Dysfunction of Lacrimal and Salivary   Glands in Sjögren′s Syndrome: Nonimmunologic Injury in   Preinflammatory Phase and Mouse Model

Hayashi, Toshiharu

doi:10.1155/2011/407031

Cited by 59 publications

(49 citation statements)

References 120 publications

(156 reference statements)

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“…[29][30][31][32] Some of the proinflammatory mediators increased during dry eye disease include matrix metalloproteinases (MMPs), cytokines, elastases, and other proteolytic enzymes that destroy components of the ECM and damage the growth factors and their receptors, which are essential for tissue repair and cell differentiation. 22,23,33 Matrix metalloproteinases belong to a family of zinc-requiring neutral endopeptidases that are involved in remodeling of ECM and basement membrane during various physiological and pathological processes. 34 Matrix metalloproteinases are tightly regulated by tissue inhibitors of metalloproteinases (TIMPs), and disturbances in the delicate balance between MMPs and TIMPs lead to tissue destruction in various inflammatory and malignant diseases.…”

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confidence: 99%

Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome

Aluri

Kublin

Thotakura

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Aluri HS, Kublin CL, Thotakura S, et al. Role of matrix metalloproteinases 2 and 9 in lacrimal gland disease in animal models of Sjögren's syndrome. Invest Ophthalmol Vis Sci. 2015;56:5218-5228. DOI:10.1167/ iovs.15-17003 PURPOSE. Chronic inflammation of the lacrimal gland results in changes in the composition of the extracellular matrix (ECM), which is believed to compromise tissue repair. We hypothesized that increased production/activity of matrix metalloproteinases (MMPs), especially MMP-2 and -9, in inflamed lacrimal glands modifies the ECM environment, therefore disrupting tissue repair.METHODS. The lacrimal glands from female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for histology, immunohistochemistry, zymography, Western blotting, and RNA analyses. In another study, MRL/lpr mice were treated for 5 weeks with a selective MMP2/9 inhibitor peptide or a control peptide. At the end of treatment, the lacrimal glands were excised and the tissue was processed as described above.RESULTS. There was a 2.5-and 2.7-fold increase in MMP2 gene expression levels in MRL/lpr and NOD mice, respectively. Matrix metalloproteinase 2 and 9 enzymatic activities and protein expression levels were significantly upregulated in the lacrimal glands of MRL/lpr and NOD mice compared to controls. Treatment with the MMP2/9 inhibitor resulted in decreased activity of MMP-2 and -9 both in vitro and in vivo. Importantly, MMP2/9 inhibitor treatment of MRL/lpr mice improved aqueous tear production and resulted in reduced number and size of lymphocytic foci in diseased lacrimal glands.CONCLUSIONS. We conclude that MMP2/9 expression and activity are elevated in lacrimal glands of two murine models of Sjögren's syndrome, suggesting that manipulation of MMP2/9 activity might be a potential therapeutic target in chronically inflamed lacrimal glands.

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Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome

Aluri

Kublin

Thotakura

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…24 Changes in the components of TJ proteins ZO-1 and occludins could be involved in LG pathogenesis in SjS or aging. 13,26,27 In addition, E-cadherin (a component of adherens junction) is very important for LG epithelial integrity and epithelial differentiation. 28 Even slight downregulation of E-cadherin expression may mediate EMT in the LG.…”

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confidence: 99%

Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells

Umazume

Thomas

Campbell

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The adult lacrimal gland (LG) is highly regenerative and is able to repair itself even after substantial damage; however, this ability to regenerate is lost with the development of dry eye conditions in chronically inflamed LGs.This study compares changes in the cell adhesion and cell matrix molecules and stem cell transcription factors in the LGs of healthy mice and of two mouse models of Sjögren's syndrome: nonobese diabetic (NOD) and MRLlpr/lpr (MRL/lpr) mice during the early stage of inflammation. METHODS. TheLGs from 12-to 13-week-old female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for quantitative (q) RT-PCR and qRT-PCR Arrays, histology, immunohistochemistry, and Western blotting. RESULTS. The extracellular matrix (ECM) and adhesion molecules RT2 -PCR array combined with protein expression data revealed changes in the expression of integrins, matrix metalloproteinases, and other molecules, which are associated largely with invasion, attachment, and expansion of the lymphocytic cells, whereas changes in the stem cell transcription factors revealed substantial decrease in expression of transcription factors associated with epithelial stem/progenitor cell lineage. CONCLUSIONS.We concluded that the expression of several important ECM components is significantly deregulated in the LG of two murine models of Sjögren's syndrome, suggesting an alteration of the epithelial stem/progenitor cell niche. This may result in profound effects on localization, activation, proliferation, and differentiation of the LG stem/progenitor cells and, therefore, LG regeneration.

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“…Thus, it has been reported that cytokine homeostasis is disrupted in the plasma of SS patients with significantly increased concentration of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) (Szodoray et al, 2004). Moreover, increased expression of IL-1β, TNF-α, IFN-γ, and the anti-inflammatory cytokine IL-10 was also reported in lacrimal and submandibular glands of NOD mice (Hayashi, 2011). Furthermore, IL-10 produced by activated T cells, B cells and monocytes/macrophages has been identified as a critical cytokine, whose overproduction has been implicated in promoting the development of autoimmune lacrimal gland disease either directly or by suppression of Th1 responses (Jabs et al, 2001; Fiorentino et al, 1989; Moore et al, 1993).…”

Section: Introductionmentioning

confidence: 94%

Time course of cytokine upregulation in the lacrimal gland and presence of autoantibodies in a predisposed mouse model of Sjögren's Syndrome: The influence of sex hormones and genetic background

Czerwinski¹,

Mostafa²,

Rowan³

et al. 2014

Experimental Eye Research

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Sjögren’s Syndrome (SS) is a chronic, inflammatory autoimmune disease characterized by lacrimal gland lymphocytic infiltration and epithelial cell death, as well as by the presence of serum autoantibodies. Although the symptoms of this syndrome are well characterized, patients are not diagnosed until 5–10 years into disease progression; furthermore, the early series of events leading to the initiation of SS are not well understood. In order to better understand the early events of the disease, we have been using ovariectomized (OVX) NOD.B10.H2b mice as a genetically predisposed model of SS. Previously, we have shown that removal of ovarian hormones through ovariectomy accelerated the symptoms of this disease, and in early events of SS in the lacrimal glands, lymphocytic infiltration preceded acinar cell apoptosis. To further elucidate the earlier events of this disease in the SS animal model, we investigated the expression and concentration of pro-inflammatory cytokines in the lacrimal glands as well as the presence of autoantibodies in both lacrimal glands and serum. Six weeks old NOD.B10.H2b and C57BL/10 control mice were either sham-operated, OVX, OVX and treated with 17β-estradiol (E2), or OVX and treated with dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21, and 30 days after surgery and analyzed for cytokines IL-1β, TNF-α, IFN-γ, IL-10, and IL-4 gene expression by using quantitative RT-PCR and for cytokine levels using ELISA. Furthermore, anti-Ro/SSA and anti-La/SSB autoantibodies were measured in the serum and lacrimal glands supernatants using ELISA. The results of this study showed that OVX caused a significant increase in the expression and levels of the cytokines IL-1β, TNF-α, and IL-4 in the lacrimal glands of the NOD.B10.H2b mice starting at 3 days after OVX, while a significant increase of IL-10 gene expression and levels was observed only at later experimental time points. A small but significant increase in the expression of IL-1β and IL-4 was observed only at later experimental time points in the lacrimal glands of OVX C57BL/10 mice, while no significant changes in the expression of TNF-α and IL-10 were seen at any experimental times in this group. No significant differences were observed in the levels of the cytokines IL-1β, TNF-α, IL-4, and IL-10 in the lacrimal glands of the OVX C57BL/10 mice at any of the experimental times studied compared to the sham-operated group. IFN-γ was not detected in either mouse strains at the level of mRNA and protein. OVX in the NOD.B10.H2b mice also caused an increase in the levels of anti-Ro/SSA autoantibodies in the serum only, while no anti-La/SSB autoantibodies were found in the serum or lacrimal gland supernatants. Physiological doses of E2 or DHT at time of OVX prevented the upregulation of cytokines and the presence of anti-Ro/SSA autoantibodies in these animals. These results showed that a decrease in the concentrations of ovarian hormones in the genetically predisposed mice accelerated the onset of the disease by upregulating vario...

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Dysfunction of Lacrimal and Salivary Glands in Sjögren′s Syndrome: Nonimmunologic Injury in Preinflammatory Phase and Mouse Model

Cited by 59 publications

References 120 publications

Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome

Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome

Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells

Time course of cytokine upregulation in the lacrimal gland and presence of autoantibodies in a predisposed mouse model of Sjögren's Syndrome: The influence of sex hormones and genetic background

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