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Association of progressive structural changes in the bronchial epithelium with subepithelial fibrous remodeling: A potential role for hypoxia

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Abstract

In airway remodeling that occurs in association with chronic obstructive pulmonary disease (COPD), the relationship between the subepithelium and structural changes of the bronchial epithelium is not well defined. To investigate whether the subepithelium and epithelium undergo remodeling as an integrated unit, we performed morphological examination of 55 bronchial biopsy specimens obtained from explanted or resected lungs from tobacco smokers with COPD. Our results indicate that reticular basement membrane (RBM) thickness is increased and the subepithelial microvascular bed is reduced in association with progression from the normal epithelium to squamous metaplasia. Subsequent bronchial epithelial transformation to dysplasia is characterized by differential subepithelial remodeling with normalization of RBM thickness and subepithelial blood vessel density. Because fibrous remodeling of the subepithelium could limit delivery of nutrients and oxygen to the epithelium, we assessed expression of hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase IX (CA IX) as markers of cellular hypoxia. The number of HIF-1α-positive epithelial cells increased with progression of epithelial structural changes, RBM thickness, and reduction in blood vessels in the subepithelium. These findings suggest that the HIF-1α pathway is activated in response to subepithelial remodeling and contributes to progressive premalignant epithelial lesions in the airways of tobacco smokers with chronic airway inflammation.

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Authors and Affiliations

  1. Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, TN, 37232-2650, USA

    Vasiliy V. Polosukhin, William E. Lawson, Aaron P. Milstone, Pierre P. Massion & Timothy S. Blackwell

  2. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Timothy S. Blackwell

  3. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Pierre P. Massion & Timothy S. Blackwell

  4. Department of Veterans Affairs Medical Center, Nashville, TN, USA

    William E. Lawson, Pierre P. Massion & Timothy S. Blackwell

  5. Institute of Clinical and Experimental Lymphology, Novosibirsk, Russia

    Vasiliy V. Polosukhin

  6. Novosibirsk City Thoracic-Surgical Hospital, Novosibirsk, Russia

    Svetlana M. Egunova, Andrey G. Kulipanov & Sergey G. Tchuvakin

Authors
  1. Vasiliy V. Polosukhin
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  2. William E. Lawson
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  3. Aaron P. Milstone
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  4. Svetlana M. Egunova
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  5. Andrey G. Kulipanov
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  6. Sergey G. Tchuvakin
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  7. Pierre P. Massion
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  8. Timothy S. Blackwell
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Corresponding author

Correspondence to Vasiliy V. Polosukhin.

Additional information

Supported by: HL68121, HL66196, HL85406, ATS Research Grant, Vanderbilt Discovery Grant, and the Francis Family Foundation; WEL is a Parker B. Francis Fellow in Pulmonary Research.

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Polosukhin, V.V., Lawson, W.E., Milstone, A.P. et al. Association of progressive structural changes in the bronchial epithelium with subepithelial fibrous remodeling: A potential role for hypoxia. Virchows Arch 451, 793–803 (2007). https://doi.org/10.1007/s00428-007-0469-5

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  • DOI: https://doi.org/10.1007/s00428-007-0469-5

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