Transforming growth factor-β receptor type 1 (TGFβRI) kinase activity but not p38 activation is required for TGFβRI-induced myofibroblast differentiation and profibrotic gene expression

Ann M. Kapoun, Nicholas J. Gaspar, Ying Wang, Debby Damm, Yu Wang Liu, Gilbert O'Young, Diana Quon, Andrew Lam, Kimberly Munson, Thomas Toan Tran, Ying Ma Jing, Alison Murphy, Sundeep Dugar, Sarvajit Chakravarty, Andrew A. Protter, Fu Qiang Wen, Xiang-de Liu, Stephen I. Rennard, Linda Slanec Higgins

Research output: Contribution to journalArticle

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Abstract

Transforming growth factor-β (TGFβ) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFβ also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFβRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFβRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGFβ-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGFβ-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)518-531
Number of pages14
JournalMolecular pharmacology
Volume70
Issue number2
DOIs
StatePublished - Jul 26 2006

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Myofibroblasts
Growth Factor Receptors
Transforming Growth Factors
Phosphotransferases
Gene Expression
Fibrosis
Lung
Collagen
Fibroblasts
Idiopathic Pulmonary Fibrosis
Pulmonary Fibrosis
Interstitial Lung Diseases
Bleomycin
Dermatoglyphics
Microarray Analysis
Mitogens
Wound Healing
SD-208
Gels
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Transforming growth factor-β receptor type 1 (TGFβRI) kinase activity but not p38 activation is required for TGFβRI-induced myofibroblast differentiation and profibrotic gene expression. / Kapoun, Ann M.; Gaspar, Nicholas J.; Wang, Ying; Damm, Debby; Liu, Yu Wang; O'Young, Gilbert; Quon, Diana; Lam, Andrew; Munson, Kimberly; Tran, Thomas Toan; Jing, Ying Ma; Murphy, Alison; Dugar, Sundeep; Chakravarty, Sarvajit; Protter, Andrew A.; Wen, Fu Qiang; Liu, Xiang-de; Rennard, Stephen I.; Higgins, Linda Slanec.

In: Molecular pharmacology, Vol. 70, No. 2, 26.07.2006, p. 518-531.

Research output: Contribution to journalArticle

Kapoun, AM, Gaspar, NJ, Wang, Y, Damm, D, Liu, YW, O'Young, G, Quon, D, Lam, A, Munson, K, Tran, TT, Jing, YM, Murphy, A, Dugar, S, Chakravarty, S, Protter, AA, Wen, FQ, Liu, X, Rennard, SI & Higgins, LS 2006, 'Transforming growth factor-β receptor type 1 (TGFβRI) kinase activity but not p38 activation is required for TGFβRI-induced myofibroblast differentiation and profibrotic gene expression', Molecular pharmacology, vol. 70, no. 2, pp. 518-531. https://doi.org/10.1124/mol.105.021600
Kapoun, Ann M. ; Gaspar, Nicholas J. ; Wang, Ying ; Damm, Debby ; Liu, Yu Wang ; O'Young, Gilbert ; Quon, Diana ; Lam, Andrew ; Munson, Kimberly ; Tran, Thomas Toan ; Jing, Ying Ma ; Murphy, Alison ; Dugar, Sundeep ; Chakravarty, Sarvajit ; Protter, Andrew A. ; Wen, Fu Qiang ; Liu, Xiang-de ; Rennard, Stephen I. ; Higgins, Linda Slanec. / Transforming growth factor-β receptor type 1 (TGFβRI) kinase activity but not p38 activation is required for TGFβRI-induced myofibroblast differentiation and profibrotic gene expression. In: Molecular pharmacology. 2006 ; Vol. 70, No. 2. pp. 518-531.
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abstract = "Transforming growth factor-β (TGFβ) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFβ also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFβRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFβRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGFβ-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGFβ-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.",
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AU - Kapoun, Ann M.

AU - Gaspar, Nicholas J.

AU - Wang, Ying

AU - Damm, Debby

AU - Liu, Yu Wang

AU - O'Young, Gilbert

AU - Quon, Diana

AU - Lam, Andrew

AU - Munson, Kimberly

AU - Tran, Thomas Toan

AU - Jing, Ying Ma

AU - Murphy, Alison

AU - Dugar, Sundeep

AU - Chakravarty, Sarvajit

AU - Protter, Andrew A.

AU - Wen, Fu Qiang

AU - Liu, Xiang-de

AU - Rennard, Stephen I.

AU - Higgins, Linda Slanec

PY - 2006/7/26

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N2 - Transforming growth factor-β (TGFβ) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFβ also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFβRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFβRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGFβ-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGFβ-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.

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