A<scp>sthma</scp>: Mechanisms of Disease Persistence and Progression

Cohn, Lauren; Elias, Jack A.; Chupp, Geoffrey

doi:10.1146/annurev.immunol.22.012703.104716

Cited by 762 publications

(654 citation statements)

References 179 publications

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“…Th2-type cytokines such as IL-4, IL-5, and IL-13 play important roles in the development of allergic asthmatic responses in humans [20]. SCTE treatment reduced the number of eosinophils in BALF and in the lung tissue surrounding the airways, and decreased the extent of goblet cell hyperplasia compared with untreated mice.…”

Section: Discussionmentioning

confidence: 99%

A water extract of Samchulkunbi-tang attenuates airway inflammation by inhibiting inos and MMP-9 activities in an ovalbumin-induced murine asthma model

Lee

Shin

Lim

et al. 2012

BMC Complement Altern Med

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BackgroundIn this study, we investigated the effect of Samchulkunbi-tang water extract (SCTE) in an established mouse model of ovalbumin (OVA)-induced allergic asthma. The effects of SCTE on the production of Th1 and Th2 cytokines, eotaxin, and total and OVA-specific immunoglobulin E, inducible nitric oxide synthase expression, and matrix metalloproteinase-9 activity were measured.MethodsMice were sensitized on days 0 and 14 with an intraperitoneal injection of 20 μg ovalbumin (OVA) emulsified in 2 mg aluminum hydroxide in 200 μL PBS buffer. On days 21, 22, and 23, mice received an airway exposure to OVA (1%, w/v, in PBS) for 1 h. SCTE was administered orally to mice at doses of 200 and 400 mg/kg per day from days 18 to 23.ResultsSCTE reduced the number of inflammatory cells, cytokines, and chemokines in bronchoalveolar lavage fluids and iNOS expression and MMP-9 activity in mouse lung tissue. Histological studies using hematoxylin & eosin and periodic acid-schiff staining showed that SCTE substantially inhibited OVA-induced inflammatory cell infiltration in lung tissue and goblet cell hyperplasia in the airway. SCTE also reduced IL-4 and IL-13 expression in concanavalin-A-stimulated splenocytes. These results were similar to those obtained with montelukast as a positive control.ConclusionsCollectively, these results suggest that SCTE may be an effective oral treatment for allergic airway inflammation by virtue of its anti-inflammatory activity.

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Section: Discussionmentioning

confidence: 99%

A water extract of Samchulkunbi-tang attenuates airway inflammation by inhibiting inos and MMP-9 activities in an ovalbumin-induced murine asthma model

Lee

Shin

Lim

et al. 2012

BMC Complement Altern Med

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“…TGF-␤ is a primary stimulus for differentiation of fibroblasts into myofibroblasts. 1,29 When we assessed the expression of TGF-␤ during the cellular interaction, we observed an increased expression when eosinophils were co-cultured with CRA fibroblasts but not with naive fibroblasts (Figure 6). When anti-SCF was added to the co-cultures, a significant reduction in the expression of TGF-␤ was observed.…”

Section: Eosinophil-induced Fibroblast Activation and Phenotypic Chanmentioning

confidence: 99%

Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Dolgachev

Berlin

Lukacs

2008

The American Journal of Pathology

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In the present studies the role of stem cell factor (SCF) in mediating eosinophil and fibroblast activation during their interaction was investigated. SCF was significantly higher in fibroblasts grown from lungs of chronic allergen-challenged mice compared to fibroblasts grown from normal mice. When eosinophils were layered onto fibroblasts from allergic mice, a significant increase in SCF was detected compared to fibroblasts from nonallergic mice. The interaction of fibroblasts with eosinophils also increased the production of asthmaassociated chemokines, CCL5 and CCL6, was dependent on cell-to-cell interaction, and was observed only with fibroblasts derived from lungs of chronic allergen-challenged mice and not from those derived from unchallenged normal mice. Chemokine production was significantly decreased when anti-SCF antibodies were added during eosinophil-fibroblast interaction. The interaction of fibroblasts from chronic allergen-challenged mice with eosinophils also increased ␣-smooth muscle cell actin and procollagen I expression as well as induced transforming growth factor-␤. The changes in myofibroblast activation were dependent on SCF-mediated pathways because anti-SCF antibody treatment reduced the expression of all three of these latter fibrosisassociated markers. Thus , our data suggest that SCF mediates an important activation pathway for fibroblasts during chronic allergic responses on interaction with recruited eosinophils and suggest a potential mechanism of airway remodeling during chronic disease. Allergic airway inflammation is characterized by peribronchial eosinophil accumulation accompanied by mucus production and airway changes. Structural changes in the asthmatic airway include an increase in smooth muscle mass and deposition of extracellular matrix proteins. These changes correlate with airway hyperresponsiveness, reduced lung function, and an increase in fibroblast and myofibroblast numbers. These debilitating effects are not specifically targeted by current therapeutic agents, presenting a clinical challenge that might be better addressed by an enhanced understanding of the mechanisms. 1 In addition to contributing to airway remodeling, lung fibroblasts may also play a role in local regulation of immune and inflammatory responses. Fibroblasts are a potential source of granulocyte monocyte-colony stimulating factor (GM-CSF) and stem cell factor (SCF), known to promote differentiation, activation, and survival of eosinophils and mast cells. 2 Eosinophils have been shown to highly express c-kit (SCF receptor) on their surface. 3,4 We have previously shown that SCF is an important eosinophil-activating factor 4 that influences eosinophil recruitment in allergic airway inflammation. 5 SCF-induced activation of eosinophils has been shown to up-regulate expression of fibroblast growth factors, such as FGF5 and FGF7 (KGF). 4 Eosinophils also express at least two potent mediators [interleukin (IL)-1␤ and transforming growth factor (TGF)-␤] that induce a myofibroblast phenotype. The emergi...

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“…Pathological features of asthma include pulmonary infiltration by eosinophils, lymphocytes, and mast cells, and structural changes of the airways, including bronchial wall thickening, subepithelial fibrosis, and goblet cell and airway smooth muscle hyperplasia (Cohn et al, 2004). T-helper 2 (Th2) cells have been proposed to play an essential role in allergic airway inflammation, and there are many studies that examine the functional effects of Th2 cells in asthmatics (Robinson et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Hur

Lee²,

Lee³

et al. 2007

Exp Mol Med

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The EGFR plays an essential role in goblet cell hyperplasia and mucus hypersecretion. EGFR has an intrinsic tyrosine kinase activity that, when activated, induces the production of MUC5AC through the signaling kinase cascade in the airway epithelium. We have investigated the effects of an EGFR tyrosine kinase inhibitor, gefitinib, on ovalbumin (OVA)-induced, allergic inflammation in airway epithelia of mice. OVA-sensitized mice were pretreated with gefitinib at two different doses (12.5 and 50 mg/kg) and then challenged with OVA. The OVA challenge increased the total cell count and eosinophil count in bronchoalveolar lavage fluid (BALF), as well as the concentrations of T-helper2 (Th2) cytokines, such as IL-4 and IL-13, overall eosinophil recruitment in the lung tissue and airway hyperresponsiveness (AHR). Pretreatment with gefitinib reduced the inflammatory cell counts and released cytokine concentrations (IL-4 and IL-13) in BALF, as well as eosinophil recruitment in the lungs and AHR, in a dose-dependent manner. This was associated with decreased EGFR and Akt phosphorylation. We showed that gefitnib inhibits EGFR and phosphoinositol 3'-kinase (PI3K)/Akt activation which were activated in OVA sensitized mice. These findings suggest that inhibitors of the EGFR cascade may have a role in the treatment of asthma.

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Asthma: Mechanisms of Disease Persistence and Progression

Cited by 762 publications

References 179 publications

A water extract of Samchulkunbi-tang attenuates airway inflammation by inhibiting inos and MMP-9 activities in an ovalbumin-induced murine asthma model

A water extract of Samchulkunbi-tang attenuates airway inflammation by inhibiting inos and MMP-9 activities in an ovalbumin-induced murine asthma model

Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

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