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Am J Physiol Gastrointest Liver Physiol 292: G958-G963, 2007. First published January 4, 2007; doi:10.1152/ajpgi.00502.2006
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TRANSLATIONAL PHYSIOLOGY

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

Troy A. Markel,1 Paul R. Crisostomo,1 Meijing Wang,1 Christine M. Herring,1 Tim Lahm,3 Kirstan K. Meldrum,1 Keith D. Lillemoe,1 Frederick J. Rescorla,1 and Daniel R. Meldrum1,2,4

Departments of 1Surgery, 2Cellular and Integrative Physiology, 3Pulmonary and Critical Care Medicine and 4Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 27 October 2006 ; accepted in final form 29 December 2006

ABSTRACT

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.

intestinal ischemia; inflammation; mitogen-activated protein kinase signaling; interleukin-6; vascular endothelial growth factor; hepatocyte growth factor; extracellular signal-regulated kinase; c-Jun NH2-terminal kinase

IRON is a critical component of cellular activity and is essential for cell growth and differentiation (22). Cellular iron availability alters the proliferation and activation of leukocytes, interacts with cell-mediated immune effecter pathways, and modulates cytokine activities (3, 4, 12, 13, 39). Microbes residing on the mucosal surface of the intestine require iron for survival and key intracellular reactions (48). As such, certain microbes have adapted to the changing environment by developing mechanisms to compete with their hosts for iron. These mechanisms are capable of extracting iron from high-affinity ligands such as transferrin, lactoferrin, and ferritin and can be in the form of iron transport systems or iron-scavenging chelators such as deferoxamine (DFO).

The gastrointestinal system contributes to the immune response during sepsis, ischemia, and injury (8, 19–21, 25). Interestingly, DFO has been shown to stimulate intestinal epithelial cell production of inflammatory cytokines in the absence of bacteria; however, the mechanism of stimulation has yet to be fully elucidated (6). Intestinal epithelial cell production of IL-6 is elevated in various gastrointestinal pathologies, including acute intestinal ischemia, and may play a role in gut barrier dysfunction (10, 24, 38, 40). IL-6, whose acute release is stimulated by stress as well as a variety of other cytokines, serves to activate lymphocytes, thereby inducing antibody secretion by B cells and differentiation of cytotoxic T cells (35). IL-6 is also elevated in sepsis and is associated with increased mortality (15, 38).

Previous studies (15, 33) have demonstrated that TNF-{alpha} is also increased in intestinal inflammation. TNF-{alpha}, a prominent member of the cytokine cascade in a number of organs, serves to elicit leukocyte migration, fever, the acute phase response, and increased production of matrix metalloproteinases, which are proteolytic enzymes capable of degrading the extracellular matrix (2, 5, 26–28, 30, 32, 34, 43, 45). TNF-{alpha} has also been shown to be a crucial member of the apoptotic pathway and has been associated with the onset of septic shock (23, 29, 31, 41, 44).

HGF and VEGF also play a role in gut mucosal barrier dysfunction (14, 16). Apoptosis of specific intestinal cells, including Peyer's patches and lamina propria lymphocytes, is typically elevated in inflammation (7). However, there are studies (1, 9, 11, 17, 46, 49) that show decreased cellular apoptosis and increased angiogenic potential with the addition of HGF, indicating a possible protective effect of this growth factor. Moreover, HGF has been shown to improve rat small intestinal function and substrate absorption while increasing mucosal mass (37). On the other hand, VEGF has been shown to inhibit leukocyte/epithelial cell adherence and the effects of chronic inflammation (36). In addition, various tissue studies (42, 47) have demonstrated that VEGF promotes angiogenesis during acute inflammation and ischemia.

Thus, therapeutic strategies that simultaneously decrease IL-6 and TNF-{alpha} while increasing HGF and VEGF have theoretical appeal for acute ischemic intestinal diseases. In this regard, within the intracellular signaling cascades for IL-6, TNF-{alpha}, HGF, and VEGF, there are proposed common links within the MAPK pathway that represent previously unexplored putative targets for inhibition that may modulate the production of these cytokines during bacterial iron chelation. We hypothesized that 1) fetal human intestinal epithelial cells acutely produce increased IL-6, TNF-{alpha}, HGF, and VEGF during iron chelation and 2) these effects are regulated through the p38, ERK, and JNK arms of the MAPK pathway.

MATERIALS AND METHODS

Cell culture and reagents. Human fetal small intestinal epithelial cells [American Type Culture Collection (ATCC), Manassas, VA] were obtained at passage 25 and placed into 125-cm2 plastic flasks with Hybricare Complete growth media (ATCC) supplemented with 30 ng/ml EGF (BD Biosciences, San Joe, CA). Fetal small intestinal cells preferentially attached to the polystyrene surface of the flask. Fresh complete medium was added and replaced every 3 days. Cell cultures were maintained at 37°C in 5% CO2 in air. When the cultures reached 90% of confluence, small intestinal cells were recovered by the addition of 0.25% trypsin-EDTA (GIBCO/Invitrogen, Carlsbad, CA) and passaged to a new flask. Cells, used for experimentation between passages 27 and 30, were aliquotted into 24-well plates at a volume of 100,000 cells/well and were allowed to adhere for 24 h prior to experimentation.

DFO (1 mM, Sigma, St. Louis, MO) and MAPK inhibitors for p38 MAPK (SB-203580 inhibitor, 10–6 M), ERK (ERK II inhibitor, 10–6 M), and JNK (JNK VI, TI JIP153–163 inhibiter, 10–6 M) (Calbiochem, San Diego, CA) were added to fresh media. DFO dose-response analysis demonstrated optimal responses for the majority of cytokines measured at a dose of 1 mM. In addition, micromolar doses of MAPK inhibitors were chosen based on similar kinetic profiles between the three inhibitors. DMSO was used to dissolve all reagents. Cells were incubated for an additional 24 h, after which time the supernatant and cells were collected.

ELISA. Human IL-6, TNF-{alpha}, VEGF, and HGF release from intestinal epithelial cells were determined by ELISA (n = 3–5 per experimental group) using commercially available ELISA sets (R&D Systems, Minneapolis, MN; and BD Biosciences, San Diego, CA). In addition, cellular apoptosis was assayed via a Cell Death Detection ELISA (Roche). ELISA was performed according to the manufacturer's instructions. All samples and standards were measured in duplicate.

Western blot analysis. Western blot analysis was performed to measure MAPK protein activation within chelation-stimulated cells. Intestinal cell lysates were obtained by exposing cells to cold lysis buffer containing 20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mM Na3VO4, 1 µg/ml leupeptin, and 1 mM PMSF. Cell lysates were then centrifuged at 12,000 rpm for 5 min. Protein extracts were subjected to electrophoresis on an 8–16% Precise Protein gel (Pierce Biotechnology, Rockford, IL) and transferred to a nitrocellulose membrane, which was stained by naphthol blue-black to confirm protein loading. Membranes were incubated in 5% dry milk for 1 h and then incubated with the following primary antibodies: p38 MAPK antibody, phospho-p38 MAPK (Thr180/Tyr182) antibody, ERK antibody, phospho-ERK (Thr202/Tyr204) antibody, JNK antibody, and phospho-JNK (Thr183/Tyr185) antibody (Cell Signaling Technology, Beverly, MA). Subsequently, membranes were incubated with horseradish peroxidase-conjugated goat anti-rabbit IgG secondary antibody. Detection was performed using Supersignal West Pico Stable Peroxide Solution (Pierce). Films were scanned using an Epson Perfection 3200 Scanner (Epson America, Long Beach, CA).

Presentation of data and statistical analysis. All reported values are means ± SE. Data were compared using a Student's t-test. A two-tailed P value of <0.05 was considered statistically significant.

RESULTS

DFO acutely stimulates fetal human small intestinal cell production of IL-6 and VEGF, but decreases HGF, and results in no detectable TNF-{alpha} production. Production of IL-6 and VEGF were significantly elevated in fetal human small intestinal cells exposed to DFO for 24 h (IL-6: control 125.5 ± 15.33 pg/ml vs. DFO 182.9 ± 3.927 pg/ml, P < 0.05; and VEGF: control 189.3 ± 6.101 pg/ml vs. DFO 935.9 ± 17.50 pg/ml, P < 0.001). Conversely, the addition of DFO to intestinal epithelial cells resulted in decreased HGF production (control 5,300 ± 497.2 pg/ml vs. DFO 4,257 ± 39.96 pg/ml, P < 0.05). Fetal small intestinal cells had no detectable basal or DFO-stimulated TNF-{alpha} production (Fig. 1).


Figure 1
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  		Fig. 1. Deferoxamine (DFO) acutely affects fetal human intestinal cell production of cytokines and growth factors. A and B: DFO significantly increased fetal human intestinal cell production of IL-6 (A) and VEGF (B). *P < 0.05 vs. vehicle (Veh). C: Intestinal cells produced less HGF after DFO stimulation. *P < 0.05 vs. vehicle. D: fetal small intestinal cells had no detectable (ND) baseline or DFO-stimulated production of TNF-{alpha}.

 
IL-6, VEGF, and HGF production depend on p38, ERK, and JNK MAPK pathways. The addition of the p38 inhibitor SB-203580 (Fig. 2), ERK II inhibitor (Fig. 3), or the JNK VI TI JIP153–163 inhibitor (Fig. 4) significantly decreased fetal small intestinal cell production of IL-6, VEGF, and HGF (P < 0.05). To ensure that these differences were due to stimulation and signaling of viable cells, cellular apoptosis was assayed. There were no significant differences in apoptosis between experimental groups (data not shown).


Figure 2
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  		Fig. 2. DFO-stimulated fetal human intestinal cell production of cytokines is dependent on the p38 MAPK pathway. A–C: fetal small intestinal cell production of IL-6 (A), VEGF (B), and HGF (C) was significantly decreased with the addition of the p38 inhibitor (p38i) SB-203580. **P < 0.05 vs. DFO. D: representative Western blot from 2 independent experiments confirmed active phosphorylation of p38 in DFO-stimulated cells. p38, total p38; p-p38, active phosphorylated p38.

 

Figure 3
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  		Fig. 3. DFO-stimulated intestinal cell cytokine production requires the activation of ERK. A–C: fetal small intestinal cell production of IL-6 (A), VEGF (B), and HGF (C) was significantly decreased with the addition of the ERK II inhibitor (ERKi). **P < 0.05 vs. DFO. D: representative Western blot from 2 independent experiments confirmed active phosphorylation of ERK in DFO-stimulated cells. ERK, total ERK; p-ERK, active phosphorylated ERK.

 

Figure 4
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  		Fig. 4. Cytokine expression in DFO-stimulated intestinal cells is dependent on the JNK MAPK pathway. A–C: fetal small intestinal cell production of IL-6 (A), VEGF (B), and HGF (C) was significantly decreased with the JNK inhibitor (JNKi). **P < 0.05 vs. DFO. D: representative Western blot from 2 independent experiments confirmed active phosphorylation of JNK in DFO-stimulated cells. JNK, total JNK; p-JNK, active phosphorylated JNK.

 
Western blot assays were performed to ensure the presence of total and active phosphorylated forms of p38, ERK, and JNK within fetal small intestinal cells. These members of the MAPK pathway were present in both control and DFO-stimulated cells (Figs. 2D, 3D, and 4D).

DISCUSSION

Iron is critical for a variety of cellular actions. As bacteria also require iron for survival, a competition between human hosts and mucosa-residing microbes develops (22). Bacteria have developed the capacity to acquire iron from human hosts via iron chelators such as DFO, which has been shown to activate the intestinal immune system in the absence of bacteria (6). This discovery revealed a unique manner of immune system activation and proposed an intracellular signaling cascade that, if understood, could attenuate the inflammatory cascade associated with acute intestinal ischemic disorders.

As mentioned, DFO stimulated human fetal intestinal cells to increase the production of IL-6 and VEGF while conversely causing a decrease in HGF production. IL-6 is known to be an acute-phase reactant and may act as both an inflammatory mediator acutely as well as an anti-inflammatory mediator chronically (21). The results of this study may indicate that the human host has adapted to microbial iron chelation by initiating the proinflammatory pathway, thereby activating the immune system for combating the offending bacterial agent. Likewise, elevated VEGF may indicate an attempt for stressed cells to acutely promote angiogenesis, thereby increasing leukocyte influx to the area of ischemia.

It is indeed perplexing that HGF was decreased with DFO stimulation, as HGF has been shown to increase mucosal integrity and mass (37). In addition, HGF is known to stimulate angiogenesis and decrease apoptosis in ischemic and proinflammatory environments (46). Therefore, HGF would be expected to be elevated with the activation of the inflammatory cascade to protect ischemic cells. It is possible, though, that HGF elevation is not acutely seen in the setting of DFO-induced inflammation and that peak elevation occurs after 24 h. Further work is needed to determine if DFO stimulation chronically increases HGF production in fetal human intestinal epithelial cells.

The lack of TNF-{alpha} expression in this model was also perplexing. Despite the lack of baseline TNF-{alpha} expression in control groups, we expected to see an elevation in TNF-{alpha} with DFO stimulation, thereby further supporting immune system activation. A previous study (50) has confirmed that the fetal human small intestinal cell line is capable of producing TNF-{alpha}. However, it is possible that TNF-{alpha} production is not stimulated by DFO in this cell line, as the DFO dose-response analysis failed to yield any TNF-{alpha} production, even at a maximum dose of 5 mM. It is also possible that these cells require a longer incubation with DFO to generate enough TNF-{alpha} to be recognized by the commercial ELISA kit. Further studies to assay the chronic stimulation of TNF-{alpha} production with DFO are therefore needed.

Our results also illustrate that the production of IL-6, VEGF, and HGF depend on the p38, ERK, and JNK enzymes of the MAPK pathway. Although not yet identified in this model, it is likely that DFO utilizes the same downstream signaling pathways that have been previously well described, namely, c-Fos and c-Jun, for the localization of transcriptional factors to the cell nucleus. It is perplexing, though, that DFO activated all three MAPK pathways simultaneously. Typically, ERK signaling is influenced by cell proliferation and growth factor stimulation, whereas p38 and JNK pathways largely respond to stress conditions, which include bacterial translocation as seen in acute intestinal ischemia (18). It is possible that DFO acutely induced the production of VEGF and other growth factors, which then stimulated further growth factor production and activation of the ERK MAPK pathway. Further work to assay the chronic relation of DFO-induced cytokine and growth factor production needs to be performed. This may provide clarity as to the reason all three pathways are involved.

In conclusion, this study confirms that DFO alone can acutely stimulate the inflammatory cascade within fetal human small intestinal cells. The data show that IL-6, VEGF, and HGF, but not TNF-{alpha}, are affected by iron chelation in the fetal small intestinal cell line. Furthermore, the production of these cytokines and growth factors depends on members of the MAPK pathway, namely, p38, ERK, and JNK. Further defining the signaling pathway that bacterial siderophores utilize to induce the inflammatory cascade during acute ischemic disorders may lead to novel therapies designed to inhibit chelator-induced inflammation and ischemia.

GRANTS

This investigation was conducted in a facility constructed with support from National Center for Research Resources Grant C06-RR-015481-01.

FOOTNOTES


Address for reprint requests and other correspondence: D. R. Meldrum, 545 Barnhill Drive, Emerson Hall 215, Indianapolis, IN 46202 (e-mail: dmeldrum{at}iupui.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

REFERENCES

  1. Bardelli A, Longati P, Albero D, Goruppi S, Schneider C, Ponzetto C, Comoglio PM. HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death. EMBO J 15: 6205–6212, 1996.[ISI][Medline]
  2. Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11: 372–377, 2001.[CrossRef][ISI][Medline]
  3. Bierer BE, Nathan DG. The effect of desferrithiocin, an oral iron chelator, on T-cell function. Blood 76: 2052–2059, 1990.[Abstract/Free Full Text]
  4. Brieva JA, Stevens RH. Involvement of the transferrin receptor in the production and NK-induced suppression of human antibody synthesis. J Immunol 133: 1288–1292, 1984.[Abstract]
  5. Caplan MS, Hsueh W. Necrotizing enterocolitis: role of platelet activating factor, endotoxin, and tumor necrosis factor. J Pediatr 117: S47–S51, 1990.[CrossRef][ISI][Medline]
  6. Choi EY, Oh HM, Kim S, Lee HJ, Cho EY, Yoon KH, Kim EA, Han WC, Choi SC, Hwang JY, Park C, Oh BS, Kim Y, Kimm KC, Park KI, Chung HT, Jun CD. Iron chelator triggers inflammatory signals in human intestinal epithelial cells: involvement of p38 and extracellular signal-regulated kinase signaling pathways. J Immunol 172: 7069–7077, 2004.[Abstract/Free Full Text]
  7. Chung CS, Wang W, Chaudry IH, Ayala A. Increased apoptosis in lamina propria B cells during polymicrobial sepsis is FasL but not endotoxin mediated. Am J Physiol Gastrointest Liver Physiol 280: G812–G818, 2001.[Abstract/Free Full Text]
  8. Chung CS, Watkins L, Funches A, Lomas-Neira J, Cioffi WG, Ayala A. Deficiency of {gamma}{delta}T lymphocytes contributes to mortality and immunosuppression in sepsis. Am J Physiol Regul Integr Comp Physiol 291: R1338–R1343, 2006.[Abstract/Free Full Text]
  9. Conner EA, Wirth PJ, Kiss A, Santoni-Rugiu E, Thorgeirsson SS. Growth inhibition and induction of apoptosis by HGF in transformed rat liver epithelial cells. Biochem Biophys Res Commun 236: 396–401, 1997.[CrossRef][ISI][Medline]
  10. Goepfert AR, Andrews WW, Carlo W, Ramsey PS, Cliver SP, Goldenberg RL, Hauth JC. Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity. Am J Obstet Gynecol 191: 1375–1381, 2004.[CrossRef][ISI][Medline]
  11. Gohda E, Okauchi H, Iwao M, Yamamoto I. Induction of apoptosis by hepatocyte growth factor/scatter factor and its augmentation by phorbol esters in Meth A cells. Biochem Biophys Res Commun 245: 278–283, 1998.[CrossRef][ISI][Medline]
  12. Golding S, Young SP. Iron requirements of human lymphocytes: relative contributions of intra- and extra-cellular iron. Scand J Immunol 41: 229–236, 1995.[CrossRef][ISI][Medline]
  13. Gray CP, Arosio P, Hersey P. Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells. Blood 99: 3326–3334, 2002.[Abstract/Free Full Text]
  14. Griga T, Tromm A, Schmiegel W, Pfisterer O, Muller KM, Brasch F. Collagenous colitis: implications for the role of vascular endothelial growth factor in repair mechanisms. Eur J Gastroenterol Hepatol 16: 397–402, 2004.[CrossRef][ISI][Medline]
  15. Harris MC, Costarino AT Jr, Sullivan JS, Dulkerian S, McCawley L, Corcoran L, Butler S, Kilpatrick L. Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J Pediatr 124: 105–111, 1994.[CrossRef][ISI][Medline]
  16. Jeschke MG, Bolder U, Finnerty CC, Przkora R, Muller U, Maihofer R, Thompson JC, Wolf SE, Herndon DN. The effect of hepatocyte growth factor on gut mucosal apoptosis and proliferation, and cellular mediators after severe trauma. Surgery 138: 482–489, 2005.[CrossRef][ISI][Medline]
  17. Kosai K, Matsumoto K, Nagata S, Tsujimoto Y, Nakamura T. Abrogation of Fas-induced fulminant hepatic failure in mice by hepatocyte growth factor. Biochem Biophys Res Commun 244: 683–690, 1998.[CrossRef][ISI][Medline]
  18. Kyriakis JM, Avruch J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271: 24313–24316, 1996.[Free Full Text]
  19. Li X, Rana SN, Kovacs EJ, Gamelli RL, Chaudry IH, Choudhry MA. Corticosterone suppresses mesenteric lymph node T cells by inhibiting p38/ERK pathway and promotes bacterial translocation after alcohol and burn injury. Am J Physiol Regul Integr Comp Physiol 289: R37–R44, 2005.[Abstract/Free Full Text]
  20. Li X, Rana SN, Schwacha MG, Chaudry IH, Choudhry MA. A novel role for IL-18 in corticosterone-mediated intestinal damage in a two-hit rodent model of alcohol intoxication and injury. J Leukoc Biol 80: 367–375, 2006.[Abstract/Free Full Text]
  21. Markel TA, Crisostomo PR, Wairiuko GM, Pitcher J, Tsai BM, Meldrum DR. Cytokines in necrotizing enterocolitis. Shock 25: 329–337, 2006.[CrossRef][ISI][Medline]
  22. Markel TA, Crisostomo PR, Wang M, Herring CM, Meldrum KK, Lillemoe KD, Meldrum DR. The struggle for iron: gastrointestinal microbes modulate the host immune response during infection. J Leukoc Biol. In press.
  23. Matsuda A, Furukawa K, Suzuki H, Matsutani T, Tajiri T, Chaudry IH. Dehydroepiandrosterone modulates toll-like receptor expression on splenic macrophages of mice after severe polymicrobial sepsis. Shock 24: 364–369, 2005.[CrossRef][ISI][Medline]
  24. Matsutani T, Kang SC, Miyashita M, Sasajima K, Choudhry MA, Bland KI, Chaudry IH. Liver cytokine production and ICAM-1 expression following bone fracture, tissue trauma, and hemorrhage in middle-aged mice. Am J Physiol Gastrointest Liver Physiol 292: G268–G274, 2007.[Abstract/Free Full Text]
  25. Mayr S, Walz CR, Angele P, Hernandez-Richter T, Chaudry IH, Loehe F, Jauch KW, Angele MK. Castration prevents suppression of MHC class II (Ia) expression on macrophages after trauma-hemorrhage. J Appl Physiol 101: 448–453, 2006.[Abstract/Free Full Text]
  26. Meldrum DR. Estrogen increases protective proteins following trauma and hemorrhage. Am J Physiol Regul Integr Comp Physiol 290: R809–R811, 2006.[Free Full Text]
  27. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol Regul Integr Comp Physiol 274: R577–R595, 1998.[Abstract/Free Full Text]
  28. Meldrum DR, Partrick DA, Cleveland JC Jr, Shenkar R, Meldrum KK, Raiesdana A, Ayala A, Brown JW, Harken AH. On-pump coronary artery bypass surgery activates human myocardial NF-kappaB and increases TNF-alpha in the heart. J Surg Res 112: 175–179, 2003.[CrossRef][ISI][Medline]
  29. Meldrum KK, Burnett AL, Meng X, Misseri R, Shaw MB, Gearhart JP, Meldrum DR. Liposomal delivery of heat shock protein 72 into renal tubular cells blocks nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and subsequent ischemia-induced apoptosis. Circ Res 92: 293–299, 2003.[Abstract/Free Full Text]
  30. Meldrum KK, Meldrum DR, Meng X, Ao L, Harken AH. TNF-{alpha}-dependent bilateral renal injury is induced by unilateral renal ischemia-reperfusion. Am J Physiol Heart Circ Physiol 282: H540–H546, 2002.[Abstract/Free Full Text]
  31. Meldrum KK, Metcalfe P, Leslie JA, Misseri R, Hile KL, Meldrum DR. TNF-alpha neutralization decreases nuclear factor-kappaB activation and apoptosis during renal obstruction. J Surg Res 131: 182–188, 2006.[CrossRef][ISI][Medline]
  32. Meng X, Ao L, Song Y, Raeburn CD, Fullerton DA, Harken AH. Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-{alpha} receptor. Am J Physiol Regul Integr Comp Physiol 288: R600–R606, 2005.[Abstract/Free Full Text]
  33. Morecroft JA, Spitz L, Hamilton PA, Holmes SJ. Plasma cytokine levels in necrotizing enterocolitis. Acta Paediatr Suppl 396: 18–20, 1994.[Medline]
  34. Pender SL, Braegger C, Gunther U, Monteleone G, Meuli M, Schuppan D, Macdonald TT. Matrix metalloproteinases in necrotising enterocolitis. Pediatr Res 54: 160–164, 2003.[CrossRef][ISI][Medline]
  35. Romagnoli C, Frezza S, Cingolani A, De Luca A, Puopolo M, De Carolis MP, Vento G, Antinori A, Tortorolo G. Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis. Eur J Pediatr 160: 345–350, 2001.[CrossRef][ISI][Medline]
  36. Scalia R, Booth G, Lefer DJ. Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide. FASEB J 13: 1039–1046, 1999.[Abstract/Free Full Text]
  37. Schwartz MZ, Kato Y, Yu D, Lukish JR. Growth-factor enhancement of compromised gut function following massive small-bowel resection. Pediatr Surg Int 16: 174–175, 2000.[CrossRef][ISI][Medline]
  38. Szalay L, Shimizu T, Suzuki T, Hsieh YC, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. Androstenediol administration after trauma-hemorrhage attenuates inflammatory response, reduces organ damage, and improves survival following sepsis. Am J Physiol Gastrointest Liver Physiol 291: G260–G266, 2006.[Abstract/Free Full Text]
  39. Testa U, Petrini M, Quaranta MT, Pelosi-Testa E, Mastroberardino G, Camagna A, Boccoli G, Sargiacomo M, Isacchi G, Cozzi A, et al. Iron up-modulates the expression of transferrin receptors during monocyte-macrophage maturation. J Biol Chem 264: 13181–13187, 1989.[Abstract/Free Full Text]
  40. Thobe BM, Frink M, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. Src family kinases regulate p38 MAPK-mediated IL-6 production in Kupffer cells following hypoxia. Am J Physiol Cell Physiol 291: C476–C482, 2006.[Abstract/Free Full Text]
  41. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330: 662–664, 1987.[CrossRef][Medline]
  42. von Dobschuetz E, Meyer S, Thorn D, Marme D, Hopt UT, Thomusch O. Targeting vascular endothelial growth factor pathway offers new possibilities to counteract microvascular disturbances during ischemia/reperfusion of the pancreas. Transplantation 82: 543–549, 2006.[ISI][Medline]
  43. Wang M, Baker L, Tsai BM, Meldrum KK, Meldrum DR. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 288: E321–E326, 2005.[Abstract/Free Full Text]
  44. Wang M, Meng X, Tsai B, Wang JF, Turrentine M, Brown JW, Meldrum DR. Preconditioning up-regulates the soluble TNF receptor I response to endotoxin. J Surg Res 121: 20–24, 2004.[CrossRef][ISI][Medline]
  45. Wang M, Tsai BM, Crisostomo PR, Meldrum DR. Tumor necrosis factor receptor 1 signaling resistance in the female myocardium during ischemia. Circulation 114: I282–I289, 2006.[ISI][Medline]
  46. Wang Y, Ahmad N, Wani MA, Ashraf M. Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis. J Mol Cell Cardiol 37: 1041–1052, 2004.[CrossRef][ISI][Medline]
  47. Wang Y, Haider HK, Ahmad N, Xu M, Ge R, Ashraf M. Combining pharmacological mobilization with intramyocardial delivery of bone marrow cells over-expressing VEGF is more effective for cardiac repair. J Mol Cell Cardiol 40: 736–745, 2006.[CrossRef][ISI][Medline]
  48. Weinberg ED. Microbial pathogens with impaired ability to acquire host iron. Biometals 13: 85–89, 2000.[CrossRef][ISI][Medline]
  49. Yo Y, Morishita R, Nakamura S, Tomita N, Yamamoto K, Moriguchi A, Matsumoto K, Nakamura T, Higaki J, Ogihara T. Potential role of hepatocyte growth factor in the maintenance of renal structure: anti-apoptotic action of HGF on epithelial cells. Kidney Int 54: 1128–1138, 1998.[CrossRef][ISI][Medline]
  50. Zachrisson K, Neopikhanov V, Samali A, Uribe A. Interleukin-1, interleukin-8, tumour necrosis factor alpha and interferon gamma stimulate DNA synthesis but have no effect on apoptosis in small-intestinal cell lines. Eur J Gastroenterol Hepatol 13: 551–559, 2001.[CrossRef][ISI][Medline]




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