Mast Cells and Gastrointestinal Dysmotility in the Cystic Fibrosis Mouse

Lisle, Robert C. De; Meldi, Lauren; Roach, Eileen; Flynn, Maureen; Sewell, R. F.

doi:10.1371/journal.pone.0004283

Cited by 19 publications

(11 citation statements)

References 38 publications

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“…As shown in Fig. 5B, and in agreement with previous reports on adult CF mice (8,32), the number of mast cells was increased in the small intestine of CF compared with non-CF mice (P ϭ 0.025 by t-test), and, within the CF mice, the double knockouts had the fewest mast cells (P ϭ 0.068 by ANOVA, P ϭ 0.033 compared with Tlr4 ϩ/ϩ CF). An increase of mucosal F4/80 ϩ cells was evident in the non-CF compared with the CF mice (P ϭ 0.016 by t-test), but no difference in this phenotype by Tlr4 genotype was observed within the CF mice (P ϭ 0.64 by ANOVA) (Fig.…”

Section: Survival Of Cftr-deficient Mice Is Dependent On Tlr4 Genotypesupporting

confidence: 92%

Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice

Canale-Zambrano

Auger

Haston

2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Toll-like receptor (Tlr) 4 is a lipopolysaccharide (LPS) receptor that contributes to the regulation of intestinal cell homeostasis, a condition that is altered in the intestines of cystic fibrosis mice. Herein, we assessed whether Tlr4 genotype influences cystic fibrosis intestinal disease by producing and phenotyping 12-wk (adult)- and 4-day (neonate)-old mice derived from BALB cystic fibrosis transmembrane conductance regulator, Cftr(+/tm1Unc) and C.C3-Tlr4(Lps-d)/J (Tlr4(-/-)), progenitors. Intestinal disease was assayed through mouse survival, crypt-villus axis (CVA) length, cell proliferation, bacterial load, bacterial classification, inflammatory cell infiltrate, and mucus content measures. Of the 77 Cftr(-/-) (CF) mice produced, only one Cftr/Tlr4 double-mutant mouse lived to the age of 12 wk while the majority of the remainder succumbed at approximately 4 days of age. The survival of CF Tlr4(+/-) mice exceeded that of both CF Tlr4(+/+) and Cftr/Tlr4 double-mutant mice. Adult CF mice presented increased Tlr4 expression, CVA length, crypt cell proliferation, and bacterial load relative to non-CF mice, but no differences were detected in Tlr4(+/-) compared with Tlr4(+/+) CF mice. The double-mutant neonates did not differ from Tlr4(+/+) or Tlr4(+/-) CF mice by intestinal CVA length or bacterial load, but fewer Tlr4(+/-) CF neonates presented with luminal mucus obstruction in the distal ileum, and the intestinal mast cell increase of CF mice was not evident in double-mutant neonates. We conclude that Tlr4 deficiency reduces the survival, but does not alter the intestinal phenotypes, of extended CVA or increased bacterial load in BALB CF mice.

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Section: Survival Of Cftr-deficient Mice Is Dependent On Tlr4 Genotypesupporting

confidence: 92%

Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice

Canale-Zambrano

Auger

Haston

2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The effect of parasitic infection on the intestinal muscular function has been examined in guinea pigs infected intraperitoneally with Toxocara canis. Nonetheless, it remains difficult to reconcile the observed enhanced muscle mechanics with the slower intestinal transit time in mice with CFTR deficiency in the C57 background (9,10). Infection of mice with T. spiralis also resulted in hyperreactivity of the longitudinal muscle layer associated with a greater degree of shortening and hypersensitivity in response to MCh (1).…”

Section: Discussionmentioning

confidence: 99%

Ileal smooth muscle dysfunction and remodeling in cystic fibrosis

Risse

Kachmar

Matusovsky

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Patients with cystic fibrosis (CF) often suffer from gastrointestinal cramps and intestinal obstruction. The CF transmembrane conductance regulator (CFTR) channel has been shown to be expressed in vascular and airway smooth muscle (SM). We hypothesized that the absence of CFTR expression alters the gastrointestinal SM function and that these alterations may show strain-related differences in the mouse. The aim of this study was to measure the contractile properties of the ileal SM in two CF mouse models. CFTR(-/-) and CFTR(+/+) mice were studied on BALB/cJ and C57BL/6J backgrounds. Responsiveness of ileal strips to electrical field stimulation (EFS), methacholine (MCh), and isoproterenol was measured. The mass and the cell density of SM layers were measured morphometrically. Finally, the maximal velocity of shortening (Vmax) and the expression of the fast (+)insert myosin isoform were measured in the C57BL/6J ileum. Ileal hyperreactivity was observed in response to EFS and MCh in CFTR(-/-) compared with CFTR(+/+) mice in C57BL/6J background. This latter observation was not reproduced by acute inhibition of CFTR with CFTR(inh)172. BALB/cJ CFTR(-/-) mice exhibited a significant increase of SM mass with a lower density of cells compared with CFTR(+/+), whereas no difference was observed in the C57BL/6J background. In addition, in this latter strain, ileal strips from CFTR(-/-) exhibited a significant increase in Vmax compared with control and expressed a greater proportion of the fast (+)insert SM myosin isoform with respect to total myosin. BALB/cJ CFTR(-/-) ilium had a greater relaxation to isoproterenol than the CFTR(+/+) mice when precontracted with EFS, but no difference was observed in response to exogeneous MCh. In vivo, the lack of CFTR expression induces a different SM ileal phenotype in different mouse strains, supporting the importance of modifier genes in determining intestinal SM properties.

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“…Integrated optical density (IOD) of each section was analyzed by Image-Pro Plus image analysis software. Analysis of mast cells in lung sections was performed as described previously [18]. …”

Section: Methodsmentioning

confidence: 99%

Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents

Wang

et al. 2013

PLoS ONE

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A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine’s anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

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Mast Cells and Gastrointestinal Dysmotility in the Cystic Fibrosis Mouse

Cited by 19 publications

References 38 publications

Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice

Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice

Ileal smooth muscle dysfunction and remodeling in cystic fibrosis

Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents

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