Biomedical subjects

Troy A Markel

Publications and source records attributed to Troy A Markel.

7 recordsLinked to original sources

PubMed2007

Iron chelation acutely stimulates fetal human intestinal cell production of IL-6 and VEGF while decreasing HGF: the roles of p38, ERK, and JNK MAPK signaling.

Bacteria have developed mechanisms to sequester host iron via chelators such as deferoxamine (DFO). Interestingly, DFO has been shown to stimulate acute intestinal epithelial cell inflammatory cytokine production in the absence of bacteria; however, this mechanism has not been elucidated. Intestinal epithelial cell production of IL-6 and TNF-alpha is elevated in various gastrointestinal pathologies, including acute intestinal ischemia. Similarly, VEGF and HGF are essential to intestinal epithelial cell integrity. Therapeutic strategies that decrease IL-6 and TNF-alpha while increasing VEGF and HGF therefore have theoretical appeal. We hypothesized that 1) fetal human intestinal epithelial cells acutely produce increased IL-6, TNF-alpha, VEGF, and HGF during iron chelation and 2) the MAPK pathway mediates these effects. Fetal human intestinal epithelial cells were stimulated by iron chelation (1 mM DFO) with and without p38 MAPK, ERK, or JNK inhibition. Supernatants were harvested after 24 h of incubation, and IL-6, TNF-alpha, VEGF, and HGF levels were quantified by ELISA. Activation of MAPK pathways was confirmed by Western blot analysis. DFO stimulation resulted in a significant increase in epithelial cell IL-6 and VEGF production while yielding a decrease in HGF production (P<0.05). Unexpectedly, TNF-alpha was not detectable. p38 MAPK, ERK, and JNK inhibition significantly decreased IL-6, VEGF, and HGF production (P<0.05). In conclusion, DFO acutely increases fetal human intestinal epithelial cell IL-6 and VEGF expression while causing an unexpected decrease in HGF expression and no detectable TNF-alpha production. Furthermore, chelator-induced intestinal epithelial cell cytokine expression depends on p38, ERK, and JNK MAPK pathways.

Blotting, Western↗

PubMed2006

Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1).

Concomitant pro- and anti-inflammatory properties of bone marrow stem cells (BMSC) may be an important aspect of their ability to heal injured tissue. However, very few studies have examined whether gender differences exist in BMSC function. Indeed, it remains unknown whether gender differences exist in BMSC function and ability to resist apoptosis, and if so, whether TNF receptor 1 (TNFR1) plays a role in these differences. We hypothesized that TNFR1 ablation equalizes gender differences in bone marrow mesenchymal stem cell (MSC) apoptosis, as well as expression of vascular endothelial growth factor (VEGF), TNF and interleukin (IL)-6. Mouse MSCs from male wild type (WT), female WT, male TNFR1 knockouts (TNFR1KO) and female TNFR1KO were stressed by endotoxin 200 ng/ml or 1 h hypoxia. MSC activation was determined by measuring VEGF, TNF and IL-6 production (ELISA). Differences considered significant if p<0.05. LPS and hypoxia resulted in significant activation in all experimental groups compared to controls. Male WT demonstrated significantly greater TNF and IL-6 and significantly less VEGF release than female WT MSCs. However, release of TNF, IL-6 and VEGF in male TNFR1 knockouts differed from male WT, but was not different from female WT MSCs. Similarly apoptosis in hypoxic male TNFRIKO differed from male WT, but it was not different from apoptosis from WT female. Female WT did not differ in TNF, IL-6 and VEGF release compared to female TNFR1KO. Gender differences exist in injury induced BMSC VEGF, TNF and IL-6 expression. TNFR1 may autoregulate VEGF, TNF and IL-6 expression in males more than females. MSCs are novel therapeutic agents for organ protection, but further study of the disparate expression of VEGF, TNF and IL-6 in males and females as well as the role of TNFR1 in these gender differences is necessary to maximize this protection.

Animals↗

PubMed2006

Therapeutic concepts for hypoxic pulmonary vasoconstriction involving ion regulation and the smooth muscle contractile apparatus.

Hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension present a common and formidable clinical problem for practicing intensivists, thoracic, transplant, and trauma surgeons. The Redox Theory for the mechanisms of HPV has provided researchers with a new understanding of the etiology behind HPV that has opened the door to many new avenues of therapy for the disease. Potassium channels have been proposed to be the main mediator contributing to HPV, and treatment concepts that attempt to manipulate the function and number of those channels have been explored. Additionally, attempts to transfer genes that express the formation of specific potassium channels directly into pulmonary hypertensive lungs have proven to be very promising. Finally, rho kinase (ROK) has been discovered to play a very central role in the formation of hypoxia-induced pulmonary hypertension, and the advent of very specific ROK inhibitors has shown positive clinical results. The purposes of this review are to: (1) briefly discuss some of the basic mechanisms that undergird HPV, including the Redox Theory for the mechanisms of HPV; (2) address current research involving treatments concepts related to ion channels; (3) report on research involving gene therapy to combat pulmonary hypertension; and (4) examine potential therapeutic avenues associated with inhibition of rho kinase.

Humans↗

PubMed2006

Cytokines in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating intra-abdominal emergency in the newborn period. The disease involves bowel wall inflammation, ischemic necrosis, eventual perforation, and the need for urgent surgical intervention. Unrecognized or left untreated, the neonate can decompensate quickly, often progressing to shock, multisystem organ failure, and eventual death. During the past several years, a number of basic science and clinical trials have been established in an attempt to understand the pathophysiology of NEC. As many researchers feel that NEC develops as an uncontrolled inflammatory response that leads to intestinal ischemia, a large number of studies have been focused on the inflammatory cascade and the role that cytokines play within that cascade. Although a large amount of data has been generated from these studies, the events leading to the ischemic injury of the intestine are still not fully understood. This article will therefore focus on the key cytokines involved with NEC, in an attempt to present the current literature and studies that support their involvement.

Cytokines↗

PubMed2005

Stem cell transplantation as a therapeutic approach to organ failure.

BACKGROUND: Stem cell transplantation is one of the next great frontiers for surgery. Stem cells, which are undifferentiated and self-renewing, have shown the ability to differentiate into cardiomyocytes, as well as many other cell types for potential therapeutic use by surgeons. MATERIALS AND METHODS: As a result, stem cells have the potential to undo irreversible cellular damage, something traditional therapies could not cure. However, numerous issues must be resolved to permit safe and effective clinical application of stem cell therapy. These include the interpretation of cellular labeling, the origin of replicating myocytes, the homing mechanism of stem cells, and the differentiation process. RESULTS: Successful translational research will depend on precise delivery of these cells in real time to the area of interest, e.g., the spinal cord, liver, or heart. Surgeons will be better able to excise and replace/regrow, rather than excise alone. As such, a basic understanding of stem cell biology will benefit the surgeon scientist and clinical surgeon. CONCLUSIONS: The review: 1) discusses myocardial regeneration; 2) defines and categorizes stem cells; 3) presents evidence of stem cell transdifferentiation into cardiomyocytes; and, 4) delineates the therapeutic potential of stem cells in the treatment of ischemic heart disease.

Cardiomyopathies↗

PubMed2005

Sex differences in the myocardial inflammatory response to acute injury.

Hemorrhage, trauma, ischemia/reperfusion, burn, and sepsis each lead to cardiac dysfunction. These insults lead to an inflammatory cascade, which plays an important role in this process. Gender has been shown to influence the inflammatory response, as well as outcomes after acute injury. The mechanisms by which gender affects the inflammatory response to and the outcome of acute injury are being actively investigated. We searched PubMed for articles in the English language by using the search words sex, gender, estrogen, testosterone, inflammation, acute injury, ischemia reperfusion, sepsis, trauma, and burns. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full articles were then extracted. References from extracted articles were checked for any additional relevant articles. This review will examine evidence for gender differences in the outcome to acute injury, explain the myocardial inflammatory response to acute injury, and elucidate the various mechanisms by which gender affects the myocardial response to acute injury.

Adenosine Triphosphate↗

PubMed2003

Aging and the exercise pressor reflex in humans.

BACKGROUND: Blood flow limitation to exercising muscles engages the muscle reflex during exercise, evoking an increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). METHODS AND RESULTS: In the current study, we examined forearm flow and autonomic responses to ischemic handgrip in young and older subjects. We studied 6 younger subjects (mean age 23.5+/-2.2 years) and 7 older subjects (mean age 65.0+/-2.4 years). Subjects performed rhythmic handgrip (thirty 1-sec contractions/min) at 30% maximal voluntary contraction during six 1-minute stages: freely perfused exercise (E1) and exercise with forearm pressure of +10, +20, +30, +40, and +50 mm Hg (E2 through E6). We measured HR, BP, MSNA, forearm flow velocity, forearm venous oxygen saturation, H(+), and lactate. Compared with E1, ischemic exercise (E2 through E6) increased HR, BP, and MSNA, reduced forearm velocity, lowered venous oxygen saturation, and raised venous lactate and H(+). Compared with the younger subjects, the older subjects had attenuated BP at E6, attenuated MSNA indices (%(Delta)bursts, bursts/100 heart beats and signal averaged MSNA), attenuated H(+) at E6, a trend toward higher levels of oxygen saturation, and similar forearm velocity and HR responses. CONCLUSIONS: Aging attenuates the muscle reflex.

Adult↗