Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms

Holgate, Stephen T.; Davies, Donna E.; Powell, Rob M.; Howarth, Peter H.; Haitchi, Hans Michael; Holloway, John W.

doi:10.1183/09031936.00087506

Cited by 119 publications

(76 citation statements)

References 98 publications

(99 reference statements)

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“…We therefore hypothesize that PCDH1 plays a role in epithelial integrity of the airways and that loss of function of PCDH1 is associated with increased BHR, which may lead to symptomatic asthma (34). It is tempting to speculate that PCDH1 dysfunction may provide a functional explanation for the observed epithelial vulnerability and increased epithelial shedding in asthma (35).…”

Section: Discussionmentioning

confidence: 99%

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Koppelman¹,

Meyers²,

Howard³

et al. 2009

Am J Respir Crit Care Med

122

136

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Rationale: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33. Objectives: To identify a gene for BHR on chromosome 5q31-q33. Methods: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages. Conclusions: PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.

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Section: Discussionmentioning

confidence: 99%

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Koppelman¹,

Meyers²,

Howard³

et al. 2009

Am J Respir Crit Care Med

122

136

View full text Add to dashboard Cite

show abstract

“…However, we failed to detect significant IFN-␤ protein at 24 h, suggesting that insufficient induction of IFN-␤ mRNA expression had occurred to result in an increase in protein synthesis. In vivo, localization of TLR-3 on the surface of fibroblasts would allow them to detect extracellular dsRNA released from infected epithelial cells and, as a consequence, serve as sensors of infection in the epithelial-mesenchymal trophic unit, propagating and amplifying signals to the immune system (29).…”

Section: Discussionmentioning

confidence: 99%

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Bedke

Haitchi

Xatzipsalti

et al. 2009

The Journal of Immunology

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Human rhinoviruses (HRV) are a major cause of asthma exacerbations and hospitalization. Studies using primary cultures suggest that this may be due to impaired production of type I and type III IFNs by asthmatic bronchial epithelial cells. Although epithelial cells are the main target for HRV infection, HRV can be detected in the subepithelial layer of bronchial mucosa from infected subjects by in situ hybridization. Therefore, we postulated that submucosal fibroblasts are also involved in the innate antiviral response to HRV infection in asthma. We found that regardless of subject group, bronchial fibroblasts were highly susceptible to RV1b infection. IL-8 and IL-6 were rapidly induced by either HRV or UV-irradiated virus, suggesting that these responses did not require viral replication. In contrast, RANTES expression was dependent on viral replication. Regardless of disease status, fibroblasts did not respond to HRV infection with significant induction of IFN-␤, even though both groups responded to synthetic dsRNA with similar levels of IFN-␤ expression. Exogenous IFN-␤ was highly protective against viral replication. Our data suggest that fibroblasts respond to HRV with a vigorous proinflammatory response but minimal IFN-␤ expression. Their susceptibility to infection may cause them to be a reservoir for HRV replication in the lower airways, especially in asthmatic subjects where there is reduced protection offered by epithelialderived IFNs. Their ability to support viral replication coupled with their vigorous proinflammatory response following infection may contribute to asthma exacerbations.

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“…Most recently, invariant natural killer T cells have been reported as essential cellular mediators of immunological persistence because of microbial influence (22). In addition to serving as cellular mediators of immunity, evidence suggests that the airway epithelium may also be capable of retaining a "memory" immune phenotype, as demonstrated by the differential inflammatory response of asthmatic airway epithelium compared with that in normal subjects (23)(24)(25). Furthermore, the expression of proinflammatory cytokines and remodeling proteins is intrinsically different in airway epithelium from asthmatic children compared with children without asthma, indicating that a persistent epithelial cell disease phenotype is initiated during early childhood (26,27).…”

mentioning

confidence: 99%

Innate Immune Response to LPS in Airway Epithelium Is Dependent on Chronological Age and Antecedent Exposures

Maniar-Hew¹,

Clay²,

Postlethwait³

et al. 2013

Am J Respir Cell Mol Biol

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The immune mechanisms for neonatal susceptibility to respiratory pathogens are poorly understood. Given that mucosal surfaces serve as a first line of host defense, we hypothesized that the innate immune response to infectious agents may be developmentally regulated in airway epithelium. To test this hypothesis, we determined whether the expression of IL-8 and IL-6 in airway epithelium after LPS exposure is dependent on chronological age. Tracheas from infant, juvenile, and adult rhesus monkeys were first exposed to LPS ex vivo, and then processed for air-liquid interface primary airway epithelial cell cultures and secondary LPS treatment in vitro. Compared with adult cultures, infant and juvenile cultures expressed significantly reduced concentrations of IL-8 after LPS treatment. IL-8 protein in cultures increased with animal age, whereas LPS-induced IL-6 protein was predominantly associated with juvenile cultures. Toll-like receptor (TLR) pathway RT-PCR arrays showed differential expressions of multiple mRNAs in infant cultures relative to adult cultures, including IL-1a, TLR10, and the peptidoglycan recognition protein PGLYRP2. To determine whether the age-dependent cytokine response to LPS is reflective of antecedent exposures, we assessed primary airway epithelial cell cultures established from juvenile monkeys housed in filtered air since birth. Filtered air-housed animal cultures exhibited LPS-induced IL-8 and IL-6 expression that was discordant with age-matched ambient air-housed animals. A single LPS aerosol in vivo also affected this cytokine profile. Cumulatively, our findings demonstrate that the innate immune response to LPS in airway epithelium is variable with age, and may be modulated by previous environmental exposures.

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Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms

Cited by 119 publications

References 98 publications

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Innate Immune Response to LPS in Airway Epithelium Is Dependent on Chronological Age and Antecedent Exposures

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