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Cigarette Smoke Drives Small Airway Remodeling by Induction of Growth Factors in the Airway Wall

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Andrew Churg, M.D., Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5. E-mail: achurg{at}interchange.ubc.ca

Background: Small airway remodeling (SAR) is an important cause of airflow obstruction in cigarette smokers with chronic obstructive pulmonary disease, but the pathogenesis of SAR is not understood.

Objective: To determine whether smoke causes production of profibrotic growth factors in the airway wall.

Methods: We exposed C57Bl/6 mice to cigarette smoke for up to 6 mo and examined growth factor/procollagen gene expression in laser-capture microdissected small airways by real-time reverse transcription–polymerase chain reaction.

Results: With a single smoke exposure, increases in procollagen, connective tissue growth factor (CTGF), transforming growth factor (TGF)-₁, platelet-derived growth factor (PDGF)-A and -B expression were seen 2 h after the start of smoking and declined to baseline by 24 h. With repeated exposures and at killing of animals 24 h after the last exposure, increases in procollagen, CTGF, PDGF-B, and (minimally) PDGF-A expression persisted through 1 wk, 1 mo, and 6 mo. TGF-₁ gene expression declined over time; however, increased immunochemical staining for phopho-Smad 2 was present at all time points, indicating continuing TGF- downstream signaling. Morphometric analysis showed that the small airways in smoke-exposed mice had more collagen at 6 mo.

Conclusions: These findings suggest that smoke can induce growth factor and procollagen production in small airways in a time frame that initially is too short for a significant inflammatory response and that profibrotic growth factor and procollagen gene expression become self-sustaining with repeated smoke exposures. These results imply that the pathogenesis of and possible treatment approaches to emphysema and small airway remodeling might be quite different.

Key Words: cigarette smoke • connective tissue growth factor • platelet-derived growth factor • small airway remodeling • transforming growth factor-

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Small airway remodeling in cigarette smokers causes airflow obstruction. The pathogenesis of small airway remodeling is unknown but usually attributed to smoke-induced inflammation. What This Study Adds to the Field We show that small airway remodeling is caused by smoke-induced production of growth factors in the airway wall rather than inflammation, implying that growth factor antagonism may be an approach to treatment and prevention of small airway remodeling.

 

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