Short-term exposure to transforming growth factor beta induces long-term fibrotic responses.
Transforming growth factor beta (TGFbeta), a potent inducer of cell transdifferentiation, is heavily implicated in fibrotic disorders. Following cataract surgery, aberrant cell growth across the collagenous matrix of the lens capsule leads to fibrosis, and in turn secondary visual loss, known as posterior capsule opacification (PCO). These modifications are associated with transdifferentiated cells. Following surgery, protein levels in the eye transiently increase, lasting a matter of days whereas PCO takes much longer to reach clinical significance. In the present study, a human lens culture model was employed to show that a relatively brief 2-day exposure to TGFbeta gives rise to persistent, long-term signalling events resulting 28 days later in matrix contraction and transdifferentiation. These events can be suppressed by application of the human monoclonal anti-TGFbeta2 antibody CAT-152 either simultaneously or after TGFbeta2 exposure. Radiolabel binding studies revealed the lens capsule serves as a store for TGFbeta2. Importantly, similar binding studies showed that the capsule could also serve as a reservoir for CAT-152. The data reveal the longevity of TGFbeta2 action through matrix association, but also demonstrate how early application of a TGFbeta2 antibody can overcome the detrimental TGFbeta actions leading to potential inhibition of PCO development and other fibrotic disorders.
Wormstone
I Michael
IM
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK. i.m.wormstone@uea.ac.uk
Anderson
Ian K
IK
Eldred
Julie A
JA
Dawes
Lucy J
LJ
Duncan
George
G
D000199:Actins / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D002386:Cataract / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000276:immunology; D005136:Eye Proteins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007903:Lens Capsule, Crystalline / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007908:Lens, Crystalline / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008858:Microscopy, Phase-Contrast / Q000379:methods; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology*
D000199:Actins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005136:Eye Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C475848:Lerdelimumab