Table 1.
Demographics.
Figure 1.
Increased TGF-β signaling in lung tissue from cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) compared to non-CF human normal lung tissue (HNL).
A) Immunohistochemical staining for phosphorylated Smad2 (pSmad2 shown in brown). The downstream signal of TGF-β is significantly increased in CF compared to HNL tissue and comparable to that seen in IPF. Images are shown at approximately 100× from 2 separate CF, HNL and IPF specimens (bar = 250 µm). B) Comparison of TGF-β signaling (pSmad2 staining) by semiquantitative score (1–5). C) Comparison of TGF-β signaling (pSmad2 expression) by quantitative morphometry. D) Correlation between semiquantitative scale (1–5 scale) and morphometric measures of pSmad2.
Figure 2.
Increased peripheral lung fibrosis in cystic fibrosis (CF).
A) Histochemical staining for fibrosis (Masson trichrome stain, collagen shown in blue) in human normal lung (HNL), cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF). Images are shown at approximately 100× from 2 separate HNL, CF and IPF specimens (bar = 250 µm). B) Comparison of collagen deposition (Masson trichrome stain) by semiquantitative analysis and C) quantitative morphometry. D) Correlation between quantitative morphometry (% collagen deposition) and semiquantitative analysis (1–5 scale).
Figure 3.
Myofibroblast differentiation in human normal (HNL), cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) lung tissue.
A) Immunohistochemical staining for α-smooth muscle actin (α-SMA), the contractile element in myofibrobroblasts. Myofibroblast accumulation is significantly accentuated in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) compared to non-diseased controls. Images at 100× (bar = 250 µm). B) Comparison of myofibroblast differentiation in HNL, CF and IPF lung tissue analyzed semi-quantitatively. C) Comparison of myofibroblast differentiation in HNL, CF and IPF lung tissue analyzed by quantitative morphology. D) Correlation between semiquantitative and quantitative measures of myofibroblast differentiation in HNL, CF and IPF lung tissue specimens. E) Myofibroblast differentiation versus tissue fibrosis in HNL, CF and IPF lung tissue specimens.
Figure 4.
Association between TGF-β signaling, myofibroblast differentiation and tissue fibrosis.
A) Myofibroblast differentiation is significantly increased in lung tissue with increased TGF-β signaling (defined as ≥ positive control on semiquantitative scale) B) Lung fibrosis is similarly increased in lung tissue with increased TGF-β signaling.
Figure 5.
Schematic model depicting myofibroblast differentiation in cystic fibrosis (CF).
TGF-β signaling and mechanostimulation in CF lungs induce precursor cells such as resident fibroblasts to undergo myofibroblast differentiation. TGF-β activation is robust and likely multifactorial due to well-established mechanisms including integrin expression and proteases such as the matrix metalloproteases (MMPs). Mechanical strain (e.g. from luminal obstruction, tissue fibrosis and persistent coughing) further augments TGF-β activation and contributes to development and persistence of the myofibroblast phenotype. Sources of myofibroblast precursors include resident lung tissue fibroblasts, circulating fibrocytes, epithelial mesenchymal transition (EMT) or endothelial mesenchymal transition (EndMT). Persistence of the myofibroblast leads to progressive tissue fibrosis with collagen production, extracellular matrix synthesis and tissue contracture.