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John H. Schwab - One of the best experts on this subject based on the ideXlab platform.

  • Polymers from Cell Walls of Pathogenic and Normal-Flora Bacteria Which Colonize Humans
    2014
    Co-Authors: J H Schwab, John H. Schwab
    Abstract:

    bacteria which colonize humans. cell walls of pathogenic and normal-flora Peptidoglycan-Polysaccharide polymers from Phlogistic properties o

  • LIPOPolysaccharide INDUCES RECURRENCE OF ARTHRITIS IN RAT JOINTS PREVIOUSLY INJURED BY Peptidoglycan-Polysaccharide
    2013
    Co-Authors: A. Stimpson, Ronald E Esser, Philip B. Carter, Balfour R. Sartor, William T J. Cromartie, John H. Schwab
    Abstract:

    LPS and Peptidoglycan or covalent Peptidoglycan-Polysaccharide (PG-PS)' complexes are the major toxic components of bacterial cell walls. Lipid A and PG possess many of the biologic activities that LPS and PG-PS, respectively, have in common, such as pyrogenicity, polyclonal activation of lymphoid cells, complement activation, mitogenicity, macrophage activation, and adjuvanticity (1-3). Both also induce arthritis after injection into laboratory animals. Systemic injection of rats with a sterile, aqueous suspension of PG-PS from the group A streptococcus (PG-APS) induces a chronic erosive relapsing arthritis that has many features of rheumatoid arthritis (4-6). Distinct PG-PS structures from a number of other bacteria, including human indigenous intestinal species, induce arthritis of varying chronicity (7-10). LPS induces primarily an acute arthritis of relatively short duration after intraarticular (i.a.) injection (7, 11-15), but there have been few reports of its arthropathic activity after systemic administration (16, 17, 17a). In spite of the shared biologic properties and ubiquitous distribution of LP

  • selective kallikrein kinin system activation in inbred rats differentially susceptible to granulomatous enterocolitis
    Gastroenterology, 1996
    Co-Authors: R B Sartor, John H. Schwab, R Dela A Cadena, K D Green, A Stadnicki, S W Davis, A A Adam, P Raymond, R W Colman
    Abstract:

    Abstract BACKGROUND & AIMS: Crohn's disease is characterized by unrestrained inflammation with a genetic component. Genetic susceptibility and activation of the kalli-krein-kinin (contact) system were investigated in experimental enterocolitis and extraintestinal inflammation induced by bacterial polymers. METHODS: Kinetics of inflammation in inbred Lewis and Buffalo rats injected subserosally with Peptidoglycan- Polysaccharide polymers were correlated with in vivo and in vitro activation of the contact system. RESULTS: Lewis rats had a biphasic course of enterocolitis. Acute inflammation peaked 1 day after injection, gradually decreasing until day 14 when intestinal inflammation spontaneously reactivated and persisted for 16 weeks, accompanied by arthritis, granulomatous hepatitis, anemia, and leukocytosis. Self-limited acute enterocolitis in Buffalo rats resolved by 24 days without extraintestinal involvement. Consumption of the precursor proteins prekalli-krein and high-molecular-weight kininogen indicated activation of the plasma contact system in Lewis rats and closely correlated with chronic intestinal inflammation. Contact system activation did not occur in Buffalo rats, even during acute inflammation. In vitro studies showed a decreased rate of kininogen cleavage in Buffalo plasma. CONCLUSIONS: Selective in vivo and in vitro activation of the contact system in susceptible Lewis rats suggests that this pathway is one determinant of genetic susceptibility to granulomatous enterocolitis and systemic complications. (Gastroenterology 1996 May;110(5):1467-81)

  • reactivation of arthritis induced by small bowel bacterial overgrowth in rats role of cytokines bacteria and bacterial polymers
    Infection and Immunity, 1995
    Co-Authors: Steven N Lichtman, R B Sartor, Jian Wang, Chuan Zhang, D E Bender, F G Dalldorf, John H. Schwab
    Abstract:

    Arthritis is often associated with intestinal diseases, but the etiology is not known. We developed a rat model whereby arthritis was reactivated by experimental small bowel bacterial overgrowth (SBBO). Self-limited monoarticular arthritis was induced by intra-articular injection of 2 micrograms of rhamnose Peptidoglycan-Polysaccharide derived from group A streptococci into the ankle joints in female Lewis rats. Eleven days after intra-articular injection, when swelling was resolving, experimental SBBO induced by surgical creation of jejunal self-filling blind loops reactivated arthritis, but SBBO induced by creation of self-emptying blind loops, which minimally increases luminal bacteria, and sham operation did not (P < 0.001). Increased joint diameters in rats with self-filling blind loops persisted for at least 56 days after surgery. Reactivation of arthritis due to SBBO was prevented by anti-tumor necrosis factor alpha antiserum and interleukin 1 receptor antagonist (P < 0.001), indicating that these cytokines mediate joint swelling secondary to intestinal injury. Recombinant bactericidal/permeability-increasing protein, an agent which neutralizes endotoxin, and metronidazole, which is active against anaerobic bacteria, prevented arthritis (P < 0.001), but polymyxin B (which also neutralizes endotoxin) and gentamicin had no effect. Mutanolysin, an enzyme which degrades Peptidoglycan-Polysaccharide from group A streptococci, exacerbated arthritis for the first 6 days but then diminished joint swelling from 12 to 21 days after surgery (P < 0.001). These studies introduce a reproducible animal model of reactivation of arthritis secondary to intestinal injury and demonstrate a role for bacterial products from endogenous enteric organisms.

  • superantigen can reactivate bacterial cell wall induced arthritis
    Journal of Immunology, 1993
    Co-Authors: John H. Schwab, S K Anderle, R R Brown, Patrick M Schlievert
    Abstract:

    Intravenous injection of toxic shock syndrome toxin-1 (TSST-1) produced by Staphylococcus aureus, can reactivate arthritis in a rat ankle joint that has been previously inflamed by injection of PeptidoglycanPolysaccharide polymers isolated from the cell walls of group A streptococci. The severity and chronicity of this renewed arthritis is dose dependent and at higher doses (125 micrograms/kg) a prolonged joint inflammation with pannus formation and marginal erosion of cartilage and bone is induced after a single injection of TSST-1. Only modest synovial hyperplasia is induced in control ankle joints by systemic injection of TSST-1. Another superantigen, streptococcal pyrogenic exotoxin induces a much weaker, acute reactivation of arthritis that resolves by 2 days. Repeated injections of TSST-1 at 7-day intervals give the same undiminished pattern of joint response, but the joint swelling persists at a higher level with each succeeding injection. Cyclosporin A suppresses all phases of the recurrent arthritis, indicating that TSST-1 could be functioning through its property of a superantigen activating T lymphocytes. II-1 receptor antagonist and anti-TNF-alpha neutralizing antibody, which reduce reactivation of arthritis by Peptidoglycan-Polysaccharide polymers, have no effect on reactivation by TSST-1. This experimental model provides a means to examine in vivo the possible role of superantigens in rheumatoid arthritis and related diseases, and to analyze the cellular and molecular pathways induced by this family of microbial products.

R B Sartor - One of the best experts on this subject based on the ideXlab platform.

  • bradykinin receptor antagonists type 2 attenuate the inflammatory changes in Peptidoglycan induced acute arthritis in the lewis rat
    Inflammation Research, 2001
    Co-Authors: Audrey B Uknis, R Dela A Cadena, R Janardham, R B Sartor, E T Whalley, Robert W. Colman
    Abstract:

    Objective and Design: We studied the ability of bradykinin (BK) receptor antagonists type 1 and 2 (B1-RA, B2-RA) to prevent acute inflammation.¶Material: A Peptidoglycan-Polysaccharide (PG-APS)-induced model of arthritis in the Lewis rat was analyzed.¶Treatment: Four groups of animals were studied for 5 days. Treatment was administered subcutaneously (s.c.) 1 mg/kg every 12 h. Group I received PG-APS and was treated with the B2-RA, CP-0597 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-NChg-Arg). Group II received PG-APS and was treated with a combined B1 and B2-RA, B9430 (DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg). Group III received PG-APS and albumin control. Group IV received albumin control.¶Methods: Joint diameter, liver weight, hematocrit, white blood count and plasma concentrations of prekallikrein, high molecular weight kininogen, HK and IL-1β were measured. Groups were compared by ANOVA.¶Results: Acute arthritis and hepatomegaly were attenuated in the B2-RA-treated animals (p<0.05). Weight loss was more pronounced in the B1/B2-RA-treated animals. Anemia induced by PG-APS was prevented by B2-RA and B1/B2-RA treatment (p<0.001). A marked decrease in plasma HK to 64% of normal was found in the disease-untreated animals, which was completely normalized by B2-RA treatment and partially attenuated by the B1/B2-RA (78%). The decrease in plasma prekallikrein levels was prevented by combined B1/B2-RA treatment (p<0.05). Finally, elevated plasma IL-1β levels were lowered by B1/B2-RA treatment and were below detection limits with the B2-RA treatment.¶Conclusions: These results indicate that the systemic inflammation is due in part to BK generation which can be blocked by B2-RA, while inhibiting the B1 receptor prevents an anti-inflammatory response.¶

  • interleukin 10 suppresses experimental chronic granulomatous inflammation induced by bacterial cell wall polymers
    Gut, 1996
    Co-Authors: Hans H Herfarth, Heiko C Rath, S P Mohanty, Susan L Tonkonogy, R B Sartor
    Abstract:

    BACKGROUND AND AIMS: Interleukin 10 (IL10) inhibits monocyte/macrophage and T lymphocyte effector functions. This study examined the effect of systemically administered IL10 on acute and chronic granulomatous enterocolitis, hepatitis, and arthritis in a rat model. METHODS: Lewis rats were injected intramurally with streptococcal Peptidoglycan-Polysaccharide (PG-APS) polymers. Beginning 12 hours before PG-APS injection, rats were treated daily with subcutaneous murine recombinant IL10 or vehicle for three or 17 days. RESULTS: IL10 attenuated acute enterocolitis in a dose dependent fashion (p < 0.01). Protective effects were more profound in the chronic granulomatous phase with decreased enterocolitis and markedly inhibited leucocytosis, hepatic granulomas, and chronic erosive arthritis (p < 0.001). IL10 downregulated tissue IL1, IL6, tumour necrosis factor alpha, and interferon gamma gene expression, consistent with the in vitro effects of IL10 on PG-APS-stimulated splenocytes. Caecal IL1 protein concentrations and IL2 and interferon gamma secretion by in vitro stimulated mesenteric lymph nodes were downregulated in IL10 treated animals. CONCLUSIONS: These results indicate that exogenous IL10 can inhibit experimental granulomatous inflammatory responses and suggest that IL10 treatment could be an effective new therapeutic approach in human disorders such as Crohn's disease, rheumatoid arthritis, and sarcoidosis.

  • selective kallikrein kinin system activation in inbred rats differentially susceptible to granulomatous enterocolitis
    Gastroenterology, 1996
    Co-Authors: R B Sartor, John H. Schwab, R Dela A Cadena, K D Green, A Stadnicki, S W Davis, A A Adam, P Raymond, R W Colman
    Abstract:

    Abstract BACKGROUND & AIMS: Crohn's disease is characterized by unrestrained inflammation with a genetic component. Genetic susceptibility and activation of the kalli-krein-kinin (contact) system were investigated in experimental enterocolitis and extraintestinal inflammation induced by bacterial polymers. METHODS: Kinetics of inflammation in inbred Lewis and Buffalo rats injected subserosally with Peptidoglycan- Polysaccharide polymers were correlated with in vivo and in vitro activation of the contact system. RESULTS: Lewis rats had a biphasic course of enterocolitis. Acute inflammation peaked 1 day after injection, gradually decreasing until day 14 when intestinal inflammation spontaneously reactivated and persisted for 16 weeks, accompanied by arthritis, granulomatous hepatitis, anemia, and leukocytosis. Self-limited acute enterocolitis in Buffalo rats resolved by 24 days without extraintestinal involvement. Consumption of the precursor proteins prekalli-krein and high-molecular-weight kininogen indicated activation of the plasma contact system in Lewis rats and closely correlated with chronic intestinal inflammation. Contact system activation did not occur in Buffalo rats, even during acute inflammation. In vitro studies showed a decreased rate of kininogen cleavage in Buffalo plasma. CONCLUSIONS: Selective in vivo and in vitro activation of the contact system in susceptible Lewis rats suggests that this pathway is one determinant of genetic susceptibility to granulomatous enterocolitis and systemic complications. (Gastroenterology 1996 May;110(5):1467-81)

  • reactivation of arthritis induced by small bowel bacterial overgrowth in rats role of cytokines bacteria and bacterial polymers
    Infection and Immunity, 1995
    Co-Authors: Steven N Lichtman, R B Sartor, Jian Wang, Chuan Zhang, D E Bender, F G Dalldorf, John H. Schwab
    Abstract:

    Arthritis is often associated with intestinal diseases, but the etiology is not known. We developed a rat model whereby arthritis was reactivated by experimental small bowel bacterial overgrowth (SBBO). Self-limited monoarticular arthritis was induced by intra-articular injection of 2 micrograms of rhamnose Peptidoglycan-Polysaccharide derived from group A streptococci into the ankle joints in female Lewis rats. Eleven days after intra-articular injection, when swelling was resolving, experimental SBBO induced by surgical creation of jejunal self-filling blind loops reactivated arthritis, but SBBO induced by creation of self-emptying blind loops, which minimally increases luminal bacteria, and sham operation did not (P < 0.001). Increased joint diameters in rats with self-filling blind loops persisted for at least 56 days after surgery. Reactivation of arthritis due to SBBO was prevented by anti-tumor necrosis factor alpha antiserum and interleukin 1 receptor antagonist (P < 0.001), indicating that these cytokines mediate joint swelling secondary to intestinal injury. Recombinant bactericidal/permeability-increasing protein, an agent which neutralizes endotoxin, and metronidazole, which is active against anaerobic bacteria, prevented arthritis (P < 0.001), but polymyxin B (which also neutralizes endotoxin) and gentamicin had no effect. Mutanolysin, an enzyme which degrades Peptidoglycan-Polysaccharide from group A streptococci, exacerbated arthritis for the first 6 days but then diminished joint swelling from 12 to 21 days after surgery (P < 0.001). These studies introduce a reproducible animal model of reactivation of arthritis secondary to intestinal injury and demonstrate a role for bacterial products from endogenous enteric organisms.

Raul Dela A Cadena - One of the best experts on this subject based on the ideXlab platform.

  • Induced by Peptidoglycan Polysaccharide in Rats Is Aggravated by Prasugrel Treatment
    2016
    Co-Authors: Raul Dela A Cadena, Elisabetta Liverani, Mario C Rico, Analia E Garcia, Paul F. Bray
    Abstract:

    Erosive arthritis and hepatic granuloma formation induced by Peptidoglycan Polysaccharide in rats is aggravated by prasugrel treatment

  • Erosive Arthritis and Hepatic Granuloma Formation Induced by Peptidoglycan Polysaccharide in Rats Is Aggravated by Prasugrel Treatment
    2016
    Co-Authors: Analia E Garcia, Raul Dela A Cadena, Elisabetta Liverani, Mario C Rico, Paul F. Bray, Satya P Kunapuli
    Abstract:

    Administration of the thienopyridine P2Y12 receptor antagonist, clopidogrel, increased the erosive arthritis induced by Peptidoglycan Polysaccharide (PG-PS) in rats or by injection of the arthritogenic K/BxN serum in mice. To determine if the detrimental effects are caused exclusively by clopidogrel, we evaluated prasugrel, a third-generation thienopyridine pro-drug, that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine. Prasugrel effects were examined on the PG-PS-induced arthritis rat model. Erosive arthritis was induced in Lewis rats followed by treatment with prasugrel for 21 days. Prasugrel treated arthritic animals showed a significant increase in the inflammatory response, compared with untreated arthritic rats, in terms of augmented macroscopic joint diameter associated with significant signs of inflammation, histomorphometric measurements of the hind joints and elevated platelet number. Moreover, fibrosis at the pannus, assessed by immunofluorescence of connective tissue growth factor, was increased in arthritic rats treated with prasugrel. In addition to the arthritic manifestations, hepatomegaly, liver granulomas and giant cell formation were observed after PG-PS induction and even more after prasugrel exposure. Cytokine plasma levels of IL-1 beta, IL-6, MIP1 alpha, MCP1, IL-17 and RANTES were increased in arthritis-induced animals. IL-10 plasma levels were significantly decrease

  • Clopidogrel, a P2Y12 Receptor Antagonist, Potentiates the Inflammatory Response in a Rat Model of Peptidoglycan Polysaccharide-Induced Arthritis
    2013
    Co-Authors: Analia E Garcia, Raul Dela A Cadena, Mario C Rico, Sripal R. Mada, Satya P Kunapuli
    Abstract:

    The P2Y12 receptor plays a crucial role in the regulation of platelet activation by several agonists, which is irreversibly antagonized by the active metabolite of clopidogrel, a widely used anti-thrombotic drug. In this study, we investigated whether reduction of platelet reactivity leads to reduced inflammatory responses using a rat model of erosive arthritis. We evaluated the effect of clopidogrel on inflammation in Lewis rats in a Peptidoglycan Polysaccharide (PG-PS)-induced arthritis model with four groups of rats: 1) untreated, 2) clopidogrel-treated, 3) PG-PS-induced, and 4) PG-PS-induced and clopidogrel-treated. There were significant differences between the PG-PS+clopidogrel group when compared to the PG-PS group including: increased joint diameter and clinical manifestations of inflammation, elevated plasma levels of proinflammatory cytokines (IL-1 beta, interferon (IFN) gamma, and IL-6), an elevated neutrophil blood count and an increased circulating platelet count. Plasma levels of IL-10 were significantly lower in the PG-PS+clopidogrel group compared to the PG-PS group. Plasma levels of platelet factor 4 (PF4) were elevated in both the PG-PS and the PG-PS+clopidogrel groups, however PF4 levels showed no difference upon clopidogrel treatment, suggesting that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. Histology indicated an increase in leukocyte infiltration at the inflammatory area of the joint, increased pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in PG-PS-induced arthritis animals. In summary, animals treated with clopidogre

  • modulation of inflammation by kininogen deficiency in a rat model of inflammatory arthritis
    Arthritis & Rheumatism, 2005
    Co-Authors: Irma M Sainz, Balfour R. Sartor, Raul Dela A Cadena, Albert Adam, Irma Isordiasalas, Julian L Castaneda, Alexis Agelan, Bo Liu, Robin A Pixley, Robert W. Colman
    Abstract:

    Objective To compare inflammatory peripheral arthritis in wild-type and high molecular weight kininogen (HK)–deficient rats, both on the genetically susceptible Lewis background. Methods By backcrossing Brown-Norway HK-deficient rats with Lewis rats for 6 generations, 2 new strains were produced, wild-type F6 and HK-deficient F6, each with a 98.5% Lewis genome. Inflammatory arthritis was induced by intraperitoneal injection of Peptidoglycan–Polysaccharide (PG-PS), and the clinical, histopathologic, and biochemical responses were compared in both strains. Results Eighteen days after PG-PS injection, rats with normal concentrations of HK showed weight loss and marked increase in hind ankle diameter with severe synovial inflammation and cartilage abnormalities. In contrast, HK-deficient rats showed no weight loss (P < 0.05), no increase in hind ankle diameter (P < 0.05), and an absence of inflammatory changes (P < 0.05), as measured by the histologic and morphometric Mankin grading system for synovial and cartilage injury. Conclusion Plasma HK is a key mediator of acute and chronic inflammatory arthritis in genetically susceptible Lewis rats.

  • selective plasma kallikrein inhibitor attenuates acute intestinal inflammation in lewis rat
    Digestive Diseases and Sciences, 1996
    Co-Authors: Antoni Stadnicki, Charles A Kettner, Balfour R. Sartor, Raul Dela A Cadena, Diane Bender, Heiko C Rath, Albert Adam, Robert W. Colman
    Abstract:

    A specific plasma kallikrein inhibitor, Bz-Pro-Phe-boroArg (P8720), was used to define the relationship between the kallikrein-kinin (K-K) system and acute intestinal inflammation induced by bacterial Peptidoglycan-Polysaccharide (PG-APS) in Lewis rats. Group I received human serum albumin (HSA) intramurally in the intestine and was treated with HSA. Group II received PG-APS and was treated with P8720. Group III received PG-APS and was treated with HSA. P8720 attenuated the decrease of high-molecular-weight kininogen and factor XI activity (group II vs group III,P<0.01). P8720 therapy significantly but modestly decreased acute intestinal inflammation measured by gross gut score (P<0.01) and more dramatically reduced the tissue myeloperoxidase activity (P<0.05), a measure of granulocyte recruitment, in group II compared with group III. We conclude that the K-K system is directly involved in the pathogenesis of the acute phase of experimental acute inflammation. A specific inhibitor may modulate inflammatory bowel disease.

Balfour R. Sartor - One of the best experts on this subject based on the ideXlab platform.

  • LIPOPolysaccharide INDUCES RECURRENCE OF ARTHRITIS IN RAT JOINTS PREVIOUSLY INJURED BY Peptidoglycan-Polysaccharide
    2013
    Co-Authors: A. Stimpson, Ronald E Esser, Philip B. Carter, Balfour R. Sartor, William T J. Cromartie, John H. Schwab
    Abstract:

    LPS and Peptidoglycan or covalent Peptidoglycan-Polysaccharide (PG-PS)' complexes are the major toxic components of bacterial cell walls. Lipid A and PG possess many of the biologic activities that LPS and PG-PS, respectively, have in common, such as pyrogenicity, polyclonal activation of lymphoid cells, complement activation, mitogenicity, macrophage activation, and adjuvanticity (1-3). Both also induce arthritis after injection into laboratory animals. Systemic injection of rats with a sterile, aqueous suspension of PG-PS from the group A streptococcus (PG-APS) induces a chronic erosive relapsing arthritis that has many features of rheumatoid arthritis (4-6). Distinct PG-PS structures from a number of other bacteria, including human indigenous intestinal species, induce arthritis of varying chronicity (7-10). LPS induces primarily an acute arthritis of relatively short duration after intraarticular (i.a.) injection (7, 11-15), but there have been few reports of its arthropathic activity after systemic administration (16, 17, 17a). In spite of the shared biologic properties and ubiquitous distribution of LP

  • modulation of inflammation by kininogen deficiency in a rat model of inflammatory arthritis
    Arthritis & Rheumatism, 2005
    Co-Authors: Irma M Sainz, Balfour R. Sartor, Raul Dela A Cadena, Albert Adam, Irma Isordiasalas, Julian L Castaneda, Alexis Agelan, Bo Liu, Robin A Pixley, Robert W. Colman
    Abstract:

    Objective To compare inflammatory peripheral arthritis in wild-type and high molecular weight kininogen (HK)–deficient rats, both on the genetically susceptible Lewis background. Methods By backcrossing Brown-Norway HK-deficient rats with Lewis rats for 6 generations, 2 new strains were produced, wild-type F6 and HK-deficient F6, each with a 98.5% Lewis genome. Inflammatory arthritis was induced by intraperitoneal injection of Peptidoglycan–Polysaccharide (PG-PS), and the clinical, histopathologic, and biochemical responses were compared in both strains. Results Eighteen days after PG-PS injection, rats with normal concentrations of HK showed weight loss and marked increase in hind ankle diameter with severe synovial inflammation and cartilage abnormalities. In contrast, HK-deficient rats showed no weight loss (P < 0.05), no increase in hind ankle diameter (P < 0.05), and an absence of inflammatory changes (P < 0.05), as measured by the histologic and morphometric Mankin grading system for synovial and cartilage injury. Conclusion Plasma HK is a key mediator of acute and chronic inflammatory arthritis in genetically susceptible Lewis rats.

  • selective plasma kallikrein inhibitor attenuates acute intestinal inflammation in lewis rat
    Digestive Diseases and Sciences, 1996
    Co-Authors: Antoni Stadnicki, Charles A Kettner, Balfour R. Sartor, Raul Dela A Cadena, Diane Bender, Heiko C Rath, Albert Adam, Robert W. Colman
    Abstract:

    A specific plasma kallikrein inhibitor, Bz-Pro-Phe-boroArg (P8720), was used to define the relationship between the kallikrein-kinin (K-K) system and acute intestinal inflammation induced by bacterial Peptidoglycan-Polysaccharide (PG-APS) in Lewis rats. Group I received human serum albumin (HSA) intramurally in the intestine and was treated with HSA. Group II received PG-APS and was treated with P8720. Group III received PG-APS and was treated with HSA. P8720 attenuated the decrease of high-molecular-weight kininogen and factor XI activity (group II vs group III,P<0.01). P8720 therapy significantly but modestly decreased acute intestinal inflammation measured by gross gut score (P<0.01) and more dramatically reduced the tissue myeloperoxidase activity (P<0.05), a measure of granulocyte recruitment, in group II compared with group III. We conclude that the K-K system is directly involved in the pathogenesis of the acute phase of experimental acute inflammation. A specific inhibitor may modulate inflammatory bowel disease.

  • insulinlike growth factor i and interleukin 1β messenger rna in a rat model of granulomatous enterocolitis and hepatitis
    Gastroenterology, 1993
    Co-Authors: Ellen M Zimmermann, Balfour R. Sartor, Diane Bender, Robert D Mccall, Matthew Pardo, Kay P Lund
    Abstract:

    Abstract Background: Insulinlike growth factor I (IGF-I) is mitogenic for fibroblasts and smooth muscle cells and stimulates collagen synthesis. The present study tested the hypothesis that IGF-I is important in the development of granulomatous inflammation and fibrosis. Methods: IGF-I messenger RNA (mRNA) was measured in bowel and liver of rats with Peptidoglycan-Polysaccharide-induced chronic granulomatous enterocolitis and hepatitis using RNase protection. Cellular sites of IGF-I mRNA and IGF-I peptide precursor were localized by in situ hybridization and immunohistochemistry, respectively. Sites of IGF-I synthesis were compared with sites of interleukin 1β mRNA expression. Results: IGF-I mRNA was increased 3.7-fold in cecal tissue from Peptidoglycan-Polysaccharide-injected rats compared with controls. IGF-I mRNA was up-regulated in fibroblastlike cells in the intensely fibrotic periphery of cecal and hepatic granulomas. This region also expressed IGF-I peptide precursor. Interleukin 1 mRNA localized to macrophage-like cells in the center of granulomas. Conclusions: IGF-I may be important in the development of fibrosis in this model of Crohn's disease. The localization of IGF-I and interleukin 1 mRNAs to distinct but adjacent sites is consistent with a paracrine interaction between cells expressing IGF-I and interleukin 1.

Ellen M Zimmermann - One of the best experts on this subject based on the ideXlab platform.

  • anti tumor necrosis factor α prevents bowel fibrosis assessed by messenger rna histology and magnetization transfer mri in rats with crohn s disease
    Inflammatory Bowel Diseases, 2013
    Co-Authors: Jeremy Adler, Kinan Rahal, Phyllissa Schmiedlinren, Ahren C Rittershaus, Laura J Reingold, Barbara J Mckenna, Scott D Swanson, Josh S Brudi, David Shealy, Ellen M Zimmermann
    Abstract:

    OBJECTIVE: Treatment of Crohn's disease (CD) with anti-tumor necrosis factor α (TNFα) decreases intestinal inflammation, but the effect on fibrosis remains unclear. We hypothesized that treatment with rat-specific anti-TNFα will decrease the development of intestinal fibrosis in a rat model of CD. We further hypothesized that magnetization transfer magnetic resonance imaging (MT-MRI) will be sensitive in detecting these differences in collagen content. METHODS: Rats were injected in the distal ileum and cecum with Peptidoglycan-Polysaccharide (PG-PS) or human serum albumin (control) at laparotomy and then received intraperitoneal injections of rat-specific anti-TNFα or vehicle daily for 21 days after laparotomy. Rats underwent MT-MRI abdominal imaging on day 19 or 20. MT ratio was calculated in the cecal wall. Cecal tissue histologic inflammation was scored. Cecal tissue procollagen, cytokine, and growth factor messenger RNAs were measured by quantitative real-time PCR. RESULTS: PG-PS-injected rats treated with anti-TNFα had less histologic inflammation, and cecal tissue expressed lower levels of proinflammatory cytokine messenger RNAs than vehicle-treated PG-PS-injected rats (IL-1β: 5.59 ± 1.53 versus 10.41 ± 1.78, P = 0.02; IL-6: 23.23 ± 9.33 versus 45.89 ± 11.79, P = 0.07). PG-PS-injected rats treated with anti-TNFα developed less intestinal fibrosis than vehicle-treated PG-PS-injected rats by tissue procollagen I (2.87 ± 0.66 versus 9.28 ± 1.11; P = 0.00002), procollagen III (2.25 ± 0.35 versus 7.28 ± 0.76; P = 0.0000009), and MT-MRI (MT ratio: 17.79 ± 1.61 versus 27.95 ± 1.75; P = 0.0001). Insulin-like growth factor I (2.52 ± 0.44 versus 5.14 ± 0.60; P = 0.0007) and transforming growth factor β1 (2.34 ± 0.29 versus 3.45 ± 0.29; P = 0.006) were also decreased in anti-TNFα-treated PG-PS-injected rats. CONCLUSIONS: Anti-TNFα prevents the development of bowel wall inflammation and fibrosis in the PG-PS rat model of CD. MT-MRI measurably demonstrates this decrease in intestinal fibrosis.

  • insulinlike growth factor i and interleukin 1β messenger rna in a rat model of granulomatous enterocolitis and hepatitis
    Gastroenterology, 1993
    Co-Authors: Ellen M Zimmermann, Balfour R. Sartor, Diane Bender, Robert D Mccall, Matthew Pardo, Kay P Lund
    Abstract:

    Abstract Background: Insulinlike growth factor I (IGF-I) is mitogenic for fibroblasts and smooth muscle cells and stimulates collagen synthesis. The present study tested the hypothesis that IGF-I is important in the development of granulomatous inflammation and fibrosis. Methods: IGF-I messenger RNA (mRNA) was measured in bowel and liver of rats with Peptidoglycan-Polysaccharide-induced chronic granulomatous enterocolitis and hepatitis using RNase protection. Cellular sites of IGF-I mRNA and IGF-I peptide precursor were localized by in situ hybridization and immunohistochemistry, respectively. Sites of IGF-I synthesis were compared with sites of interleukin 1β mRNA expression. Results: IGF-I mRNA was increased 3.7-fold in cecal tissue from Peptidoglycan-Polysaccharide-injected rats compared with controls. IGF-I mRNA was up-regulated in fibroblastlike cells in the intensely fibrotic periphery of cecal and hepatic granulomas. This region also expressed IGF-I peptide precursor. Interleukin 1 mRNA localized to macrophage-like cells in the center of granulomas. Conclusions: IGF-I may be important in the development of fibrosis in this model of Crohn's disease. The localization of IGF-I and interleukin 1 mRNAs to distinct but adjacent sites is consistent with a paracrine interaction between cells expressing IGF-I and interleukin 1.