Enhanced osteopontin expression in a murine model of allergen‐induced airway remodelling

Kohan, Martin; Bader, Reem; Puxeddu, Ilaria; Levi‐Schaffer, Francesca; Breuer, Raphael; Berkman, Neville

doi:10.1111/j.1365-2222.2007.02801.x

Cited by 54 publications

(74 citation statements)

References 49 publications

(68 reference statements)

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“…RNA samples were reverse transcribed and subjected to PCR analysis (MiniCycler; MJ Research, Waltham, MA) as we have previously detailed (27). The following primers were used: forward, FLIP L (the long isoform of FLIP) 59TGCTGAAGTCATCCAT CAGG39; reverse, FLIP L 59ATTCCTAGGGGC TTGCTCT39.…”

Section: Real-time Pcrmentioning

confidence: 99%

Cellular FLICE-like Inhibitory Protein Deviates Myofibroblast Fas-Induced Apoptosis Toward Proliferation during Lung Fibrosis

Golan-Gerstl

Wallach-Dayan

Zisman

et al. 2012

Am J Respir Cell Mol Biol

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A prominent feature of fibrotic tissue in general and of lungs in particular is fibroblast proliferation and accumulation. In patients overcoming fibrosis, apoptosis limits this excessive cell growth. We have previously shown resistance to Fas-induced apoptosis of primary lung fibroblasts from mice with bleomycin-induced lung fibrosis, their escape from immune surveillance, and continued accumulation in spite of overexpression of the Fas death receptor. Cellular FLICE-like inhibitory protein (c-FLIP) is a regulator of cell death receptor-induced apoptosis in many cell types. We aimed to determine c-FLIP levels in myofibroblasts from fibrotic lungs and to directly assess c-FLIP's role in apoptosis and proliferation of primary lung myofibroblasts. c-FLIP levels were determined by apoptosis gene array, flow cytometry, Western blot, and immunofluorescence before and after down-regulation with a specific small interfering RNA. Apoptosis was assessed by caspase cleavage in Western blot and by Annexin V affinity labeling after FACS and tissue immunofluorescence. Proliferation was assessed by BrdU uptake, also using FACS and immunofluorescence. We show that myofibroblasts from lungs of humans with idiopathic pulmonary fibrosis and from bleomycin-treated versus normal saline-treated mice up-regulate c-FLIP levels. Using the animal model, we show that fibrotic lung myofibroblasts divert Fas signaling from apoptosis to proliferation and that this requires signaling by TNF receptor-associated factor (TRAF) and NF-kB. c-FLIP down-regulation reverses the effect of Fas activation, causing increased apoptosis, decreased proliferation, and diminished recruitment of TRAF to the DISC complex. This indicates that c-FLIP is essential for myofibroblast accumulation and may serve as a potential target to manipulate tissue fibrosis.

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Section: Real-time Pcrmentioning

confidence: 99%

Cellular FLICE-like Inhibitory Protein Deviates Myofibroblast Fas-Induced Apoptosis Toward Proliferation during Lung Fibrosis

Golan-Gerstl

Wallach-Dayan

Zisman

et al. 2012

Am J Respir Cell Mol Biol

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“…13 The elevated OPN levels found in subepithelial inflammatory cells of asthmatic airways suggests that eosinophils may be a cellular source of this mediator. 14 Venom immunotherapy has been shown to increase OPN levels significantly, 15 and animal studies demonstrate that OPN levels are increased in allergen-induced chronic airway remodelling, whereas OPN J-J Zhao, L Yang, F-Q Zhao et al…”

Section: Introductionmentioning

confidence: 99%

“…12 Studies of endobronchial biopsies from asthma patients have found increased OPN immunostaining in the epithelial layer, as well as in eosinophils, macrophages and lymphocytes present in the submucosal inflammatory infiltrate. 13,14 Xanthou et al 13 found that OPN has a bimodal immunomodulatory effect in a murine model of allergen-induced airway inflammation: a Th2-enhancing effect was observed during antigenic sensitization, and a Th2-repressor effect was seen during antigen challenge. These effects are mediated by the inhibition of migration of plasmacytoid and conventional dendritic cells, respectively.…”

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confidence: 99%

Osteopontin Levels are Elevated in Patients with Asthma

Zhao

Yang

et al. 2011

J Int Med Res

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Osteopontin (OPN) plays a role in T cellmediated immunity, but its involvement in Th2-associated allergic responses, especially asthma, has not been investigated. This cross-sectional casecontrol study was designed to determine whether serum OPN levels are elevated in asthma patients and whether these correlated with disease severity. Serum samples were obtained from patients with mild (n = 42), moderate (n = 48) and severe (n = 39) asthma, and 41 healthy control subjects. OPN protein concentrations were measured by enzyme-linked immunosorbent assay and were found to be significantly higher in all three asthma patient groups compared with healthy controls. There was no significant association between OPN concentration and disease severity. The data suggest a role for OPN in the pathogenesis of asthma. Further studies are needed to clarify the involvement of OPN in various aspects of asthma.

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“…[16][17][18] Further, several human studies have suggested that osteopontin level is increased in airway of asthmatic subjects and is associated with various asthma phenotypes. 15,[20][21][22] Additionally, the chromosomal region of 4q24 where SPP1 gene is located (4q21-q25) has been reported to be associated with atopy and with atopic disease in asthmatic subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Osteopontin deficiency, either through administration of blocking antibody or genetic deficiency (knockout mice), has been reported to be protective against airway hyperresponsiveness (AHR) and airway remodeling in these murine models. [15][16][17][18][19] In humans, immunohistochemistry of endobronchial biopsies has shown increased osteopontin expression in bronchial epithelial cells and subepithelial inflammatory cells in asthmatic subjects compared with nonasthmatic controls. 15 In addition, several recent studies have reported an increased level of osteopontin in bronchoalveolar lavage fluid and induced sputum in asthmatic subjects.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism in Osteopontin Gene (SPP1) Is Associated with Asthma and Related Phenotypes in a Puerto Rican Population

Arjomandi

Galanter

Choudhry

et al. 2011

Pediatric Allergy, Immunology, and Pulmonology

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Recent studies have shown that osteopontin, a cytokine with suggested immunoregulatory functions, may contribute to pathogenesis of asthma. To determine whether single-nucleotide polymorphisms (SNPs) in SPP1, the gene encoding osteopontin, are associated with risk of asthma, we genotyped 6 known SNPs in SPP1 in the well-characterized Genetics of Asthma in Latino Americans population of 294 Mexican and 365 Puerto Rican parent-child asthma trios. The associations between SNPs and asthma or asthma-related phenotypes were examined by transmission disequilibrium tests as implemented in the family-based association test program. Three polymorphisms, 1 in exon 7 (rs1126616C) and 2 in the 3¢-untranslated region (rs1126772A and rs9138A) of SPP1, were associated with diagnosis of asthma, severity of asthma, asthma in subjects with elevated immunoglobulin E (IgE) (IgE > 100 IU/mL), and postbronchodilator FEV 1 in Puerto Ricans (P values = 0.00007-0.04). The CC genotype of rs1126616 conferred an odds ratio of 1.7 (95% CI = [1.3, 2.3], P value adjusted for multiple comparisons = 0.001) for asthma compared with the CT and TT genotypes. Furthermore, haplotype analysis identified rs1126616C-rs1126772A-rs9138A to be associated with an increased risk for asthma, severity of asthma, and asthma in subjects with elevated IgE (P = 0.03). There was no association between the SPP1 SNPs and asthma outcomes in Mexicans. Our findings suggest that the SPP1 gene is a risk factor for asthma and asthma-related phenotypes in Puerto Ricans, and are consistent with previous animal and human studies on the role of osteopontin in pathogenesis of asthma.

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Enhanced osteopontin expression in a murine model of allergen‐induced airway remodelling

Abstract: OPN expression in the lungs is increased in a murine model of allergen-induced chronic airway remodelling, suggesting a role for this cytokine in airway remodelling in asthma.

Cited by 54 publications

References 49 publications

Cellular FLICE-like Inhibitory Protein Deviates Myofibroblast Fas-Induced Apoptosis Toward Proliferation during Lung Fibrosis

Cellular FLICE-like Inhibitory Protein Deviates Myofibroblast Fas-Induced Apoptosis Toward Proliferation during Lung Fibrosis

Osteopontin Levels are Elevated in Patients with Asthma

Polymorphism in Osteopontin Gene (SPP1) Is Associated with Asthma and Related Phenotypes in a Puerto Rican Population

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