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ABSTRACT: IL-18 is an important mediator of obstruction-induced renal fibrosis and tubular epithelial cell injury independent of TGF-β1 activity. We sought to determine if IL-18s pro-fibrotic effect is mediated through TLR4. Male C57BL6 wild type and mice transgenic for human IL-18-binding protein were subjected to left unilateral ureteral obstruction (UUO) vs. sham operation. The kidneys were harvested 1 week postoperatively and analyzed for IL-18 production and TLR4 expression. In a separate arm, renal tubular epithelial cells (TECs; HK-2) were directly stimulated with IL-18 in the presence or absence of a TLR4 agonist, TLR4 antagonist, or TLR4 siRNA knockdown. Cell lysates were analyzed for TLR4, α-smooth muscle actin (α-SMA), and E-cadherin expression. TLR4 promotor activity, as well as AP-1 activation and the effect of AP-1 knockdown on TLR4 expression, were evaluated in HK-2 cells in responshe to IL-18 stimulation. Results demonstrate that IL-18 induces TLR4 expression during UUO, and induces TLR4 expression in HK-2 cells via AP-1 activation. Inhibition of TLR4 or knockdown of TLR4 gene expression, in turn, prevents IL-18-induced pro-fibrotic changes in HK2 cells. These results suggest that IL-18 induces pro-fibrotic changes in TECs via increased TLR4 expression/signaling.
Journal of Biological Chemistry 10/2012; · 4.77 Impact Factor
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ABSTRACT: Mesenchymal stem cell (MSC) therapy improves cardiac function after ischemia/reperfusion injury, but its effectiveness is limited by MSC survival in hypoxic environments. Toll-like receptor 4 (TLR4) contributes to pro-apoptotic signaling under hypoxic conditions. Activation of intracellular AKT and ERK pathways opposes this signal and improves cell survival. It is unknown whether ablation of TLR4 affects these pathways after hypoxic injury in MSCs. We hypothesized that: 1) TLR4 knockout (TLR4KO) in MSCs improves survival after hypoxic injury; and 2) this survival difference is due to improved signaling in the AKT and ERK pathways.
Murine wild-type (WT) and TLR4KO MSCs were harvested from bone marrow and grown in vitro. A total of 0.1 × 10(6) cells/well were incubated in hypoxic conditions versus normoxic controls. After 24 h, these groups were examined for cell survival via counting and compared using a t-test with P < 0.05 = statistical significance. AKT and ERK concentrations were measured in lysate using Western blot analysis.
The morphology of WT and TLR4KO MSCs was similar. In line with our previous findings, hypoxia did significantly increase cell death in WT cells (1.79 × 10(5) living cells/mL control versus 0.88 × 10(5) hypoxia, P < 0.05). Hypoxic injury did not increase cell death in the TLR4KO group (1.68 × 10(5) control versus 1.82 × 10(5) hypoxia, P < 0.05). Increased AKT activation was observed in all TLR4KO groups. TLR4 did not affect phosphorylated ERK levels.
TLR4-knockout MSCs show improved survival after hypoxic injury because of increased AKT pathway signal. Use of TLR4-knockout MSCs in ischemia/reperfusion studies results in enhanced cardioprotection; improved stem cell survival was likely a contributing factor.
Journal of Surgical Research 05/2012; 177(2):330-3. · 2.25 Impact Factor
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ABSTRACT: Sepsis remains a source of morbidity and mortality in the postoperative patient despite appropriate resuscitative and antimicrobial approaches. Recent research has focused upon additional interventions such as exogenous cell-based therapy. Mesenchymal stem cells (MSCs) exhibit multiple beneficial properties through their capacity for homing, attenuating the inflammatory response, modulating immune cells, and promoting tissue healing. Recent animal trials have provided evidence that MSCs may be useful therapeutic adjuncts.
A directed search of recent medical literature was performed utilizing PubMed to examine the pathophysiology of sepsis, mechanisms of mesenchymal stem cell interaction with host cells, sepsis animal models, and recent trials utilizing stem cells in sepsis.
MSCs continue to show promise in the treatment of sepsis by their intrinsic ability to home to injured tissue, secrete paracrine signals to limit systemic and local inflammation, decrease apoptosis in threatened tissues, stimulate neoangiogenesis, activate resident stem cells, beneficially modulate immune cells, and exhibit direct antimicrobial activity. These effects are associated with reduced organ dysfunction and improved survival in animal models.
Research utilizing animal models of sepsis has provided a greater understanding of the beneficial properties of MSCs. Their capacity to home to sites of injury and use paracrine mechanisms to change the local environment to ultimately improve organ function and survival make MSCs attractive in the treatment of sepsis. Future studies are needed to further evaluate the complex interactions between MSCs and host tissues.
Journal of Surgical Research 03/2012; 173(1):113-26. · 2.25 Impact Factor
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ABSTRACT: Neonatal mesenchymal stem cells exhibit less cardioprotective potential than their adult counterparts. Transforming growth factor-α (TGF-α) has been shown to stimulate adult stem cell VEGF production, however, it remains unknown whether it may augment neonatal stem cell paracrine function. We hypothesized that TGF-α would equalize adult and neonatal stem cell paracrine function and cardioprotection during acute ischemia/reperfusion.
Bone marrow mesenchymal stem cells isolated from adult and 2.5 wk-old mice were treated with TGF-α (250 ng/mL) for 24 h. VEGF, HGF, IGF-1, IL-1β, and IL-6 production were measure in vitro, and cells were infused via an intracoronary route using a model of isolated heart perfusion.
TGF-α equalized adult and neonatal stem cell VEGF production but did not affect production of HGF, IGF-1, IL-1β, or IL-6. ERK, p38 MAPK, and JNK phosphorylation were greater in adult cells in response to TGF-α. Whereas infusion of adult but not neonatal stem cells was associated with improved myocardial functional recovery during reperfusion, infusions of either TGF-α-pretreated cell group were associated with the greatest functional recovery. TGF-α equalizes adult and neonatal mesenchymal stem cell VEGF production and cardioprotection in association with differential regulation of ERK, p38 MAPK, and JNK phosphorylation.
Journal of Surgical Research 12/2011; 176(2):386-94. · 2.25 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) improve postischemic myocardial function in part through their secretion of growth factors such as vascular endothelial growth factor (VEGF). Pretreating MSCs with various cytokines or small molecules can improve VEGF secretion and MSC-mediated cardioprotection. However, whether 1 cytokine can potentiate the effect of another cytokine in MSC pretreatment to achieve a synergistic effect on VEGF production and cardioprotection is poorly studied.
MSCs were treated with interleukin (IL)-1β and/or transforming growth factor (TGF)-β1 for 24 hours before experiments. VEGF production was determined by enzyme-linked immunosorbent assay. Isolated hearts from adult male Sprague-Dawley rats were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes reperfusion. Hearts (n = 5-7 per group) were randomly infused with vehicle, untreated MSCs, or MSCs pretreated with IL-1β and/or TGF-β1. Specific inhibitors were used to delineate the roles of p38 mitogen-activated protein kinase (MAPK) and SMAD3 in IL-1β- and TGF-β1-mediated stimulation of MSCs.
MSCs cotreated with IL-1β and TGF-β1 exhibited synergistically increased VEGF secretion, and they greatly improved postischemic myocardial functional recovery. Ablation of p38 MAPK and SMAD3 activation with specific inhibitors negated both IL-1β- and TGF-β1-mediated VEGF production in MSCs and the ability of these pretreated MSCs to improve myocardial recovery after ischemia.
Pretreating MSCs with 2 cytokines may be useful to fully realize the potential of cell-based therapies for ischemic tissues.
Surgery 11/2011; 151(3):353-63. · 3.10 Impact Factor
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ABSTRACT: Transforming growth factor-α (TGF-α) has been shown to augment mesenchymal stem cell-mediated cardioprotection during acute ischemia and reperfusion in isolated heart models. To determine whether this pretreatment strategy would be effective in vivo, we hypothesized that the intramyocardial injection of mesenchymal stem cells pretreated with TGF-α after coronary artery ligation would confer greater preservation of cardiac function, reduction in infarct size, and reduction myocardial inflammation.
Sprague-Dawley rats underwent left anterior descending coronary artery ligation. Ischemic border zones were injected 30 minutes later with vehicle (n = 11), 1 million mesenchymal stem cells (n = 9), or mesenchymal stem cells pretreated with TGF-α (250 ng/mL for 24 hours; n = 10). Cardiac function was assessed by echocardiography at 7 and 28 days after ligation. Infarct size was measured using triphenyltetrazolium chloride. Ischemic border zone cytokine expression was measured 30 days after infarction.
Myocardial function after ligation was greatest in hearts injected with cells pretreated with TGF-α in association with reduced ventricular remodeling and infarct size compared with vehicle-injected hearts. Myocardial interleukin 1β, interleukin 6, and TNF-α concentrations were lower, and Bcl-2 expression was higher, in hearts injected with either cell type. Vascular endothelial growth factor and matrix metalloproteinase-2 expression were highest in hearts that received pretreated cells.
Intramyocardial injection of mesenchymal stem cells pretreated with TGF-α further protects cardiac function and reduces infarct size compared with injection of untreated cells. Pretreating donor cells with TGF-α may be useful for enhancing cell-based therapies for myocardial ischemia.
The Annals of thoracic surgery 09/2011; 92(5):1719-25. · 3.74 Impact Factor
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ABSTRACT: The activation of the epidermal growth factor family of receptors may improve cardiac protection after injury. One epidermal growth factor family ligand, transforming growth factor-alpha, promotes wound healing in multiple tissues in response to oxidative injury and might confer resistance to myocardial depressant factors, although the role of transforming growth factor-alpha in myocardial ischemia/reperfusion injury is unknown. We hypothesized that preischemic infusion of transforming growth factor-alpha would improve myocardial functional recovery after acute ischemia/reperfusion.
The hearts from adult male rats were isolated and perfused via the Langendorff model. Immediately prior to ischemia, the hearts received an intracoronary infusion of either vehicle or transforming growth factor-alpha (1 ng, 10 ng, or 100 ng). After reperfusion, the hearts were assessed for activation of the prosurvival pathway, Akt.
Infusion of transforming growth factor-alpha did not confer any additional functional protection compared with the vehicle, but myocardial tissue analysis revealed significantly increased activation of the Akt pathway in both the 10-ng and 100-ng groups.
Preischemic infusion of transforming growth factor-alpha does not improve myocardial functional recovery after ischemia/reperfusion injury. Whereas transforming growth factor-alpha treatment does affect actions at the molecular level, these actions do not translate into an observable functional effect. This lack of improvement may point to a relative unimportance of transforming growth factor-alpha in myocardial signaling compared with other epidermal growth factor ligands.
Surgery 08/2011; 150(2):339-46. · 3.10 Impact Factor
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ABSTRACT: Cytoprotective growth factors such as vascular endothelial growth factor (VEGF) play important roles in myocardial protection from ischemia/reperfusion (I/R). Accumulating evidence suggests that the hypoxia-inducible factor 1 (HIF-1) pathway is a key regulator of VEGF production in the setting of I/R. The prolyl hydroxylase inhibitor mimosine can increase VEGF production through the HIF-1 pathway. We hypothesized that infusion of preischemic intracoronary mimosine would improve myocardial functional recovery after I/R.
Isolated male rat hearts were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes of reperfusion. Immediately prior to ischemia, ischemic hearts received intracoronary infusions of vehicle or solutions of 0.3, 3, or 30 μM mimosine. Myocardial function was recorded throughout the experiments. Functional data were analyzed with two-way analysis of variance adjusted with the Bonferroni correction.
Preischemic myocardial function was equivalent. All hearts had significant reductions in function at the beginning of reperfusion. Hearts treated with 0.3 or 3 μM mimosine infusions exhibited greater recovery of left ventricular developed pressure compared to vehicle. The maximal positive value of the first derivative of pressure (+dP/dt) was greater in hearts treated with 0.3 μM mimosine compared to hearts treated with vehicle. No differences were observed in recovery of end-diastolic pressure or the maximal negative value of the first derivative of pressure (-dP/dt).
Preischemic intracoronary mimosine infusion improves myocardial functional recovery after I/R.
Surgery 08/2011; 150(2):191-6. · 3.10 Impact Factor
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ABSTRACT: Stem cells protect the heart from ischemic damage in part by the release of cytoprotective growth factors, particularly vascular endothelial growth factor (VEGF). Production of VEGF is regulated in part by levels of the transcription factor hypoxia inducible factor 1-α (HIF-1α). Dimethyloxalylglycine (DMOG) prevents the deactivation of HIF-1α and increases VEGF production. However, the effects of systemic DMOG treatment on myocardial tolerance for ischemia are unknown. We hypothesized that systemic pretreatment with DMOG would improve myocardial ischemic tolerance.
To study this hypothesis, adult male rats were randomly given an intraperitoneal injection of DMOG (40 mg/kg in 1 mL saline, n = 5) or saline (1 mL, n = 6) 24 h before cardiectomy and isolated heart perfusion. All hearts were subjected to 15 min equilibration, 25 min ischemia and 40 min reperfusion. Myocardial function was continuously monitored. Following reperfusion, myocardial homogenates were analyzed for HIF-1α and VEGF production.
We observed that hearts in the DMOG group exhibited greater recovery of left ventricular developed pressure LVDP, +dP/dt and -dP/dt. Myocardial HIF-1α and VEGF levels were increased by DMOG therapy.
In conclusion, systemic pretreatment with DMOG augments post-ischemic myocardial functional recovery through increased HIF-1α levels and greater VEGF production.
Surgery 08/2011; 150(2):278-83. · 3.10 Impact Factor
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Mariuxi C Manukyan,
Collin H Alvernaz,
Jeffrey A Poynter,
Yue Wang,
Benjamin D Brewster,
Brent R Weil,
Aaron M Abarbanell,
Jeremy L Herrmann,
Brandon J Crowe,
Andrew C Keck, Daniel R Meldrum
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ABSTRACT: Cardiac surgery induces the release of inflammatory mediators that can prolong cardiac dysfunction after operative intervention. Interleukin-10 (IL-10), a potent inhibitor of myocardial inflammation, is a known factor in myocardial protection after ischemia/reperfusion (I/R) injury. We hypothesized that IL-10 activity during initial reperfusion is mediated through the signal transducer and activator of transcription 3 (STAT3) pathway.
Adult rat hearts were isolated and perfused via Langendorff protocol and subjected to global I/R. After determining the effective IL-10 dose, hearts were administered vehicle, IL-10, or IL-10 + Stattic (specific STAT3 inhibitor) 1 min prior to ischemia. After reperfusion, hearts were sectioned and assessed for levels of myocardial inflammatory cytokines and protein.
The IL-10 minimum effective dose was 1 μg. IL-10-treated hearts had improved markedly myocardial function after global I/R compared to both vehicle and IL-10 + Stattic groups. In addition, IL-10 treatment was associated with a significant decrease in myocardial interleukin-1β (IL-1β) and interleukin-6 (IL-6) and increase in myocardial IL-10. Myocardial STAT3 was elevated markedly in IL-10 treated hearts.
IL-10 improves myocardial function after acute global I/R and suppresses inflammation through the STAT3 pathway. The administration of anti-inflammatory agents may have potential therapeutic applications in cardiac surgery.
Surgery 06/2011; 150(2):231-9. · 3.10 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) hold promise for the treatment of renal disease. While MSCs have been shown to accelerate recovery and prevent acute renal failure in multiple disease models, the effect of MSC therapy on chronic obstruction-induced renal fibrosis has not previously been evaluated.
Male Sprague-Dawley rats underwent renal artery injection of vehicle or fluorescent-labeled human bone marrow-derived MSCs immediately prior to sham operation or induction of left ureteral obstruction (UUO). One or 4 wk later, the kidneys were harvested and the renal cortex analyzed for evidence of stem cell infiltration, epithelial-mesenchymal transition (EMT) as evidenced by E-cadherin/α-smooth muscle actin (α-SMA) expression and fibroblast specific protein (FSP+) staining, renal fibrosis (collagen content, Masson's trichrome staining), and cytokine and growth factor activity (ELISA and real time RT-PCR).
Fluorescent-labeled MSCs were detected in the interstitium of the kidney up to 4 wk post-obstruction. Arterially delivered MSCs significantly reduced obstruction-induced α-SMA expression, FSP+ cell accumulation, total collagen content, and tubulointerstitial fibrosis, while simultaneously preserving E-cadherin expression, suggesting that MSCs prevent obstruction-induced EMT and renal fibrosis. Exogenous MSCs reduced obstruction-induced tumor necrosis factor-α (TNF-α) levels, but did not alter transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), fibroblast growth factor (FGF), or hepatocyte growth factor (HGF) expression.
Human bone marrow-derived MSCs remain viable several weeks after delivery into the kidney and provide protection against obstruction-induced EMT and chronic renal fibrosis. While the mechanism of MSCs-induced renal protection during obstruction remains unclear, our results demonstrate that alterations in TNF-α production may be involved.
Journal of Surgical Research 06/2011; 168(1):e51-9. · 2.25 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) possess immunomodulatory properties and may curtail the inflammatory response that characterizes sepsis and other systemic inflammatory states. We aimed to determine whether intravenous infusion of MSCs is associated with reduced inflammation and improved myocardial function in a rat model of endotoxemia. Adult Sprague-Dawley rats were administered saline (vehicle) or LPS (5 mg/kg) via tail vein injection. Treatments, either vehicle or 2 × 10(6) MSCs, were infused 1 h later via tail vein. Animals were randomly assigned to the following groups: (a) vehicle + vehicle (control; n = 6), (b) LPS + vehicle (n = 6), or (c) LPS + MSCs (n = 6). Six hours after induction of endotoxemia, left ventricular ejection fraction (EF) and fractional shortening (FS) was assessed via parasternal short-axis M-mode echocardiography. Hearts and serum were collected for determination of cytokine levels via enzyme-linked immunosorbent assay. Animals injected with LPS + vehicle exhibited depressed cardiac function as indicated by a 26% and 37% reduction in EF and FS from baseline, respectively. Treatment with MSCs was associated with improved cardiac function compared with vehicle treatment as indicated by a reduction in EF and FS of only 10% and 17%, respectively (P < 0.05). Myocardial levels of TNF-α, IL-1β, and IL-6 were elevated in LPS-treated animals versus control. Similarly, serum levels of IL-1β, IL-6, and IL-10 were increased in LPS-treated animals. Treatment with MSCs, however, was associated with significant reductions in serum levels of IL-1β and IL-6 and in myocardial levels of TNF-α, IL-1β, and IL-6. In addition, treatment with MSCs was associated with a further increase in serum IL-10. Infusion of MSCs modulates the systemic inflammatory response and is associated with improved cardiac function during endotoxemia.
Shock (Augusta, Ga.) 05/2011; 36(3):235-41. · 2.87 Impact Factor
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ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling.
With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro.
Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs.
Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism.
Journal of the American College of Surgeons 05/2011; 213(2):253-60. · 4.55 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) have been used experimentally and clinically in the treatment of a wide variety of pathologies. It is now clear that a number of different mechanisms contribute to the therapeutic effects exerted by these cells. The ability of MSCs to interact with and modulate the functions of a wide variety of immune cells has been recognized as one such mechanism. The implications that the immunomodulatory properties of MSCs may have for the treatment of solid organ rejection, the Systemic Inflammatory Response Syndrome, cancer, and Crohn's disease are reviewed herein.
Journal of Surgical Research 05/2011; 167(1):78-86. · 2.25 Impact Factor
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ABSTRACT: High-mobility group box 1 (HMGB1) is a mediator of inflammation with dose-dependent effects. In the setting of regional myocardial infarction, a high-dose HMGB1 treatment decreases myocardial function, whereas low-dose HMGB1 improves function; however, it is unknown what role HMGB1 has in the setting of global ischemia/reperfusion (I/R) injury. We hypothesized that a low-dose HMGB1 treatment would improve myocardial functional recovery and decrease infarct size after global I/R injury in association with increased levels of cardioprotective paracrine factors and decreased inflammation.
Adult rat hearts were isolated and perfused using the Langendorff method and were subjected to global I/R and treatment with either the vehicle, 200-ng HMGB1, or 1-μg HMGB1. The treatment was administered during 1 min at the start of reperfusion, and myocardial function was measured for 60 min of reperfusion. At the end of reperfusion, the hearts were sectioned and incubated in triphenyltetrazolium chloride to assess myocardial infarct size or homogenized to measure levels of inflammatory cytokines and growth factors.
Postischemic treatment with 200-ng HMGB1 significantly improved myocardial functional recovery after global I/R in association with decreased infarct size and decreased interleukin-1 (IL-1), IL-6, IL-10, and vascular endothelial growth factor (VEGF) levels. In addition, 1-μg HMGB1 decreased myocardial inflammation but did not result in subsequent improvement in functional recovery.
In the setting of global I/R, 200-ng postischemic HMGB1 treatment improves myocardial function and decreases infarct size in association with suppressed myocardial inflammation. These results suggest a potential role for exogenous HMGB1therapy in the acute postischemic period.
Surgery 03/2011; 149(3):329-35. · 3.10 Impact Factor
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ABSTRACT: Stem cell-based therapies for myocardial ischemia have demonstrated promising early clinical results, but their benefits have been limited in duration due to impaired donor cell engraftment and function. Several strategies have emerged for enhancing stem cell function prior to their therapeutic use particularly with regard to stem cell homing, paracrine function, and survival. This review discusses current understandings of stem cell-mediated cardioprotection as well as methods of enhancing post-transplantation stem cell function and survival through hypoxic preconditioning, genetic manipulation, and pharmacologic pretreatment.
A literature search was performed using the MEDLINE and PubMed databases using the keywords "stem cell therapy," "myocardial ischemia," "hypoxic preconditioning," "paracrine function," and "stem cell pretreatment." Studies published in English since January 1990 were selected. In addition, studies were identified from references cited in publications found using the search terms.
All included studies utilized animal studies and/or in vitro techniques. Stem cell modifications generally targeted stem cell homing (SDF-1, CXCR4), paracrine function (VEGF, angiogenin, Ang-1, HGF, IL-18 binding protein, TNFR1/2), or survival (Akt, Bcl-2, Hsp20, HO-1, FGF-2). However, individual modifications commonly exhibited pleiotropic effects involving some or all of these general categories.
These strategies for optimizing stem cell-mediated cardioprotection present unique potential sets of advantages and disadvantages for clinical application. Additional questions remain including those that are most efficacious in terms of magnitude and duration of benefit as well as whether combinations may yield greater benefits in both the preclinical and clinical settings.
Journal of Surgical Research 03/2011; 166(1):138-45. · 2.25 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) may offer therapeutic benefit in the setting of sepsis and endotoxemia. Previous studies suggest that MSCs from female donors may possess better protective capabilities than their male counterparts. The present study examined whether female MSCs may offer a greater protective advantage in the setting of endotoxemic cardiac dysfunction compared with male MSCs. Adult male Sprague-Dawley rats were injected intraperitoneally with LPS and then treated with intraperitoneal injections of either saline, female MSCs, or male MSCs. Hearts and serum were then collected for analysis of myocardial function, myocardial protein, and myocardial and serum cytokines. Compared with male MSC or vehicle-treated animals, female MSC treatment resulted in greater preservation of myocardial function (P < 0.001). Serum and myocardial levels of all measured cytokines were comparable between rats given MSCs from male or female donors but substantially improved over rats given vehicle (P < 0.05). Reduced myocardial inflammation correlated with reduced levels of phosphorylated p38 MAPK expression in the myocardium of animals injected with MSCs of either sex (P < 0.05). The Bcl-xL/Bax ratio was increased to a greater extent following treatment with female MSCs vs. male MSCs (P < 0.05). Intraperitoneal administration of MSCs is effective in limiting myocardial inflammation and dysfunction in the rat endotoxemia model. Compared with treatment with their male counterparts, MSC treatment from female donors is associated with greater cardiac protection against acute endotoxemic injury.
AJP Regulatory Integrative and Comparative Physiology 03/2011; 300(6):R1506-14. · 3.34 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) protect ischemic tissues in part through paracrine growth factor production. IL-6, which is upregulated in the heart during ischemia, has been shown to enhance stem cell proliferation and migration. The effect of IL-6 on MSC paracrine function, however, remains unknown. In addition, TGF-α increases MSC vascular endothelial growth factor (VEGF) production and may share downstream signaling pathways with IL-6 involving ERK, JNK, and PI3K. We hypothesize that cotreatment with IL-6 and TGF-α will result in greater MSC VEGF production than by either treatment alone via these signaling pathways. Murine MSCs were treated with IL-6 (0.05 ng/mL) with or without TGF-α (250 ng/mL) and in combination with inhibitors of ERKI/II, JNK, and PI3K for 24 h. Vascular endothelial growth factor concentrations in the supernatants were measured using enzyme-linked immunosorbent assay. Phosphorylation of ERK, JNK, and PI3K was measured using Western blot analysis. IL-6 increased MSC VEGF production at a dose of 0.05 ng/mL, and the combination of IL-6 and TGF-α (250 ng/mL) increased VEGF production to a greater extent than IL-6 or TGF-α alone. IL-6 induced phosphorylation of ERK, JNK, and PI3K, and inhibition of each suppressed IL-6-induced VEGF production. TGF-α cotreatment overcame VEGF suppression after ERK2 inhibition but not ERK1, JNK, or PI3K. These data suggest that IL-6 stimulates MSC VEGF production alone and additively with TGF-α via ERK-, JNK-, and PI3K-mediated mechanisms. IL-6 and TGF-α cotreatment may be a useful strategy for enhancing MSC VEGF production and cardioprotection during myocardial ischemia.
Shock (Augusta, Ga.) 01/2011; 35(5):512-6. · 2.87 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) is the most common chronic arrhythmia in the United States and is associated with high morbidity rates and significant healthcare costs. Although medical therapy for AF modestly reduces complications, cardiac surgery continues to have an important role in the treatment of AF and is constantly evolving. Cardiothoracic surgeons are uniquely positioned to offer effective operations to patients with lone AF, in addition to those undergoing concomitant elective cardiac surgery. This review discusses (1) the burden of AF, (2) classification and electrophysiology of AF, (3) surgical techniques and outcomes, and (4) future directions in surgical therapy.
The Annals of thoracic surgery 12/2010; 90(6):2079-86. · 3.74 Impact Factor
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ABSTRACT: Acute right ventricular (RV) failure is a frequent and serious clinical challenge in the intensive care unit. It is usually seen as a consequence of left ventricular failure, pulmonary embolism, pulmonary hypertension, sepsis, acute lung injury or after cardiothoracic surgery. The presence of acute RV failure not only carries substantial morbidity and mortality, but also complicates the use of commonly used treatment strategies in critically ill patients. In contrast to the left ventricle, the RV remains relatively understudied, and investigations of the treatment of isolated RV failure are rare and usually limited to nonrandomized observations. We searched PubMed for papers in the English language by using the search words right ventricle, right ventricular failure, pulmonary hypertension, sepsis, shock, acute lung injury, cardiothoracic surgery, mechanical ventilation, vasopressors, inotropes, and pulmonary vasodilators. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full papers were then extracted. References from extracted papers were checked for any additional relevant papers. This review summarizes the general measures, ventilation strategies, vasoactive substances, and surgical as well as mechanical approaches that are currently used or actively investigated in the treatment of the acutely failing RV.
Journal of the American College of Cardiology 10/2010; 56(18):1435-46. · 14.16 Impact Factor
