Distribution of TGF-beta isoforms and signaling intermediates in corneal fibrotic wound repair.
In this study, temporal and spatial distribution of three TGF-beta isoforms and their downstream signaling pathways including pSmad2 and p38MAPK were examined during fibrotic wound repair. In normal chick corneas, TGF-beta1, -2, and -3 were weakly detected in Bowman's layer (BL). In healing corneas, TGF-beta1 was primarily deposited in the fibrin clot and the unwounded BL. TGF-beta2 was highly expressed in healing epithelial and endothelial cells, and numerous active fibroblasts/myofibroblasts. TGF-beta3 was mainly detected in the unwound region of basal epithelial cells. alpha-Smooth muscle actin (alpha-SMA) was initially appeared in the posterior region of repairing stroma at day 3, and was detected in the entire healing stroma by day 7. Notably, alpha-SMA was absent in the central region of healing stroma by day 14, and its staining pattern was similar to those of TGF-beta2 and p38MAPK. By contrast, pSmad2 was mainly detected in the fibroblasts. In normal cornea, laminin was mainly detected in both epithelial basement membrane (BM) and Descemet's membrane (DM). By contrast to reconstitution of the BM in the wound region, the DM was not repaired although endothelial layer was regenerated, indicating that high levels of TGF-beta2 were released into the posterior region of healing stroma on day 14. High levels of alpha-SMA staining, shown in cultured repair stromal cells from healing corneas on day 14 and in TGF-beta2 treated normal stromal cells, were significantly reduced by p38MAPK inhibition. Collectively, this study suggests that TGF-beta2-mediated myofibroblast transformation is mediated, at least partly, by the p38MAPK pathway in vivo.
Huh
Man-Il
MI
Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, South Korea.
Kim
Yeoun-Hee
YH
Park
Jong-Hyuck
JH
Bae
Sung-Won
SW
Kim
Min-Hee
MH
Chang
Yongmin
Y
Kim
Song-Ja
SJ
Lee
Sun-Ryung
SR
Lee
Young-Sup
YS
Jin
Eun-Jung
EJ
Sonn
Jong-Kyung
JK
Kang
Shin-Sung
SS
Jung
Jae-Chang
JC
D055011:Ablation Techniques; D000199:Actins / Q000378:metabolism; D000375:Aging; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D050541:Bowman Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D003315:Cornea / Q000473:pathology / Q000601:surgery; D065306:Corneal Injuries; D003886:Descemet Membrane / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005355:Fibrosis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D051899:Smad2 Protein / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D005337:Fibrin; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I