{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T17:07:23Z","timestamp":1791133643730,"version":"4.1.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2006,8,1]],"date-time":"2006-08-01T00:00:00Z","timestamp":1154390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of \u201cclassical\u201d 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-\u03b3 and interleukin (IL)-13, respectively, both caused emphysema. The IFN-\u03b3 response was associated with neutrophilia but was not associated with mucus metaplasia or a major fibrotic response. In this setting, IFN-\u03b3 was a potent stimulator of matrix metalloproteinases (MMPs), cathepsins, and CXC and other chemokines while inhibiting secretory leukocyte proteinase inhibitor (SLPI). Interestingly, IFN-\u03b3 induced its destructive effects via at least two mechanisms, a CCR5\/cathepsin-dependent and apoptosis-mediated pathway and an MMP-12\u2013dependent\/apoptosis-independent pathway. CS-induced inflammation, apoptosis, and emphysema were also induced by IFN-\u03b3\u2013 and CCR5-dependent mechanisms. In contrast, IL-13\u2013induced 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 \u03b11-antitrypsin. A cathepsin-dependent apoptosis pathway also contributed to this remodeling response. Interestingly, abnormalities in vascular endothelial growth factor (VEGF) were also appreciated with VEGF165 excess producing an asthmalike pulmonary response and IFN-\u03b3 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.<\/jats:p>","DOI":"10.1513\/pats.200603-068ms","type":"journal-article","created":{"date-parts":[[2006,8,18]],"date-time":"2006-08-18T20:10:47Z","timestamp":1155931847000},"page":"494-498","source":"Crossref","is-referenced-by-count":75,"title":["State of the Art. Mechanistic Heterogeneity in Chronic Obstructive Pulmonary Disease: Insights from Transgenic Mice"],"prefix":"10.1093","volume":"3","author":[{"given":"Jack A.","family":"Elias","sequence":"first","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University School of Medicine, New Haven; and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Jong","family":"Kang","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University School of Medicine, New Haven; and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Crouthers","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University School of Medicine, New Haven; and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Homer","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University School of Medicine, New Haven; and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Geun","family":"Lee","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University School of Medicine, New Haven; and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2006,8,1]]},"reference":[{"key":"2026020501585284200_BIB1"},{"key":"2026020501585284200_BIB2"},{"key":"2026020501585284200_BIB3"},{"key":"2026020501585284200_BIB4","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1056\/NEJMra030415","volume":"350","year":"2004","journal-title":"N Engl J Med"},{"key":"2026020501585284200_BIB5","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1183\/09031936.93.04040479","volume":"4","year":"1991","journal-title":"Eur Respir 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