Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation

Matrix metalloproteinases (MMPs) are a large family of endopeptidases that proteolytically degrade extracellular matrix. Many different cells produce MMP-9, and levels have been shown to be up-regulated in patients with allergic asthma. The aim of this study was to investigate the in vivo role of MMP-9 during allergen-induced airway inflammation. Acute allergic pulmonary eosinophilia was established in MMP-9 knockout (KO) and wild-type (WT) control mice by sensitization and challenge with OVA. Cell recruitment was significantly increased in both bronchoalveolar lavage (BAL) and lung tissue compartments in MMP-9 KO mice compared with WT mice. This heightened cell recruitment was primarily due to increased eosinophils and Th2 cells in the BAL and lung tissue of MMP-9 KO mice in comparison with WT controls. Moreover, levels of the Th2 cytokines, IL-4 and IL-13, and the chemokines eotaxin/CCL11 and macrophage-derived chemokine/CCL22 were substantially increased in MMP-9 KO mice compared with WT after OVA challenge. Resolution of eosinophilia was similar between MMP-9 KO and WT mice, but Th2 cells persisted in BAL and lungs of MMP-9 KO mice for longer than in WT mice. Our results indicate that MMP-9 is critically involved in the recruitment of eosinophils and Th2 cells to the lung following allergen challenge, and suggest that MMP-9 plays a role in the development of Th2 responses to allergen.     

Matrix metalloproteinase-8 deficiency increases joint inflammation and bone erosion in the K/BxN serum-transfer arthritis model

Introduction  

Rheumatoid arthritis is an autoimmune disease in which joint inflammation leads to progressive cartilage and bone erosion. Matrix metalloproteinases (MMPs) implicated in homeostasis of the extracellular matrix play a central role in cartilage degradation. However, the role of specific MMPs in arthritis pathogenesis is largely unknown. The aim of the present study was to investigate the role of Mmp-8 (collagenase-2) in an arthritis model.     

IL-12 contributes to allergen-induced airway inflammation in experimental asthma

Lack of sufficient IL-12 production has been suggested to be one of the basic underlying mechanisms in atopy, but a potential role of IL-12 in established allergic airway disease remains unclear. We took advantage of a mouse model of experimental asthma to study the role of IL-12 during the development of bronchial inflammation. Administration of anti-IL-12p35 or anti-IL-12p40 mAb to previously OVA-sensitized BALB/c mice concomitantly with exposure to nebulized OVA, abolished both the development of bronchial hyperresponsiveness to metacholine as well as the eosinophilia in bronchoalveolar lavage fluid and peripheral blood. Anti-IL-12 treatment reduced CD4(+) T cell numbers and IL-4, IL-5, and IL-13 levels in the bronchoalveolar lavage fluid and the mRNA expression of IL-10, eotaxin, RANTES, MCP-1, and VCAM-1 in the lung. Anti-IL-12p35 treatment failed to show these effects in IFN-gamma knockout mice pointing to the essential role of IFN-gamma in IL-12-induced effects. Neutralization of IL-12 during the sensitization process aggravated the subsequent development of allergic airway inflammation. These data together with recent information on the role of dendritic cells in both the sensitization and effector phase of allergic respiratory diseases demonstrate a dual role of IL-12. Whereas IL-12 counteracts Th2 sensitization, it contributes to full-blown allergic airway disease upon airway allergen exposure in the postsensitization phase, with enhanced recruitment of CD4(+) T cells and eosinophils and with up-regulation of Th2 cytokines, chemokines, and VCAM-1. IFN-gamma-producing cells or cells dependent on IFN-gamma activity, play a major role in this unexpected proinflammatory effect of IL-12 in allergic airway disease.     

Suppression of Th2-driven, allergen-induced airway inflammation by sauchinone

Sauchinone, a lignan compound isolated from the root of Saururus chinensis, has been recently demonstrated to exhibit anti-inflammatory activity via the suppression of NF-kB p65 activity in vitro. In an effort to evaluate the in vivo anti-inflammatory function of sauchinone, we have evaluated the effects of sauchinone on allergen-induced airway inflammation using a murine model of allergic asthma. We observed that marked eosinophilic and lymphocyte infiltration in the BAL fluid were suppressed to a significant degree by sauchinone, and that mucus-secreting goblet cell hyperplasia and collagen deposition in the airways were also ameliorated by administration of sauchinone treatment. Moreover, gene expression of the inflammatory cytokines, IL-13, and IL-5 and eotaxin in the lung, and IL-5 in the draining lymph node were significantly decreased in sauchinone-treated mice. We demonstrated that sauchinone repressed Th2 cell development in vitro and IL-4 production by Th2 cells, and also inhibited GATA-3-mediated IL-5 promoter activity in a dose-dependent manner. Collectively, sauchinone ameliorated allergen-induced airway inflammation, in part, by repressing GATA-3 activity for Th2 cell development, indicating the possible therapeutic potential of sauchinone in airway inflammatory diseases including allergic asthma and rhinitis.     

Chronic mild prenatal stress exacerbates the allergen-induced airway inflammation in rats

The effects of chronic mild prenatal stress on leukocyte infiltration into the airways was investigated in rat offspring. The chronic prenatal stress consisted of transitory and variable changes in the rat's living conditions. Offspring at adult age were actively sensitized (day 0) and intratracheally challenged (day 14) with ovalbumin. Bronchoalveolar lavage was performed in the offspring at 48 h after intratracheal challenge with ovalbumin. A significant increase in total leukocyte infiltration was observed in the non-stressed offspring group and this was associated with a marked recruitment of eosinophils without a significant effect on the influx of neutrophils and mononuclear cells. In the prenatal stressed offspring, the counts of both total leukocyte and eosinophils, as well as mononuclear cells, was increased by 50% compared to the non-stressed offspring. We provide here the first experimental evidence that chronic mild unpredictable prenatal stress produces a marked increase in the allergen-induced airway inflammation in the rat offspring.     

Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs

Heme oxygenase (HO), the heme-degrading enzyme, has shown anti-inflammatory effects in several models of pulmonary diseases. HO is induced in airways during asthma; however, its functional role is unclear. Therefore, we evaluated the role of HO on airway inflammation [evaluated by bronchoalveolar lavage (BAL) cellularity and BAL levels of eotaxin, PGE(2), and proteins], mucus secretion (evaluated by analysis of MUC5AC gene expression and periodic acid-Schiff staining), oxidative stress (evaluated by quantification of 4-hydroxynonenal adducts and carbonylated protein levels in lung homogenates), and airway responsiveness to histamine in ovalbumin (OVA)-sensitized and multiple aerosol OVA or saline-challenged guinea pigs (6 challenges, once daily, OVA group and control group, respectively). Airway inflammation, mucus secretion, oxidative stress, and responsiveness were significantly increased in the OVA group compared with the control group. HO upregulation by repeated administrations of hemin (50 mg/kg i.p.) significantly decreased airway responsiveness in control animals and airway inflammation, mucus secretion, oxidative stress, and responsiveness in OVA animals. These effects were reversed by the concomitant administration of the HO inhibitor tin protoporphyrin-IX (50 micromol/kg i.p.). Repeated administrations of tin protoporphyrin-IX alone significantly increased airway responsiveness in control animals but did not modify airway inflammation, mucus secretion, oxidative stress, and responsiveness in OVA animals. These results suggest that upregulation of the HO pathway has a significant protective effect against airway inflammation, mucus hypersecretion, oxidative stress, and hyperresponsiveness in a model of allergic asthma in guinea pigs.     

Role of insulin-like growth factor-I in allergen-induced airway inflammation and remodeling

Insulin-like growth factor (IGF)-I is known to act on fibroblasts as a progression factor to push cells toward proliferation and activation to synthesize collagen. Subepithelial fibrosis, collagen deposition at the lamina reticularis, is part of the process of so-called remodeling and is a characteristic finding in the asthmatic airway. To study the role of IGF in the evolution of asthma, we used a model that involved immunization of mice with ovalbumin and alum, followed by an inhaled challenge of ovalbumin. IGF-I neutralizing antibody was continuously infused with an osmotic pump. Pulmonary function was analyzed using whole-body plethysmography before and after acetylcholine administration. It was found that OVA inhalation induced IGF-I expression at the site of the airway. IGF-I neutralizing Ab inhibited the elevation of airway resistance, airway inflammation, and an increase in airway wall thickening. The depression of ICAM-1 expression was accompanied by a diminution in airway inflammation. In conclusion, these results suggest that IGF-I is likely to be an important mediator of inflammation and remodeling in the asthmatic airway.     

Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB

Na?ve CD4+ T cells differentiate into effector T helper 1 (Th1) or Th2 cells, which are classified by their specific set of cytokines. Here we demonstrate that loss of JunB in in vitro polarized Th2 cells led to a dysregulated expression of the Th2-specific cytokines IL-4 and IL-5. These cells produce IFN-gamma and express T-bet, the key regulator of Th1 cells. In line with the essential role of Th2 cells in the pathogenesis of allergic asthma, mice with JunB-deficient CD4+ T cells exhibited an impaired allergen-induced airway inflammation. This study demonstrates novel functions of JunB in the development of Th2 effector cells, for a normal Th2 cytokine expression pattern and for a complete Th2-dependent immune response in mice.     

Matrix metalloproteinase-8: cleavage can be decisive

Matrix metalloproteinase-8 (MMP-8), also known as collagenase-2 or neutrophil collagenase, was long thought to be expressed solely by maturing neutrophils, and functionally restricted to ECM breakdown. Recent experiments, however, have revealed that this protease can be expressed by a wide variety of cell types and that it plays an important regulatory role in both acute and chronic inflammation. This review intends to give the reader an overview of the most interesting recent findings concerning the role of MMP-8 in inflammation and in cancer progression.     

Matrix metalloproteinase-9 deficiency impairs host defense against abdominal sepsis

Matrix metalloproteinase (MMP)-9 is involved in extracellular matrix degradation and leukocyte migration. To determine the role of MMP-9 in the innate immune response to peritonitis, MMP-9 gene-deficient (MMP-9(-/-)) and normal wild-type mice were i.p. infected with Escherichia coli. MMP-9 mRNA and pro-MMP-9 protein levels increased rapidly upon induction of peritonitis. Although MMP-9(-/-) neutrophils showed a normal phagocytosis of E. coli in vitro, MMP-9(-/-) mice displayed a reduced resistance against E. coli peritonitis, as indicated by an enhanced bacterial outgrowth in the peritoneal cavity and increased dissemination of the infection. Furthermore, the cytokine response to LPS was not influenced by MMP-9 deficiency. However, during E. coli peritonitis, MMP-9(-/-) mice showed much higher peritoneal chemokine and cytokine levels compared with wild-type mice. Despite the increased local chemokine concentrations, MMP-9(-/-) mice displayed a diminished recruitment of leukocytes to the site of infection, indicating that cellular migration was impaired. Moreover, MMP-9(-/-) mice developed more severe distant organ damage during infection. These data suggest that MMP-9 is an essential component of an effective host response to E. coli peritonitis.     

Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma

Although matrix metalloproteinases (MMPs) have been reported to play crucial roles in the migration of inflammatory cells through basement membrane components in vitro, the role of MMPs in the in vivo accumulation of the cells to the site of inflammation in bronchial asthma is still obscure. In this study, we investigated the role of MMPs in the pathogenesis of bronchial asthma, using a murine model of allergic asthma. In this model, we observed the increase of the release of MMP-2 and MMP-9 in bronchoalveolar lavage fluids after Ag inhalation in the mice sensitized with OVA, which was accompanied by the infiltration of lymphocytes and eosinophils. Administration of tissue inhibitor of metalloproteinase-2 to airways inhibited the Ag-induced infiltration of lymphocytes and eosinophils to airway wall and lumen, reduced Ag-induced airway hyperresponsiveness, and increased the numbers of eosinophils and lymphocytes in peripheral blood. The inhibition of cellular infiltration to airway lumen was observed also with tissue inhibitor of metalloproteinase-1 and a synthetic matrix metalloproteinase inhibitor. These data suggest that MMPs, especially MMP-2 and MMP-9, are crucial for the infiltration of inflammatory cells and the induction of airway hyperresponsiveness, which are pathophysiologic features of bronchial asthma, and further raise the possibility of the inhibition of MMPs as a therapeutic strategy of bronchial asthma.     

Cockroach allergen-induced eosinophilic airway inflammation in HLA-DQ/human CD4(+) transgenic mice

Airway eosinophilic inflammation is a characteristic feature of allergic asthma. Exposure to allergens produced by the German cockroach (Blattella germanica) is a risk factor for allergic disease in genetically predisposed individuals, and has been linked to an increase in asthma morbidity among cockroach-sensitive inner city children. To determine the role and contribution of specific HLA class II in the pathogenesis of allergic airway inflammation in cockroach-induced asthma, we generated double-transgenic, double-knockout mice expressing human HLA-DQ8, HLA-DQ6, and CD4 molecules in the absence of mouse class II and mouse CD4. Mice were actively immunized and later challenged intranasally with cockroach allergen extract. These mice developed bronchoalveolar lavage fluid (BALF) eosinophilia and pulmonary eosinophilia. This was accompanied by an increase in total protein levels, IL-5, and IL-13 in BALF. There were also elevated levels of cockroach-specific serum IgG1 and total serum IgE. Histological analysis revealed peribronchial and perivascular eosinophilic inflammation in cockroach-treated mice. Other pathologic changes in the airways were epithelial cell hypertrophy and mucus production. Treatment with anti-DQ mAb significantly reduced pulmonary and BALF eosinophilia in cockroach allergen-sensitized mice. Abeta(0) mice and transgenic mice expressing human CD4 molecule alone (without class II) or human HLA-DQ8 molecule (without CD4) treated in the same fashion showed no eosinophilia in bronchoalveolar fluid and no pulmonary parenchymal inflammation. Our results provide direct evidence that HLA-DQ molecules and CD4 T cells mediate cockroach-induced eosinophilic inflammation in the airways.     

The critical role of complement alternative pathway regulator factor H in allergen-induced airway hyperresponsiveness and inflammation

Activation of the alternative pathway of complement plays a critical role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in mice. Endogenous factor H, a potent inhibitor of the alternative pathway, is increased in the airways of sensitized and challenged mice, but its role in regulating inflammation or AHR has been unknown. We found that blocking the tissue-binding function of factor H with a competitive antagonist increased complement activation and tissue inflammation after allergen challenge of sensitized mice. Conversely, administration of a fusion protein that contains the iC3b/C3d binding region of complement receptor 2 linked to the inhibitory region of factor H, a molecule directly targeting complement-activating surfaces, protected mice in both primary and secondary challenge models of AHR and lung inflammation. Thus, although endogenous factor H does play a role in limiting the development of AHR, strategies to deliver the complement-regulatory region of factor H specifically to the site of inflammation provide greater protection than that afforded by endogenous regulators. Such an agent may be an effective therapy for the treatment of asthma.     

Matrix metalloproteinase-10 promotes Kras-mediated bronchio-alveolar stem cell expansion and lung cancer formation

Matrix metalloproteinase 10 (MMP-10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many of which have been implicated in tumor progression, invasion and metastasis. We recently identified Mmp10 as a gene that is highly induced in tumor-initiating lung bronchioalveolar stem cells (BASCs) upon activation of oncogenic Kras in a mouse model of lung adenocarcinoma. However, the potential role of Mmp10 in lung tumorigenesis has not been addressed. Here, we demonstrate that Mmp10 is overexpressed in lung tumors induced by either the smoke carcinogen urethane or oncogenic Kras. In addition, we report a significant reduction in lung tumor number and size after urethane exposure or genetic activation of oncogenic Kras in Mmp10 null (Mmp10(-/-)) mice. This inhibitory effect is reflected in a defect in the ability of Mmp10-deficient BASCs to expand and undergo transformation in response to urethane or oncogenic Kras in vivo and in vitro, demonstrating a role for Mmp10 in the tumor-initiating activity of Kras-transformed lung stem cells. To determine the potential relevance of MMP10 in human cancer we analyzed Mmp10 expression in publicly-available gene expression profiles of human cancers. Our analysis reveals that MMP10 is highly overexpressed in human lung tumors. Gene set enhancement analysis (GSEA) demonstrates that elevated MMP10 expression correlates with both cancer stem cell and tumor metastasis genomic signatures in human lung cancer. Finally, Mmp10 is elevated in many human tumor types suggesting a widespread role for Mmp10 in human malignancy. We conclude that Mmp10 plays an important role in lung tumor initiation via maintenance of a highly tumorigenic, cancer-initiating, stem-like cell population, and that Mmp10 expression is associated with stem-like, highly metastatic genotypes in human lung cancers. These results indicate that Mmp10 may represent a novel therapeutic approach to target lung cancer stem cells.     

Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18

Asthma is a respiratory disorder characterized by airway hyperreactivity (AHR) and inflammation and is associated with high serum IgE and overproduction of IL-4, IL-5, and IL-13 by allergen-specific Th2 cells. Our previous studies demonstrated that heat-killed Listeria monocytogenes (HKL) as an adjuvant in immunotherapy successfully reversed ongoing Ag-specific Th2-dominated responses toward Th1-dominated responses, but it was unclear if such immune modulation could reverse ongoing, established disease in target organs such as the lung. In this paper we show that a single dose of Ag plus HKL as adjuvant significantly reduced AHR in a murine model for asthma and reversed established AHR when given late after allergen sensitization. HKL as adjuvant also dramatically inhibited airway inflammation, eosinophilia, and mucus production, significantly reduced Ag-specific IgE and IL-4 production, and dramatically increased Ag-specific IFN-gamma synthesis. The inhibitory effect of HKL on AHR depended on the presence of IL-12 and CD8+ T cells and was associated with an increase of IL-18 mRNA expression. Thus, our results demonstrate that HKL as an adjuvant for immunotherapy mediates immune deviation from a pathological Th2-dominated response toward a protective immune response in peripheral lymphoid tissues and in the lungs and may be clinically effective in the treatment of patients with established asthma and allergic disease.     

The inhaled Rho kinase inhibitor Y-27632 protects against allergen-induced acute bronchoconstriction, airway hyperresponsiveness, and inflammation

Recently, we have shown that allergen-induced airway hyperresponsiveness (AHR) after the early (EAR) and late (LAR) asthmatic reaction in guinea pigs could be reversed acutely by inhalation of the Rho kinase inhibitor Y-27632. The present study addresses the effects of pretreatment with inhaled Y-27632 on the severity of the allergen-induced EAR and LAR, the development of AHR after these reactions, and airway inflammation. Using permanently instrumented and unrestrained ovalbumin (OA)-sensitized guinea pigs, single OA challenge-induced EAR and LAR, expressed as area under the lung function (pleural pressure, P(pl)) time-response curve, were measured, and histamine PC(100) (provocation concentration causing a 100% increase of P(pl)) values were assessed 24 h before, and at 6 and 24 h after, the OA challenge (after the EAR and LAR, respectively). Thirty minutes before and 8 h after OA challenge, saline or Y-27632 (5 mM) was nebulized. After the last PC(100) value, bronchoalveolar lavage (BAL) was performed, and the inflammatory cell profile was determined. It was demonstrated that inhalation of Y-27632 before allergen challenge markedly reduced the immediate allergen-induced peak rise in P(pl), without significantly reducing the overall EAR and LAR. Also, pretreatment with Y-27632 considerably protected against the development of AHR after the EAR and fully prevented AHR after the LAR. These effects could not be explained by a direct effect of Y-27632 on the histamine responsiveness, because of the short duration of the acute bronchoprotection of Y-27632 (<90 min). In addition, Y-27632 reduced the number of total inflammatory cells, eosinophils, macrophages, and neutrophils recovered from the BAL. Altogether, inhaled Y-27632 protects against acute allergen-induced bronchoconstriction, development of AHR after the EAR and LAR, and airway inflammation in an established guinea pig model of allergic asthma.     

Critical role of the Fc receptor gamma-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation

The FcR common gamma-chain (FcRgamma) is an essential component of the receptors FcepsilonRI, FcgammaRI, and FcgammaRIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcRgamma-deficient (FcRgamma(-/-)) and control (wild-type (WT)) mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FcRgamma-deficient (FcRgamma(-/-)) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FcRgamma(-/-) mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcRgamma(-/-) mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR(+/+) or FcgammaRIII-deficient but not FcRgamma(-/-) mice. The expression levels of FcgammaRIV on bone marrow-derived dendritic cells from FcR(+/+) mice were found to be low. These results demonstrate that expression of FcRgamma, most likely FcgammaRI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.     

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

Background

Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.

Methods

25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV₁ was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.

Results

Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV₁ (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.

Conclusions

This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.

Trial Registration

ClinicalTrials.gov: NCT01365533

     

Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness

Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells. Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T(EFF)) and central memory (T(CM)) cells, have been described. After adoptive transfer into CD8-deficient mice, T(EFF), but not T(CM), cells restored AHR, eosinophilic inflammation and IL-13 levels. T(EFF), but not T(CM), cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T(EFF) cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.     

8-Oxoguanine-DNA glycosylase 1 deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice

8-Oxoguanine-DNA glycosylase (OGG-1) is a base excision DNA repair enzyme; however, its function in modulating allergic diseases remains undefined. Using OGG-1 knockout (KO) mice, we show that this protein affects allergic airway inflammation after sensitization and challenge by ovalbumin(OVA). OGG-1 KO mice exhibited less inflammatory cell infiltration and reduced oxidative stress in the lungs after OVA challenge compared to WT mice. The KO phenotype included decreased IL-4, IL-6, IL-10, and IL-17 in lung tissues. In addition, OGG-1 KO mice showed decreased expression and phosphorylation of STAT6 as well as NF-κB. Down-regulation of OGG-1 by siRNA lowered ROS and IL-4 levels but increased IFN-γ production in cultured epithelial cells after exposure to house dust mite extracts. OGG-1 may affect the levels of oxidative stress and proinflammatory cytokines during asthmatic conditions. OGG-1 deficiency negatively regulates allergen-induced airway inflammatory response.