Increased myofibroblasts in the small airways, and relationship to remodelling and functional changes in smokers and COPD patients: potential role of epithelial–mesenchymal transition

Mathew Suji Eapen, Wenying Lu, Tillie L. Hackett, Gurpreet Kaur Singhera, Malik Q. Mahmood, Ashutosh Hardikar, Chris Ward, Eugene Haydn Walters, Sukhwinder Singh Sohal
ERJ Open Research 2021 7: 00876-2020; DOI: 10.1183/23120541.00876-2020

Figures

  • FIGURE 1
    FIGURE 1

    Representative images of the full airway wall thickness in the small airway wall of a) normal control (NC) and b) COPD. An increase in thickness was observed in the clinical (smoker/COPD) groups in the c) lamina propria (LP), d) adventitia and e) smooth muscle (SM) layer. NLFS: normal lung function smoker; COPD-CS: COPD current smoker; COPD-ES: COPD ex-smoker. Scale bars=50 μm. **: p<0.01, ***: p<0.001.

  • FIGURE 2
    FIGURE 2

    Correlation between airway wall thickness and lung function indices: a) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and b) forced expiratory flow at 25–75% of FVC (FEF25–75%) (more specific for small airways (SA)) in the combined COPD groups. LP: lamina propria.

  • FIGURE 3
    FIGURE 3

    Representative images of α-smooth muscle actin (SMA)+ cells in the airway wall of a) normal control (NC), normal lung function smoker (NLFS) and COPD current (CS) and ex-smokers (ES). Increase in small airway (SA) αSMA+ cells were observed in all three sublayers of the subepithelial areas of the small airway wall: b) reticular basement membrane (Rbm); c) lamina propria (LP); and d) adventitia. Scale bars=50 μm. *: p<0.05, **: p<0.01, ***: p<0.001.

  • FIGURE 4
    FIGURE 4

    Representative images of collagen-1 and fibronectin deposition by percentage area in the airway wall of a) normal control (NC), normal lung function smoker (NLFS) and COPD current (CS) and ex-smokers (ES), with increases in percentage collagen-1 and fibronectin expression in pathological groups in both the b,d) lamina propria (LP) and c,e) adventitia, with both CS and COPD effects. SA: small airway. Scale bars=50 μm. *: p<0.05, **: p<0.01, ***: p<0.001.

  • FIGURE 5
    FIGURE 5

    Correlations between α-smooth muscle actin (SMA)+ myofibroblasts in the a, c) reticular basement membrane (Rbm) and b, d) lamina propria (LP) of the three smoking/COPD groups (normal lung function smoker (NLFS) and COPD current (CS) and ex-smokers (ES)) and indices of airflow, done independently: a, b) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and c, d) forced expiratory flow at 25–75% of FVC (FEF25–75%); e) correlation between number of myofibroblasts and thickness of LP among the combined pathological groups. SA: small airway; r′: Spearman's r.

  • FIGURE 6
    FIGURE 6

    Correlations between the epithelial–mesenchymal transition (EMT) marker S100A4+ expression in the a) basal epithelial cells and b) reticular basement membrane (Rbm), with α-smooth muscle actin (SMA)+ cells within both small airway (SA) wall and the Rbm; and between the two EMT markers c) S100A4 and d) vimentin expressed in basal epithelial cells and lamina propria (LP) thickening.

Tables

  • TABLE 1

    Patient demographics

    NCNLFSCOPD-CSCOPD-ES
    Subjects1011910
    Age years50 (19–73)69 (52–79)**65 (59–78)**68 (56–85)**
    Smoking history pack-yearsNS27 (0.3–40)30 (2–48)30 (2–58)
    FEV1/FVC %#N/A76 (70–90)66 (59.9–70)64 (55–69)
    FEF25–75%#N/A79 (47–116)37 (28–47)41 (20–55)

    Data are presented as n or median (range). NC: normal control; NLFS: normal lung function smoker; COPD-CS: COPD current smoker; COPD-ES: COPD ex-smoker; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF25–75%: forced expiratory flow at 25–75% of FVC; NS: nonsmokers; N/A: not available. #: post-bronchodilator values after 400 µg salbutamol. **: p<0.01 over NC (ordinary one-way ANOVA followed by Dunnett's multiple comparison test).

    • TABLE 2

      Correlation of extracellular matrix proteins (collagen-1 and fibronectin) with lung function and small airway lamina propria thickness

      NLFSCOPD-CSCOPD-ES
      Collagen-1 in lamina propria area versus lung function (FEV1/FVC)r′=−0.64
      p<0.05      		r′=0.35
      p-value ns
      Fibronectin in lamina propria area versus lung function (FEV1/FVC)r′=0.35
      p-value ns      		r′=0.007
      p-value ns
      Collagen-1 in lamina propria area versus airway wall lamina propria thickness (μm)r′=0.05
      p-value ns      		r′=0.59
      p<0.05      		r′=0.37
      p<0.05
      Fibronectin in lamina propria area versus airway wall lamina propria thickness (μm)r′=0.4
      p-value ns      		r′=−0.01
      p-value ns      		r′=−0.01
      p-value ns

      NLFS: normal lung function smoker; COPD-CS: COPD current smoker; COPD-ES: COPD ex-smoker; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; r′: Spearman's r; ns: nonsignificant.

      Supplementary Materials

      • Supplementary Material

        Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

        Supplementary material 00876-2020.SUPPLEMENT

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      Increased myofibroblasts in the small airways, and relationship to remodelling and functional changes in smokers and COPD patients: potential role of epithelial–mesenchymal transition
      Mathew Suji Eapen, Wenying Lu, Tillie L. Hackett, Gurpreet Kaur Singhera, Malik Q. Mahmood, Ashutosh Hardikar, Chris Ward, Eugene Haydn Walters, Sukhwinder Singh Sohal
      ERJ Open Research Apr 2021, 7 (2) 00876-2020; DOI: 10.1183/23120541.00876-2020
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