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International Journal of Chronic Obstructive Pulmonary Disease Volume 10, 2015 - Issue
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Original Research

Epithelial mesenchymal transition in smokers: large versus small airways and relation to airflow obstruction

Malik Quasir Mahmood1 NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia
,
Sukhwinder Singh Sohal1 NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia;2 School of Health Sciences, Faculty of Health, University of Tasmania, Launceston, TAS, Australia
,
Shakti Dhar Shukla1 NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia
,
Chris Ward3 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
,
Ashutosh Hardikar4 Royal Hobart Hospital, Hobart, TAS, Australia
,
Wan Danial Noor1 NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia
,
Hans Konrad Muller1 NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia
,
Darryl A Knight5 School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
&
Eugene Haydn Walters1 NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, AustraliaCorrespondence[email protected]
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Pages 1515-1524 | Published online: 04 Aug 2015

Figures & data

Table 1 Demographic detail and lung function data of CAL patients and control subjects

Table 2 Comparison of different pathological indices in CAL large and small airways

Table 3 Comparison of different pathological indices in CAL small airway and normal control small airway

Figure 1 Large airway tissue from patient with CAL.

Notes: Black arrows indicate large-airway epithelium (chronic airflow limitation) stained positive for EGFR (epithelial activation marker). Original magnification, ×360. Scale bar =50 µm.

Abbreviations: CAL, chronic airflow limitation; EGFR, epidermal growth factor receptor.

Figure 1 Large airway tissue from patient with CAL.Notes: Black arrows indicate large-airway epithelium (chronic airflow limitation) stained positive for EGFR (epithelial activation marker). Original magnification, ×360. Scale bar =50 µm.Abbreviations: CAL, chronic airflow limitation; EGFR, epidermal growth factor receptor.

Figure 2 (A) Percentage of large-airway epithelium in CAL patients stained for EGFR compared with CAL small airway and normal control small airway. (B) Percentage of Rbm fragmentation (total length of clefts as percentage of the total length of Rbm) in large airway in CAL patients versus CAL small airway and in normal control small airway.

Abbreviations: CAL, chronic airflow limitation; EGFR, epidermal growth factor receptor; Rbm, reticular basement membrane.

Figure 2 (A) Percentage of large-airway epithelium in CAL patients stained for EGFR compared with CAL small airway and normal control small airway. (B) Percentage of Rbm fragmentation (total length of clefts as percentage of the total length of Rbm) in large airway in CAL patients versus CAL small airway and in normal control small airway.Abbreviations: CAL, chronic airflow limitation; EGFR, epidermal growth factor receptor; Rbm, reticular basement membrane.

Figure 3 Comparison of small airway in CAL subjects with normal control.

Notes: (A) Black arrows indicate epithelium stained positive for EGFR only in CAL; (B) Rbm fragmentation and cells contained in fragmented Rbm (black arrows) only in CAL. Original magnification, ×360. Scale bar =50 µm.
Abbreviations: CAL, chronic airflow limitation; EGFR, epidermal growth factor receptor; Rbm, reticular basement membrane.
Figure 3 Comparison of small airway in CAL subjects with normal control.

Figure 4 Large-airway tissue from patient with CAL.

Notes: Black arrows indicate: (A) S100A4 and (B) vimentin-positive cells in epithelium and fragmented Rbm; (C) Black arrows indicate hypervascularity of the Rbm with Type-IV collagen-stained blood vessels in the Rbm (Type-3 EMT). (D) Black arrows indicate fragmented Rbm-containing cells. Original magnification, ×360. Scale bar =50 µm.
Abbreviations: CAL, chronic airflow limitation; EMT, epithelial mesenchymal transition; Rbm, reticular basement membrane.
Figure 4 Large-airway tissue from patient with CAL.

Figure 5 (A) Comparison of S100A4 expression in the (basal) epithelial cells of large airway in CAL patients, with small airway of CAL patients and normal control small airway. (B) Comparison of S100A4 expression in Rbm of large airway in CAL patients with small airway of CAL patients and normal control small airway.

Abbreviations: CAL, chronic airflow limitation; Rbm, reticular basement membrane.

Figure 5 (A) Comparison of S100A4 expression in the (basal) epithelial cells of large airway in CAL patients, with small airway of CAL patients and normal control small airway. (B) Comparison of S100A4 expression in Rbm of large airway in CAL patients with small airway of CAL patients and normal control small airway.Abbreviations: CAL, chronic airflow limitation; Rbm, reticular basement membrane.

Figure 6 (A) Comparison of number of basal epithelial cells positive for vimentin in CAL large airway versus CAL small airways and in normal control small airway. (B) Comparison of number of vimentin-positive cells in Rbm in CAL large airway versus CAL small airway and normal control small airway.

Abbreviations: CAL, chronic airflow limitation; Rbm, reticular basement membrane.

Figure 6 (A) Comparison of number of basal epithelial cells positive for vimentin in CAL large airway versus CAL small airways and in normal control small airway. (B) Comparison of number of vimentin-positive cells in Rbm in CAL large airway versus CAL small airway and normal control small airway.Abbreviations: CAL, chronic airflow limitation; Rbm, reticular basement membrane.

Figure 7 Small airway specimens from patients with CAL stained for EMT biomarkers and vascularity marker, compared with normal control small airway for comparison.

Notes: (A) S100A4 staining, black arrows indicate cells positive for S100A4 in Rbm and basal epithelium; (B) staining with vimentin, black arrows indicate cells positive for vimentin in basal cells and in Rbm; (C) Type-IV collagen-stained blood vessels. In small airway, vessels are seen only in lamina propria (black arrows) while Rbm is devoid of vessels. Original magnification, ×360. Scale bar =50 µm.
Abbreviations: CAL, chronic airflow limitation; EMT, epithelial mesenchymal transition; Rbm, reticular basement membrane.
Figure 7 Small airway specimens from patients with CAL stained for EMT biomarkers and vascularity marker, compared with normal control small airway for comparison.

Figure 8 Number of vessels in Rbm in large airway of CAL compared with CAL small airway and normal control small airway.

Abbreviations: CAL, chronic airflow limitation; Rbm, reticular basement membrane; NS, not significant.
Figure 8 Number of vessels in Rbm in large airway of CAL compared with CAL small airway and normal control small airway.

Table 4 Linear regression of pathological data for large and small airways from CAL subjects versus spirometric indices of airflow obstruction

Figure 9 (A) Correlation between the number of small airway basal epithelial cells (per millimeter of Rbm) that were positive for S100A4 with FEF25–75% (an index of small airway caliber). (B) Correlation between the number of S100A4-positive cells in Rbm (per millimeter of Rbm) in small airway and FEF25–75%. (C) Correlation between EGFR (% epithelium) in small airway and FEF25–75%.

Abbreviations: EGFR, epidermal growth factor receptor; FEF, forced expiratory flow; Rbm, reticular basement membrane.
Figure 9 (A) Correlation between the number of small airway basal epithelial cells (per millimeter of Rbm) that were positive for S100A4 with FEF25–75% (an index of small airway caliber). (B) Correlation between the number of S100A4-positive cells in Rbm (per millimeter of Rbm) in small airway and FEF25–75%. (C) Correlation between EGFR (% epithelium) in small airway and FEF25–75%.

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