Differences in airway remodeling between subjects with severe and moderate asthma

Pepe, C.; Foley, Susan; Shannon, Joanne; Lemière, Catherine; Olivenstein, Ron; Ernst, Pierre; Ludwig, Mara S.; Martin, James G.; Hamid, Qutayba

doi:10.1016/j.jaci.2005.06.011

Cited by 300 publications

(260 citation statements)

References 34 publications

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“…In accordance, we found that IL-17RA and IL-17RC mRNA was increased in asthmatic subjects. The increased expression of IL-17RA was more pronounced in mild when compared with severe asthmatics, which could be explained by extensive tissue remodeling that occurs in severe asthma, whereas in bronchoscopies the proportional representation of various cell types may be skewed, favoring smooth muscle cells over other types in patients with severe asthma (34). We also found that the mRNA for the adhesion molecule VCAM-1 was increased in a similar fashion as that of IL-17RA in asthmatics.…”

Section: Discussionmentioning

confidence: 50%

IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation

Roussel

Houle

Chan

et al. 2010

The Journal of Immunology

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Section: Discussionmentioning

confidence: 50%

IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation

Roussel

Houle

Chan

et al. 2010

The Journal of Immunology

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244

180

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“…The activation of NF-B and expression of IL-8/CXCL8 mRNA indicate those hASM cells were at a state of active production of IL-8/CXCL8. In this regard, our results should be interpreted as the modulation effect of NE on active synthesis and release of IL-8/CXCL8 from hASM cells, as found in airway smooth muscle of severe asthma (39), rather than physiological naive. Importantly, NE also attenuates the secretion of IL-8/CXCL8 stimulated by TNF-␣, indicating the concomitant release of NE from recruited polymorphonuclear cell (PMN) to hASM may modify the cytokine-induced IL-8/XCXL8 production under inflammatory conditions.…”

Section: Discussionmentioning

confidence: 73%

Neutrophil Elastase Represses IL-8/CXCL8 Synthesis in Human Airway Smooth Muscle Cells through Induction of NF-κB Repressing Factor

Lee

Chan

et al. 2009

The Journal of Immunology

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NF-κB repressing factor (NRF), a nuclear inhibitor of NF-κB, is constitutively expressed and is implicated in the basal silencing of specific NF-κB targeting genes, including IFN-β, IL-8/CXCL8, and iNOS. Little is known about the regulation of NRF and its role in response to stimuli. Airway smooth muscle (ASM) is a rich source of inflammatory mediators that may regulate the development and progression of airway inflammation. We have previously reported that NE activates NF-κB in primary human ASM (hASM), leading to induction of TGF-β1. In this study, we describe that, instead of inducing the NF-κB response gene IL-8/CXCL8, NE suppressed IL-8/CXCL8 release and mRNA expression in hASM cells. Transcriptional blockade studies using actinomycin D revealed a similar degradation rate of IL-8/CXCL8 mRNA in the presence or absence of NE, suggesting an involvement at the transcription level. Mechanistically, the NE repressive effect was mediated by inducing NRF, as shown by RT-PCR and Western blotting, which was subsequently recruited to the native IL-8/CXCL8 promoter leading to removal of RNA polymerase II from the promoter, as demonstrated by chromatin immunoprecipitation assays. Knockdown of NRF by small interfering RNA prevented NE-induced suppression of IL-8/CXCL8 expression. In contrast, NE did not induce NRF expression in A549 and Beas-2B cells, where NE only stimulates NF-κB activation and IL-8/CXCL8 induction. Forced expression of NRF in A549 cells by an NRF expression plasmid suppressed IL-8/CXCL8 expression. Hence, we describe a novel negative regulatory mechanism of NE-induced NRF, which is restricted to hASM and mediates the suppression of IL-8/CXCL8 expression.

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“…Alterations in the connective tissue structure and composition of the airway wall, a process termed remodelling, has been documented in human asthmatic airways [71,73,202] and in animal models [203,204]. Such changes might result in alterations in the passive mechanical properties of the airway wall, leading to a change in the wall diameter at which its inward recoil is balanced by the outward pull of the parenchymal attachments.…”

Section: Effects Of Chronic Lung-volume Alteration and Smooth Muscle mentioning

confidence: 99%

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

An¹,

Bai²,

Bates³

et al. 2007

Eur Respir J

344

298

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Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

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Differences in airway remodeling between subjects with severe and moderate asthma

Cited by 300 publications

References 34 publications

IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation

IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation

Neutrophil Elastase Represses IL-8/CXCL8 Synthesis in Human Airway Smooth Muscle Cells through Induction of NF-κB Repressing Factor

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

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