Repeated enemas with hepatocyte growth factor selectively stimulate epithelial cell proliferation of injured mucosa in rats with experimental colitis

Setoyama, Hitoshi; Ido, Akio; Numata, Masatsugu; Moriuchi, Akihiro; Yamaji, Naohisa; Tamai, Tsutomu; Funakawa, Keita; Fujita, Hiroshi; Sakiyama, Toshio; Uto, Hirofumi; Oketani, Makoto; Tsubouchi, Hirohito

doi:10.1016/j.lfs.2011.06.019

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…Our findings on HGF effects on IECs are consistent with previous observations of Hirai et al (14), who showed that HGF was an important contributor to amniotic fluidinduced cell proliferation in FHs-74-Int human fetal IECs. Similar findings were reported by Setoyama et al (32), who showed that HGF enemas can promote colonocyte proliferation at sites of mucosal injury in a rat model of inflammatory bowel disease. In rats with surgical short bowel syndrome, HGF can increase mucosal protein and DNA content during intestinal adaptation (16).…”

Section: Discussionsupporting

confidence: 90%

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Jain

Baggerman

MohanKumar

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 306: G361-G369, 2014. First published January 9, 2014; doi:10.1152/ajpgi.00272.2013.-Fetal swallowing of amniotic fluid, which contains numerous cytokines and growth factors, plays a key role in gut mucosal development. Preterm birth interrupts this exposure to amniotic fluid-borne growth factors, possibly contributing to the increased risk of necrotizing enterocolitis (NEC) in premature infants. We hypothesized that supplementation of formula feeds with amniotic fluid can provide amniotic fluid-borne growth factors and prevent experimental NEC in rat pups. We compared NEC-like injury in rat pups fed with infant formula vs. formula supplemented either with 30% amniotic fluid or recombinant hepatocyte growth factor (HGF). Cytokines/growth factors in amniotic fluid were measured by immunoassays. Amniotic fluid and HGF effects on enterocyte migration, proliferation, and survival were measured in cultured IEC6 intestinal epithelial cells. Finally, we used an antibody array to investigate receptor tyrosine kinase (RTK) activation and immunoblots to measure phosphoinositide 3-kinase (PI3K) signaling. Amniotic fluid supplementation in oral feeds protected rat pups against NEC-like injury. HGF was the most abundant growth factor in rat amniotic fluid in our panel of analytes. Amniotic fluid increased cell migration, proliferation, and cell survival in vitro. These effects were reproduced by HGF and blocked by anti-HGF antibody or a PI3K inhibitor. HGF transactivated several RTKs in IEC6 cells, indicating that its effects extended to multiple signaling pathways. Finally, similar to amniotic fluid, recombinant HGF also reduced the frequency and severity of NEC-like injury in rat pups. Amniotic fluid supplementation protects rat pups against experimental NEC, which is mediated, at least in part, by HGF. amniotic fluid; NEC; HGF; inflammation; phosphoinositide 3-kinase NECROTIZING ENTEROCOLITIS (NEC), an inflammatory bowel necrosis of preterm infants, is a leading cause of death among neonates born before 32 wk of gestation or with a birth weight Ͻ1,500 g (20, 27). Although the etiology of NEC remains unclear, epidemiological studies show an association with diverse risk factors such as maternal chorioamnionitis, perinatal asphyxia, indomethacin therapy, viral infections, and blood transfusions (20). Current pathophysiological models suggest that NEC occurs when altered/disrupted epithelial barrier in the preterm intestine allows luminal bacteria to translocate across the epithelial barrier into the lamina propria, triggering a severe mucosal inflammatory response and tissue damage (21).During intrauterine development, the fetus ingests progressively large volumes of amniotic fluid, which contains several cytokines and growth factors known to promote gut mucosal development (19). In the third trimester, the human fetus swallows nearly 550 ml/day amniotic fluid (29, 40). We hypothesiz...

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Section: Discussionsupporting

confidence: 90%

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Jain

Baggerman

MohanKumar

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In vitro , HGF modulates intestinal epithelial cell proliferation and migration (15), thereby enhancing epithelial cell restitution, which is the initial step of gastrointestinal wound healing. In addition, administration of recombinant human HGF (hHGF) protein reduces the severity of colitis and accelerates colonic mucosal repair in models of TNBS-induced and DSS-induced colitis (16–19), as well as in HLA-B27 transgenic rats with colitis (20). Mukoyama et al (21) showed that the intrarectal administration of an adenoviral (Ad) vector carrying the HGF gene prevented TNBS-induced colitis.…”

Section: Introductionmentioning

confidence: 99%

Intramuscular injection of adenoviral hepatocyte growth factor at a distal site ameliorates dextran sodium sulfate-induced colitis in mice

Yuge

Takahashi

Khai

et al. 2014

International Journal of Molecular Medicine

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Inflammatory bowel disease (IBD) severely affects the quality of life of patients. At present, there is no clinical solution for this condition; therefore, there is a need for innovative therapies for IBD. Hepatocyte growth factor (HGF) exerts various biological activities in various organs. However, a clinically applicable and effective HGF-based therapy for IBD has yet to be developed. In this study, we examined the therapeutic effect of injecting an adenoviral vector encoding the human HGF gene (Ad.HGF) into the hindlimbs of mice with dextran sodium sulfate (DSS)-induced colitis. Plasma levels of circulating human HGF (hHGF) were measured in injected mice. The results showed that weight loss and colon shortening were significantly lower in Ad.HGF-infected mice as compared to control (Ad.LacZ-infected) colitic mice. Additionally, inflammation and crypt scores were significantly reduced in the entire length of the colon, particularly in the distal section. This therapeutic effect was associated with increased cell proliferation and an antiapoptotic effect, as well as a reduction in the number of CD4+ cells and a decreased CD4/CD8 ratio. The levels of inflammatory, as well as Th1 and Th2 cytokines were higher in Ad.HGF-infected mice as compared to the control colitic mice. Thus, systemically circulating hHGF protein, produced by an adenovirally transduced hHGF gene introduced at distal sites in the limbs, significantly ameliorated DSS-induced colitis by promoting cell proliferation (i.e., regeneration), preventing apoptosis, and immunomodulation. Owing to its clinical feasibility and potent therapeutic effects, this method may be developed into a clinical therapy for treating IBD.

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“…Andoh et al (2005) reported autocrine effects of PDGFA stimulating the expression of metalloproteinase and thymidine incorporation in human subepithelial myofibroblasts. Furthermore, PDGFA also has autocrine regulatory effects on the expression of hepatocyte growth factor mRNA, which is a ubiquitous regulator of epithelial proliferation and mucosal repair (Göke et al 1998;Setoyama et al 2011).…”

Section: Miró and Othersmentioning

confidence: 99%

Vasopressin regulation of epithelial colonic proliferation and permeability is mediated by pericryptal platelet‐derived growth factor A

Miró

Pérez-Bosque

Maijó

et al. 2014

Experimental Physiology

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New Findings r What is the central question of this study?Arginine vasopressin (AVP) regulates distal colonic crypt cell proliferation and permeability in vivo, but the underlying mechanism is poorly understood. Our study addresses whether AVP is acting directly on myofibroblasts and enterocytes or by mechanisms involving local regulators, in an in vitro model using human myofibroblasts and enterocyte cell lines. r What is the main finding and its importance?The effect of AVP in stimulating myofibroblast proliferation involves pericryptal platelet-derived growth factor A, which mediates local effects by an autocrine loop and epithelial proliferation and permeability by a paracrine mechanism. These data highlight the role of growth factors as local mediators of systemic hormones.Arginine vasopressin (AVP) has trophic effects on the rat distal colon, increasing the growth of pericryptal myofibroblasts and reducing the colonic crypt wall permeability. This study aimed to reproduce in vitro the effects of AVP observed in vivo using cultures of human CCD-18Co myofibroblasts and T84 colonic epithelial cells. Proliferation of myofibroblasts was quantified by bromodeoxyuridine incorporation; the expression of platelet-derived growth factor A (PDGFA), platelet-derived growth factor B, epidermal growth factor, transforming growth factor-β and vascular endothelial growth factor was measured by PCR and the expression of epithelial junction proteins by Western blot. Arginine vasopressin stimulated myofibroblast proliferation and the expression of PDGFA without affecting the expression of platelet-derived growth factor B, epidermal growth factor, transforming growth factor-β or vascular endothelial growth factor. These effects were prevented when AVP receptor inhibitors were present in the medium. Pre-incubation of CCD-18Co cells with anti-PDGF antibody or with an inhibitor of the PDGF receptor abolished the effects of AVP. When colonocytes were incubated with medium obtained from myofibroblasts incubated with AVP, both cell proliferation and the expression of epithelial junction proteins increased; however, direct incubation of colonocytes with AVP did not modify these variables. These results demonstrate that AVP stimulates myofibroblast proliferation and induces PDGFA secretion, implying that PDGFA mediates local myofibroblast proliferation by L. Miró and A. Pérez-Bosque contributed equally to this work.

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Repeated enemas with hepatocyte growth factor selectively stimulate epithelial cell proliferation of injured mucosa in rats with experimental colitis

Cited by 11 publications

References 38 publications

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Intramuscular injection of adenoviral hepatocyte growth factor at a distal site ameliorates dextran sodium sulfate-induced colitis in mice

Vasopressin regulation of epithelial colonic proliferation and permeability is mediated by pericryptal platelet‐derived growth factor A

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