Publications and source records attributed to L H Michael.

At least 19 recordsLinked to original sources
PubMed2001

Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival.

Cardiac muscle regeneration after injury is limited by "irreversible" cell cycle exit. Telomere shortening is one postulated basis for replicative senescence, via down-regulation of telomerase reverse transcriptase (TERT); telomere dysfunction also is associated with greater sensitivity to apoptosis. Forced expression of TERT in cardiac muscle in mice was sufficient to rescue telomerase activity and telomere length. Initially, the ventricle was hypercellular, with increased myocyte density and DNA synthesis. By 12 wk, cell cycling subsided; instead, cell enlargement (hypertrophy) was seen, without fibrosis or impaired function. Likewise, viral delivery of TERT was sufficient for hypertrophy in cultured cardiac myocytes. The TERT virus and transgene also conferred protection from apoptosis, in vitro and in vivo. Hyperplasia, hypertrophy, and survival all required active TERT and were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycle exit in cardiac muscle, induce hypertrophy in postmitotic cells, and promote cardiac myocyte survival.

Animals↗
PubMed2001

Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia.

Chemokine expression is associated with reperfusion of infarcted myocardium in the setting of tissue necrosis, intense inflammation, and inflammatory cytokine release. The specific synthesis of monocyte chemotactic protein (MCP)-1 mRNA by cardiac venules in reperfused infarcts corresponded to the region where leukocytes normally localize. MCP-1 could be induced by exogenous tumor necrosis factor (TNF)-alpha or by postischemic cardiac lymph containing TNF-alpha. However, the release of TNF-alpha during early reperfusion did not explain the venular localization of MCP-1 induction. To better understand the factors mediating MCP-1 induction, we examined the role of ischemia/reperfusion in a model of brief coronary occlusion in which no necrosis or inflammatory response is seen. Adult mongrel dogs were subjected to 15 minutes of coronary occlusion and 5 hours of reperfusion. Ribonuclease protection assay revealed up-regulation of MCP-1 mRNA only in ischemic segments of reperfused canine myocardium. Pretreatment with the reactive oxygen scavenger N-(2-mercaptopropionyl)-glycine completely inhibited MCP-1 induction. In situ hybridization localized MCP-1 message to small venular endothelium in ischemic areas without myocyte necrosis. Gel shift analysis of nuclear extracts from the ischemic area showed enhanced DNA binding of the transcription factors AP-1 and nuclear factor (NF)-kappaB, crucial for MCP-1 expression, in ischemic myocardial regions. Immunohistochemical staining demonstrated reperfusion-dependent nuclear translocation of c-Jun and NF-kappaB (p65) in small venular endothelium, only in the ischemic regions of the myocardium, that was inhibited by N-(2-mercaptopropionyl)-glycine. In vitro, treatment of cultured canine jugular vein endothelial cells with the reactive oxygen intermediate H2O2 induced a concentration-dependent increase in MCP-1 mRNA levels, which was inhibited by the antioxidant N-acetyl-L-cysteine, a precursor of glutathione, but not pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB and activator of AP-1. In contrast to our studies with infarction, incubation of canine jugular vein endothelial cells with postischemic cardiac lymph did not induce MCP-1 mRNA expression suggesting the absence of cytokine-mediated MCP-1 induction after a sublethal ischemic period. These results suggest that reactive oxygen intermediate generation, after a brief ischemic episode, is capable of inducing MCP-1 expression in venular endothelium through AP-1 and NF-kappaB. Short periods of ischemia/reperfusion, insufficient to produce a myocardial infarction, induce MCP-1 expression, potentially mediating angiogenesis in the ischemic noninfarcted heart.

Acetylcysteine↗
PubMed2001

Stem cell plasticity in muscle and bone marrow.

Recent discoveries have demonstrated the extraordinary plasticity of tissue-derived stem cells, raising fundamental questions about cell lineage relationships and suggesting the potential for novel cell-based therapies. We have examined this phenomenon in a potential reciprocal relationship between stem cells derived from the skeletal muscle and from the bone marrow. We have discovered that cells derived from the skeletal muscle of adult mice contain a remarkable capacity for hematopoietic differentiation. Cells prepared from muscle by enzymatic digestion and 5 day in vitro culture were harvested and introduced into each of six lethally irradiated recipients together with distinguishable whole bone marrow cells. Six and twelve weeks later, all recipients showed high-level engraftment of muscle-derived cells representing all major adult blood lineages. The mean total contribution of muscle cell progeny to peripheral blood was 56%, indicating that the cultured muscle cells generated approximately 10- to 14-fold more hematopoietic activity than whole bone marrow. Although the identity of the muscle-derived hematopoietic stem cells is still unknown, they may be identical to muscle satellite cells, some of which lack myogenic regulators and could respond to hematopoietic signals. We have also found that stem cells in the bone marrow can contribute to cardiac muscle repair and neovascularization after ischemic injury. We transplanted highly purified bone marrow stem cells into lethally irradiated mice that subsequently were rendered ischemic by coronary artery occlusion and reperfusion. The engrafted stem cells or their progeny differentiated into cardiomyocytes and endothelial cells and contributed to the formation of functional tissue.

Age Factors↗
PubMed2001

Leukocyte trafficking and myocardial reperfusion injury in ICAM-1/P-selectin-knockout mice.

P-selectin and intercellular adhesion molecule-1 (ICAM-1) mediate early interaction and adhesion of neutrophils to coronary endothelial cells and myocytes after myocardial ischemia and reperfusion. In the present study, we examined the physiological consequences of genetic deletions of ICAM-1 and P-selectin in mice. In wild-type mice, after 1 h of ischemia followed by reperfusion, neutrophil influx into the area of ischemia was increased by 3 h with a peak at 24 h and a decline by 72 h. ICAM-1/P-selectin-deficient mice showed a significant reduction in neutrophils by immunohistochemistry or by myeloperoxidase activity at 24 h but no significant difference at 3 h. Infarct size (area of necrosis/area at risk) assessed 24 h after reperfusion was not different between wild-type and deficient mice after 30 min and 1 h of occlusion. Mice with a deficiency in both ICAM-1 and P-selectin have impaired neutrophil trafficking without a difference in infarct size due to myocardial ischemia-reperfusion.

Animals↗
PubMed2001

Brief murine myocardial I/R induces chemokines in a TNF-alpha-independent manner: role of oxygen radicals.

Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-alpha, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-alpha-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-alpha double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1 alpha, -1 beta, and -2 at both the mRNA and protein levels. This induction was independent of TNF-alpha, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-kappa B and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.

Animals↗
PubMed2001

Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.

Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. To identify a source of stem cells capable of restoring damaged cardiac tissue, we transplanted highly enriched hematopoietic stem cells, the so-called side population (SP) cells, into lethally irradiated mice subsequently rendered ischemic by coronary artery occlusion for 60 minutes followed by reperfusion. The engrafted SP cells (CD34(-)/low, c-Kit(+), Sca-1(+)) or their progeny migrated into ischemic cardiac muscle and blood vessels, differentiated to cardiomyocytes and endothelial cells, and contributed to the formation of functional tissue. SP cells were purified from Rosa26 transgenic mice, which express lacZ widely. Donor-derived cardiomyocytes were found primarily in the peri-infarct region at a prevalence of around 0.02% and were identified by expression of lacZ and alpha-actinin, and lack of expression of CD45. Donor-derived endothelial cells were identified by expression of lacZ and Flt-1, an endothelial marker shown to be absent on SP cells. Endothelial engraftment was found at a prevalence of around 3.3%, primarily in small vessels adjacent to the infarct. Our results demonstrate the cardiomyogenic potential of hematopoietic stem cells and suggest a therapeutic strategy that eventually could benefit patients with myocardial infarction.

Animals↗
PubMed2000

IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury.

Reperfusion of the ischemic myocardium is associated with a dramatic inflammatory response leading to TNF-alpha release, IL-6 induction, and subsequent neutrophil-mediated cytotoxic injury. Because inflammation is also an important factor in cardiac repair, we hypothesized the presence of components of the inflammatory reaction with a possible role in suppressing acute injury. Thus, we investigated the role of IL-10, an anti-inflammatory cytokine capable of modulating extracellular matrix biosynthesis, following an experimental canine myocardial infarction. Using our canine model of myocardial ischemia and reperfusion, we demonstrated significant up-regulation of IL-10 mRNA and protein in the ischemic and reperfused myocardium. IL-10 expression was first detected at 5 h and peaked following 96-120 h of reperfusion. In contrast, IL-4 and IL-13, also associated with suppression of acute inflammation and macrophage deactivation, were not expressed. In the ischemic canine heart, CD5-positive lymphocytes were the predominant source of IL-10 in the myocardial infarct. In the absence of reperfusion, no significant induction of IL-10 mRNA was noted. In addition, IL-12, a Th1-related cytokine associated with macrophage activation, was not detected in the ischemic myocardium. In vitro experiments demonstrated late postischemic cardiac-lymph-induced tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression in isolated canine mononuclear cells. This effect was inhibited when the incubation contained a neutralizing Ab to IL-10. Our findings suggest that lymphocytes infiltrating the ischemic and reperfused myocardium express IL-10 and may have a significant role in healing by modulating mononuclear cell phenotype and inducing TIMP-1 expression.

Adjuvants, Immunologic↗
PubMed2000

Myocardial blood flow and myocardial uptake of (201)Tl and (99m)Tc-sestamibi during coronary vasodilation induced by CGS-21680, a selective adenosine A(2A) receptor agonist.

BACKGROUND: We investigated the hemodynamic and coronary vasodilatory effects of CGS-21680, a potent selective adenosine A(2A) agonist, as well as its potential use as a new stress modality in combination with perfusion scintigraphy. METHODS AND RESULTS: A stenosis of the left anterior descending coronary artery (LAD) was produced in dogs to reduce the reactive hyperemic response to <20%. Adenosine and CGS-21680 were then separately infused to maximize left circumflex coronary artery (LCx) flow velocity. (201)Tl (0.5 mCi) and (99m)Tc-sestamibi (5 mCi) were injected at the maximal dose of CGS-21680. Heart rate decreased with adenosine but increased during CGS-21680 infusion (P<0.005). The decrease in systolic blood pressure was more prominent with adenosine than with CGS-21680 (P<0.005). In the control LCx zone, maximal myocardial blood flow (MBF) (measured by radioactive microspheres) increased 3.1-fold during adenosine infusion (P<0.005) and 3.8-fold during CGS-21680 infusion (P<0.005). In the stenotic LAD zone, MBF did not change significantly. During adenosine and CGS-21680 infusion, stenosis/control zone MBF ratios were comparable (0.32+/-0.11 versus 0.27+/-0.10, P=NS), and transmural (201)Tl and (99m)Tc-sestamibi count-activity ratios (0.48+/-0.11 and 0.51+/-0.09, respectively) were also comparable (P=NS). Myocardial scintigraphy uncovered perfusion defects in all dogs. CONCLUSIONS: CGS-21680 elicits coronary vasodilation comparable to that of adenosine and produces profound heterogeneity of MBF and of (201)Tl and (99m)Tc-sestamibi myocardial uptake, rendering it a promising agent for pharmacological myocardial perfusion imaging.

Adenosine↗
PubMed2000

Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction.

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1/TNFR2-deficient mice (77.2% +/- 15.3%) when compared with either wild-type mice (46.8% +/- 19.4%) or TNFR1-deficient (47.9% +/- 10.6%) or TNFR2-deficient (41.6% +/- 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.

Acute Disease↗
PubMed2000

Time-dependent loss of Mac-1 from infiltrating neutrophils in the reperfused myocardium.

Numerous studies have shown that polymorphonuclear neutrophils (PMNs) infiltrate the myocardium immediately after reperfusion of infarcted tissue. Studies with mAbs in vivo and cellular studies in vitro suggest that PMN-induced injury of the cardiac myocyte involve Mac-1 adhesion to myocyte ICAM-1. In this study we demonstrate that PMNs that have infiltrated the ischemic area begin to lose Mac-1 within the first 3 h. By the fifth hour of reperfusion, minimal CD11b staining is seen on PMNs using immunostaining, whereas CD11a remained unchanged. Immunoreactivity of postreperfusion cardiac lymph with R15.7 (anti-CD18) or MY904 (anti-CD11b) was positive in all animals but not for CD11a (R7.1), indicating a specific loss of Mac-1. Immunoprecipitation with either R15.7 or MY904 resulted in identical peptides (a doublet at 190 kDa and a band at 80 kDa), suggesting that both alpha and beta subunits of Mac-1 heterodimer were released. Immunoprecipitation of control PMN lysates revealed bands of 198 kDa and 91 kDa slightly greater than those from the released Mac-1. An in vitro model of homotypic aggregation showed a similar loss of Mac-1 from PMNs; immunoprecipitates of the supernatant demonstrated peptide bands identical with those found in postischemic cardiac lymph. The appearance of soluble Mac-1 in vitro was prevented by anti-CD18 mAb, R15.7, and also by protease inhibition by PMSF. Thus, in vivo and in vitro, activated PMNs lose Mac-1 in a process that may be dependent upon adhesion and subsequent proteolysis.

Animals↗
PubMed2000

Decreased left ventricular ejection fraction in transgenic mice expressing mutant cardiac troponin T-Q(92), responsible for human hypertrophic cardiomyopathy.

The causality of mutant sarcomeric proteins in hypertrophic cardiomyopathy (HCM) is well established. The current emphasis is to elucidate the pathogenesis of HCM in transgenic animal models. We determined the left ventricular ejection fraction (LVEF) in transgenic mice expressing mutant cardiac troponin T (cTnT)-Q(92), known to cause HCM in humans. Transgenes were constructed by placing wild-type (R(92)) or mutant (Q(92)) full-length human cTnT cDNAs 3' into a 5.5-kb murine [alpha -myosin heavy chain (MyHC)] promoter injected into fertilized zygotes. Three wild-type and six mutant lines were produced. Transgene mRNA and proteins, detected using transgene-specific probes were expressed at high levels in all wild-type and three mutant lines. The total cTnT mRNA pool was increased by up to five-fold in transgenic mice, but the total cTnT protein remained unchanged. The mean values of LVEF, determined by(178)Ta radionuclide angiography, were 57.8+/-6% (n=4) in non-transgenic littermate (NLM), 53.3+/-10 (n=6) in wild-type and 39. 4+/-6 (n=5) in mutant transgenic mice (P=0.009). The heart/body weight ratios and the number of cells stained with terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling were similar among the groups. Three mutant mice had myocyte disarray and excess interstitial collagen and two had normal myocardial structure despite having reduced LVEF. Thus, in vivo expression of the mutant cTnT-Q(92)protein, responsible for human HCM, impaired global cardiac systolic function in transgenic mice, which also occurred in the absence of myocyte disarray and increased interstitial collagen.

Animals↗
PubMed2000

Identification of genes regulated during mechanical load-induced cardiac hypertrophy.

Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth.

Animals↗
PubMed2000

Induction of the synthesis of the C-X-C chemokine interferon-gamma-inducible protein-10 in experimental canine endotoxemia.

Endotoxemia is associated with a systemic inflammatory response leading to organ-specific leukocyte recruitment and tissue injury. Chemokine expression has been demonstrated in various models of sepsis and may mediate tissue infiltration with inflammatory cells. In this study we examined expression of the C-X-C chemokine interferon-gamma-inducible protein-10 (IP-10), a potent T-lymphocyte chemoattractant, in a canine model of endotoxemia and investigated mechanisms of cytokine-mediated IP-10 induction in endothelial cells. Control canine tissues showed negligible expression of IP-10 message, with the exception of the spleen. Endotoxemic dogs demonstrated a robust induction of IP-10 mRNA in the heart, lung, kidney, liver, and spleen. Immunohistochemical studies indicated that IP-10 was predominantly localized in cardiac venular endothelial cells, bronchial epithelial cells, renal mesangial cells, and in the splenic red pulp of endotoxemic dogs. In addition, IP-10 expression was associated with T-lymphocyte infiltration in canine tissues. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) induced a marked upregulation of IP-10 message in canine venular endothelial cells. IP-10 expression in TNF-alpha-stimulated endothelial cells peaked at 6 h of stimulation and returned to baseline levels after 24 h. In addition, macrophage colony-stimulating factor (M-CSF) induced a dose-dependent induction of IP-10 mRNA in canine endothelial cells. M-CSF-mediated IP-10 expression peaked after 6 h of incubation and returned to baseline levels after 24 h. Canine endotoxemia is associated with a robust early expression of IP-10 in multiple tissues. IP-10 induction may be important in regulating lymphocyte recruitment and function. TNF-alpha, IL-1 beta, and M-CSF are potent inducers of IP-10 in canine endothelial cells and may indirectly mediate lymphocyte chemotaxis and activation in inflammatory processes.

Animals↗
PubMed2000

Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb).

OBJECTIVE: The purpose of this study is to examine the cellular content of healing myocardial infarcts and study the phenotypic characteristics of fibroblasts during scar formation utilizing a canine model of coronary occlusion and reperfusion. METHODS: Ischemia/Reperfusion experiments were performed in dogs undergoing 1 h of coronary occlusion followed by reperfusion intervals ranging from 5 h to 28 days. Fibrotic and control areas were studied using immunohistochemistry. RESULTS: The healing ischemic and reperfused myocardium demonstrated significant proliferative activity peaking after 3 to 7 days of reperfusion, predominantly in myofibroblasts. The numbers of proliferating cells decreased during the maturation phase of the scar (PCNA index: 13.7+/-2.25% at 5 days vs. 4.8+/-1.1% at 28 days; P<0.05, n=5). During the proliferative phase of healing (3-7 days) alpha-smooth muscle actin (alpha-SMAc) expression was markedly increased in the fibrotic areas. alpha-SMAc predominantly localized in myofibroblasts which were vimentin positive, smooth muscle myosin, calponin and desmin negative. We examined expression of smooth muscle myosin heavy chain isoforms in myofibroblasts infiltrating the healing areas and found a marked induction of the embryonal isoform of myosin heavy chain (SMemb) in alpha-SMAc positive spindle shaped cells in the border of the scar. Myofibroblasts did not express SM2, a marker for mature smooth muscle cells. In contrast myocardial arterioles were positive for SM2, but did not express SMemb. CONCLUSIONS: Healing myocardial infarcts undergo rapid changes in their content of myofibroblasts. During the proliferative phase fibroblasts undergo phenotypic changes leading to expression of contractile proteins such as alpha-SMAc, and production of SMemb, a marker for dedifferentiated smooth muscle cells. Expression of embryonic isoforms indicates dedifferentiation and allows the myofibroblast pool to serve as a versatile cell population, assuming different phenotypes depending on the physiological needs.

Animals↗
PubMed2000

TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice.

The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.

Activating Transcription Factor 6↗
PubMed2000

Interleukin 6 induction in the canine myocardium after cardiopulmonary bypass.

OBJECTIVE: Interleukin 6 is a proinflammatory cytokine with a plasma concentration that has been noted to increase in response to cardiopulmonary bypass. The source of interleukin 6 after cardiopulmonary bypass is unknown. This study examined the myocardium as a potential source of interleukin 6 in this context. METHODS: Dogs underwent 90 minutes of hypothermic cardiopulmonary bypass with 60 minutes of cardioplegic arrest. After rewarming, they were reperfused with the chest open for either 3 (n = 4) or 6 (n = 4) hours, at the end of which myocardial samples were obtained. Four additional animals undergoing open thoracotomy without bypass served as time-matched controls. Northern blot analysis, reverse transcriptase-polymerase chain reaction, and in situ hybridization were used to examine the myocardium for the induction of interleukin 6 and intercellular adhesion molecule-1. RESULTS: Northern blot analysis and reverse transcriptase-polymerase chain reaction demonstrated a marked increase in myocardial interleukin 6 messenger RNA in 3 of 4 dogs at 3 hours after bypass and 3 of 4 dogs at 6 hours after bypass, which was not present in sham-bypass control animals. Northern blots at 3 hours after cardiopulmonary bypass also demonstrated myocardial intercellular adhesion molecule-1 induction. In situ hybridization studies confirmed that cardiac myocytes were a principal source of interleukin 6 messenger RNA early after cardiopulmonary bypass. Northern blots of messenger RNA extracted from isolated neutrophils and mononuclear leukocytes obtained from blood samples before bypass, at the end of bypass, and 3 hours after bypass failed to demonstrate interleukin 6 induction. CONCLUSION: Despite protection with cold cardioplegic arrest, the myocardium was a significant source of interleukin 6 synthesis after cardiopulmonary bypass. Local production of interleukin 6 may play a pivotal role in postoperative myocardial function.

Animals↗