Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall

Am J Respir Crit Care Med. 2006 Dec 15;174(12):1327-34. doi: 10.1164/rccm.200605-585OC. Epub 2006 Sep 28.


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)-beta(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-beta(1) gene expression declined over time; however, increased immunochemical staining for phopho-Smad 2 was present at all time points, indicating continuing TGF-beta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchi / drug effects*
  • Connective Tissue Growth Factor
  • Gene Expression
  • Immediate-Early Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Platelet-Derived Growth Factor / genetics
  • Procollagen / biosynthesis*
  • Procollagen / genetics
  • Pulmonary Alveoli / drug effects*
  • Smoking / physiopathology*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology


  • CCN2 protein, mouse
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Platelet-Derived Growth Factor
  • Procollagen
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor