TY - JOUR
T1 - Induction of lung fibroblast apoptosis by soluble fibronectin peptides
AU - Hadden, Hélène Levrey
AU - Henke, Craig A
PY - 2000
Y1 - 2000
N2 - Despite the importance of fibroproliferative lung disorders, no safe and effective therapies exist for reducing the size of the fibroblast population in existing fibrotic lesions. Recent work suggests that therapies that promote fibroblast apoptosis during the repair phase following lung injury may facilitate lung repair by eliminating excess fibrotic tissue. We report here our finding that three soluble fibronectin peptides (RGD, CS-1, and FN-C/H-V) induce apoptosis in lung fibroblasts. Fibroblast susceptibility to these peptides was dose and time dependent, with a maximal effect observed at 96 h (87 ± 16% [mean ± SEM] apoptosis). The peptides were able to induce fibroblast apoptosis in fibrin gels, an in vitro model of early fibroproliferative lesions. Fibroblasts were difficult to kill. All three peptides were required for maximal apoptosis of anchored cells. Apoptosis occurred by disruption of adhesion (anoikis). Treatment of fibroblasts with peptides caused proteolysis of pp125FAK, a tyrosine kinase involved in integrin-mediated signaling related to cell survival. These data show that soluble fibronectin peptides trigger nontransformed fibroblast apoptosis in routine culture and in fibrin gels by a mechanism that includes disruption of an integrin-mediated survival signaling pathway. The use of small fibronectin peptides to promote fibroblast apoptosis warrants further study as possible antifibrotic therapy.
AB - Despite the importance of fibroproliferative lung disorders, no safe and effective therapies exist for reducing the size of the fibroblast population in existing fibrotic lesions. Recent work suggests that therapies that promote fibroblast apoptosis during the repair phase following lung injury may facilitate lung repair by eliminating excess fibrotic tissue. We report here our finding that three soluble fibronectin peptides (RGD, CS-1, and FN-C/H-V) induce apoptosis in lung fibroblasts. Fibroblast susceptibility to these peptides was dose and time dependent, with a maximal effect observed at 96 h (87 ± 16% [mean ± SEM] apoptosis). The peptides were able to induce fibroblast apoptosis in fibrin gels, an in vitro model of early fibroproliferative lesions. Fibroblasts were difficult to kill. All three peptides were required for maximal apoptosis of anchored cells. Apoptosis occurred by disruption of adhesion (anoikis). Treatment of fibroblasts with peptides caused proteolysis of pp125FAK, a tyrosine kinase involved in integrin-mediated signaling related to cell survival. These data show that soluble fibronectin peptides trigger nontransformed fibroblast apoptosis in routine culture and in fibrin gels by a mechanism that includes disruption of an integrin-mediated survival signaling pathway. The use of small fibronectin peptides to promote fibroblast apoptosis warrants further study as possible antifibrotic therapy.
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U2 - 10.1164/ajrccm.162.4.2001015
DO - 10.1164/ajrccm.162.4.2001015
M3 - Article
C2 - 11029376
AN - SCOPUS:0033769831
SN - 1073-449X
VL - 162
SP - 1553
EP - 1560
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 4 I
ER -