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Narrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel Therapies

Joel Rosenbloom, MD, PhD; Susan V. Castro, PhD; and Sergio A. Jimenez, MD
[+] Article, Author, and Disclosure Information

From Thomas Jefferson University, Philadelphia, Pennsylvania.

Grant Support: By the National Institutes of Health (grant RO1 AR019616; Dr. Jimenez).

Potential Conflicts of Interest: None disclosed.

Requests for Single Reprints: Sergio A. Jimenez, MD, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 South 10th Street, Room 509, Bluemle Life Science Building, Philadelphia, PA 19107-5541; e-mail, sergio.jimenez@jefferson.edu.

Current Author Addresses: Drs. Rosenbloom, Castro, and Jimenez: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 South 10th Street, Room 509, Bluemle Life Science Building, Philadelphia, PA 19107-5541.

Author Contributions: Conception and design: J. Rosenbloom, S.V. Castro, S.A. Jimenez.

Analysis and interpretation of the data: J. Rosenbloom, S.A. Jimenez.

Drafting of the article: J. Rosenbloom, S.V. Castro, S.A. Jimenez.

Critical revision of the article for important intellectual content: J. Rosenbloom, S.A. Jimenez.

Final approval of the article: J. Rosenbloom, S.V. Castro, S.A. Jimenez.

Obtaining of funding: S.A. Jimenez.

Administrative, technical, or logistic support: S.V. Castro.

Collection and assembly of data: J. Rosenbloom, S.A. Jimenez.

Ann Intern Med. 2010;152(3):159-166. doi:10.7326/0003-4819-152-3-201002020-00007
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Abnormal and exaggerated deposition of extracellular matrix is the hallmark of many fibrotic diseases, including systemic sclerosis and pulmonary, liver, and kidney fibrosis. The spectrum of affected organs, the usually progressive nature of the fibrotic process, the large number of affected persons, and the absence of effective treatment pose an enormous challenge when treating fibrotic diseases. Delineation of the central role of transforming growth factor-β (TGF-β) and identification of the specific cellular receptors, kinases, and other mediators involved in the fibrotic process have provided a sound basis for development of effective therapies. The inhibition of signaling pathways activated by TGF-β represents a novel therapeutic approach for the fibrotic disorders. One of these TGF-β pathways results in the activation of the nonreceptor tyrosine kinase cellular Abelson (c-Abl), and c-Abl inhibitors, including imatinib mesylate, diminishing the fibrogenic effects of TGF-β. Thus, recently acquired basic knowledge about the pathogenesis of the fibrotic process has enabled the development of novel therapeutic agents capable of modifying the deleterious effects of the fibrotic diseases.


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Figure 1.
TGF-β signaling pathways critical for the fibrotic response.

This figure illustrates classic and nonclassic pathways originating from 2 representative tetrameric TGF-β receptors. After TGF-β binding, TGF-βRII recruits a TGF-βRI (either ALK-1 or ALK-5) and activates it by phosphorylation. ALK-5 then specifically phosphorylates receptor-regulated Smad2 and Smad3, which then complex with co-Smad4, resulting in their transport to the nucleus, where they cooperate with other factors to regulate transcription of critical genes, here represented by genes encoding CTGF and α1 and α2 type I collagens. Also illustrated are several nonclassic pathways. An important one involves the phosphorylation and activation of c-Abl by ALK-1, causing activation of several downstream critical factors, including Smad1; the transcription factor, EgR, and PKC-δ, all of which contribute to the fibrotic response. As pictured, imatinib blocks the activity of c-Abl, effectively inhibiting the fibrotic response by preventing the activation of downstream effectors. ALK = activin-like kinase; c-Abl = cellular Abelson nonreceptor kinase; CTGF = connective tissue growth factor; EgR = early growth response protein; P = phosphorylation; PKC-δ = protein kinase C-δ; TGF-β = transforming growth factor-β; TGF-βRII = TGF-β type II receptor.

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Figure 2.
Model for involvement of caveolae in TGF-β signal transduction and downregulation resulting in fibrosis and caveolin-1 downregulation.

Receptors activated by TGF-β can be internalized through 2 distinct endocytic pathways. The nonlipid raft pathway (green) increases TGF-β–related signal transduction, leading to tissue fibrosis and simultaneous transcriptional downregulation of Cav-1 gene expression, thus generating a vicious cycle that increases and perpetuates tissue fibrosis. In contrast, the Cav-1–positive lipid raft compartment (red) drives TGF-β receptor degradation, which prevents tissue fibrosis. Cav-1 = caveolin-1; CTGF = connective tissue growth factor; P = phosphorylation; TGF-β = transforming growth factor-β; TGF-βR = TGF-β receptor.

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Figure 3.
Model illustrating the inhibition of c-Abl by imatinib.

In the absence of imatinib, c-Abl binds ATP and activates substrate effector molecules by phosphorylation. Imatinib blocks the ATP binding site of c-Abl, effectively inhibiting its kinase activity. ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphorylation.

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