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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2006-8-21
pubmed:abstractText
Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of "classical" asthma. However, the relationship between chronic obstructive pulmonary disease (COPD) and asthma is controversial and the variety of mechanisms that can mediate the alveolar destruction in emphysema have not been adequately defined. To address these issues, we used overexpression transgenic approaches to define the effects of Th1/Tc1 and Th2/Tc2 cytokines in the mature murine lung and compared findings in these transgenic systems to the effects of similar interventions after cigarette smoke (CS) exposure. In these experiments, the Th1/Tc1 and Th2/Tc2 cytokines IFN-gamma and interleukin (IL)-13, respectively, both caused emphysema. The IFN-gamma response was associated with neutrophilia but was not associated with mucus metaplasia or a major fibrotic response. In this setting, IFN-gamma was a potent stimulator of matrix metalloproteinases (MMPs), cathepsins, and CXC and other chemokines while inhibiting secretory leukocyte proteinase inhibitor (SLPI). Interestingly, IFN-gamma induced its destructive effects via at least two mechanisms, a CCR5/cathepsin-dependent and apoptosis-mediated pathway and an MMP-12-dependent/apoptosis-independent pathway. CS-induced inflammation, apoptosis, and emphysema were also induced by IFN-gamma- and CCR5-dependent mechanisms. In contrast, IL-13-induced emphysema was associated with eosinophilia, mucus metaplasia, and pulmonary fibrosis. In this setting, IL-13 stimulated MMPs, cathepsins, and a variety of CC chemokines while inhibiting alpha(1)-antitrypsin. A cathepsin-dependent apoptosis pathway also contributed to this remodeling response. Interestingly, abnormalities in vascular endothelial growth factor (VEGF) were also appreciated with VEGF(165) excess producing an asthmalike pulmonary response and IFN-gamma abrogating this response while inducing emphysematous alveolar destruction. These findings provide molecular support for both points of view in the British/Dutch hypothesis controversy regarding the relationship between asthma and COPD. They also highlight the complexity of the pathways that can induce alveolar destruction and suggest that there is a continuum, based on VEGF, between asthma and COPD.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1546-3222
pubmed:author
pubmed:issnType
Print
pubmed:volume
3
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
494-8
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: insights from transgenic mice.
pubmed:affiliation
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 300 Cedar Street, S441 TAC, New Haven, CT 06519, USA. jack.elias@yale.edu
pubmed:publicationType
Journal Article, Review