Transforming Growth Factor-β Regulates House Dust Mite–induced Allergic Airway Inflammation but Not Airway Remodeling

Fattouh, Ramzi; Midence, N. Gabriela; Arias, Katherine; Johnson, Jill; Walker, Tina D.; Goncharova, Susanna; Souza, Kailene P.; Gregory, Richard C.; Lonning, Scott; Gauldie, Jack; Jordana, Manel

doi:10.1164/rccm.200706-958oc

Cited by 87 publications

(82 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The differential requirements to develop airway remodeling between OVA-and HDM-based models has been extensively discussed by Fattouh and Jordana (29). It has previously been shown using neutralizing antibodies to TGF-b that this cytokine mediates OVA-induced airway remodeling (11); however, remodeling can develop independently of TGF-b after respiratory exposure to HDM extract (30). The data presented in the current study suggest that activin A signaling via Smad2 is responsible for driving airway remodeling after HDM challenge.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Gregory

Mathie

Walker

et al. 2010

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: Airway hyperreactivity and remodeling are characteristic features of asthma. Interactions between the airway epithelium and environmental allergens are believed to be important in driving development of pathology, particularly because altered epithelial gene expression is common in individuals with asthma. Objectives: To investigate the interactions between a modified airway epithelium and a common aeroallergen in vivo. Methods: We used an adenoviral vector to generate mice overexpressing the transforming growth factor-b signaling molecule, Smad2, in the airway epithelium and exposed them to house dust mite (HDM) extract intranasally. Measurements and Main Results: Smad2 overexpression resulted in enhanced airway hyperreactivity after allergen challenge concomitant with changes in airway remodeling. Subepithelial collagen deposition was increased and smooth muscle hyperplasia was evident resulting in thickening of the airway smooth muscle layer. However, there was no increase in airway inflammation in mice given the Smad2 vector compared with the control vector. Enhanced airway hyperreactivity and remodeling did not correlate with elevated levels of Th2 cytokines, such as IL-13 or IL-4. However, mice overexpressing Smad2 in the airway epithelium showed significantly enhanced levels of IL-25 and activin A after HDM exposure. Blocking activin A with a neutralizing antibody prevented the increase in lung IL-25 and inhibited subsequent collagen deposition and also the enhanced airway hyperreactivity observed in the Smad2 overexpressing HDM-exposed mice. Conclusions: Epithelial overexpression of Smad2 can specifically alter airway hyperreactivity and remodeling in response to an aeroallergen. Moreover, we have identified novel roles for IL-25 and activin A in driving airway hyperreactivity and remodeling.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Gregory

Mathie

Walker

et al. 2010

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…BAL was performed as previously described (12). Briefly, lungs were dissected and the tracheae were cannulated with a polyethylene tube (outer/inner diameter ϭ 0.965/0.58 mm; BD Biosciences).…”

Section: Collection and Measurement Of Specimensmentioning

confidence: 99%

“…Levels of IL-5, IL-4, IL-13, and IFN-␥ in supernatants from mononuclear cell cultures were measured by DuoSet ELISA kits purchased from R&D Systems and used according to the manufacturer's instruction. Levels of HDMspecific IgE, IgG1, and IgG2 were measured by sandwich ELISA as previously described (2,12).…”

Section: Cytokine Analysis and Ig Measurementsmentioning

confidence: 99%

Acute, but Not Resolved, Influenza A Infection Enhances Susceptibility to House Dust Mite-Induced Allergic Disease

Al-Garawi

Fattouh

Walker

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The impact of respiratory viral infections on the emergence of the asthmatic phenotype is a subject of intense investigation. Most experimental studies addressing this issue have used the inert Ag OVA with controversial results. We examined the consequences of exposure to a low dose of the common aeroallergen house dust mite (HDM) during the course of an influenza A infection. First, we delineated the kinetics of the immune-inflammatory response in the lung of mice following intranasal infection with influenza A/PR8/34. Our data demonstrate a peak response during the first 10 days, with considerable albeit not complete resolution at day 39 postinfection (p.i.). At day 7 p.i., mice were exposed, intranasally, to HDM for 10 consecutive days. We observed significantly enhanced eosinophilic inflammation, an expansion in Th2 cells, enhanced HDM-specific IgE and IgG1 responses and increased mucous production. Furthermore, lung mononuclear cells produced enhanced IFN-␥ and IL-5, unchanged IL-13, and reduced IL-4. These immunologic and structural changes lead to marked lung dysfunction. This allergic phenotype occurs at a time when there is a preferential increase in plasmacytoid dendritic cells over myeloid dendritic cells, activated CD8؉ T cells, and increased IFN-␥ production, all of which have been proposed to inhibit allergic responses. In contrast, the inflammatory response elicited by HDM was reduced when exposure occurred during the resolution phase (day 40 p.i.). Interestingly, this was not associated with a reduction in sensitization. Thus, the proinflammatory environment established during an acute influenza A infection enhances Th2-polarized immunity to a low dose of HDM and precipitates marked lung dysfunction.

show abstract

“…TGF-β-producing T cells can suppress airway inflammation and hyperresponsiveness induced by Th2 effector cells in a murine allergic airway model [17,18]. However, it was recently shown that TGF-β/Smad2 signaling proteins were expressed in the majority of cells infiltrating into the airway in mouse models [19-22] and human asthma [19,23]. …”

Section: Introductionmentioning

confidence: 99%

Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells

et al. 2011

View full text Add to dashboard Cite

BackgroundMany studies have found that smoking reduces lung function, but the relationship between cigarette smoke and allergic asthma has not been clearly elucidated, particularly the role of mast cells. This study aimed to investigate the effects of smoke exposure on allergic asthma and its association with mast cells.MethodsBALB/c mice were sensitized and challenged by OVA to induce asthma, and bone marrow-derived mast cells (BMMCs) were stimulated with antigen/antibody reaction. Mice or BMMCs were exposed to cigarette smoke or CSE solution for 1 mo or 6 h, respectively. The recruitment of inflammatory cells into BAL fluid or lung tissues was determined by Diff-Quik or H&E staining, collagen deposition by Sircol assay, penh values by a whole-body plethysmography, co-localization of tryptase and Smad3 by immunohistochemistry, IgE and TGF-β level by ELISA, expressions of Smads proteins, activities of signaling molecules, or TGF-β mRNA by immunoblotting and RT-PCR.ResultsCigarette smoke enhanced OVA-specific IgE levels, penh values, recruitment of inflammatory cells including mast cells, expressions of smad family, TGF-β mRNA and proteins, and cytokines, phosphorylations of Smad2 and 3, and MAP kinases, co-localization of tryptase and Smad3, and collagen deposition more than those of BAL cells and lung tissues of OVA-induced allergic mice. CSE solution pretreatment enhanced expressions of TGF-β, Smad3, activities of MAP kinases, NF-κB/AP-1 or PAI-1 more than those of activated-BMMCs.ConclusionsThe data suggest that smoke exposure enhances antigen-induced mast cell activation via TGF-β/Smad signaling pathways in mouse allergic asthma, and that it exacerbates airway inflammation and remodeling.

show abstract

Transforming Growth Factor-β Regulates House Dust Mite–induced Allergic Airway Inflammation but Not Airway Remodeling

Abstract: Collectively, these data suggest that TGF-beta regulates HDM-induced chronic airway inflammation but not remodeling, and furthermore, caution against the use of therapeutic strategies aimed at interfering with TGF-beta activity in the treatment of this disease.

Cited by 87 publications

References 58 publications

Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Acute, but Not Resolved, Influenza A Infection Enhances Susceptibility to House Dust Mite-Induced Allergic Disease

Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells

Contact Info

Product

Resources

About