Modulation of Prosurvival Signaling in Fibroblasts by a Protein Kinase Inhibitor Protects against Fibrotic Tissue Injury

Vittal, Ragini; Horowitz, Jeffrey C.; Moore, Bethany B.; Zhang, Hengmin; Martínez, Fernando J.; Toews, Galen B.; Standiford, Theodore J.; Thannickal, Victor J.

doi:10.1016/s0002-9440(10)62260-2

Cited by 116 publications

(117 citation statements)

References 49 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…Stimulation of fibroblasts with endothelin-1 promotes enhanced contractile phenotype or activation, this is prevented by blockade of the PI3K/Akt pathway. 54 In agreement with this Vittal and colleagues 55 observed that inhibition of PKB/Akt in bleomycin-induced lung fibrosis markedly reduced accumulation of ␣-smooth muscle actin-expressing myofibroblasts.…”

Section: Discussionsupporting

confidence: 70%

Lipoxin A4 Modifies Platelet-Derived Growth Factor-Induced Profibrotic Gene Expression in Human Renal Mesangial Cells

Rodgers

McMahon

Mitchell

et al. 2005

The American Journal of Pathology

View full text Add to dashboard Cite

Lipoxins (LXs), endogenously produced eicosanoids, possess potent anti-inflammatory, proresolution bioactivities. We investigated the potential of LXA 4 (1 to 10 nmol/L) to modify the effects of platelet-derived growth factor (PDGF)-induced gene expression in human renal mesangial cells (hMCs). Using oligonucleotide microarray analysis we profiled profibrotic cytokines and matrix-associated genes induced in response to PDGF. LXA 4 modulated the expression of many PDGF-induced genes, including transforming growth factor-␤1, fibronectin, thrombospondin, matrix metalloproteinase 1, and several collagens. Analysis of both transcript and protein levels confirmed these findings. Because the activated glomerulus is frequently a source of injurious mediators that contribute to tubulointerstitial damage, we investigated the effect of hMC-secreted products on the integrity of renal proximal tubular epithelial cells using an in vitro model of progressive renal disease. Cell supernatant from PDGF-stimulated hMCs caused morphological and genetic changes in proximal tubular epithelial cells, consistent with a profibrotic phenotype. Interestingly, supernatant from cells pre-exposed to LXA 4 and PDGF did not induce these effects. These results suggest a novel role for LXA 4

show abstract

Section: Discussionsupporting

confidence: 70%

Lipoxin A4 Modifies Platelet-Derived Growth Factor-Induced Profibrotic Gene Expression in Human Renal Mesangial Cells

Rodgers

McMahon

Mitchell

et al. 2005

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Our observations that the PI3K-AKT and integrin-FAK pathways are activated in a combinatorial manner by TGF-β1 to promote myofibroblast survival have important implications for broader understanding of dysregulated tissue repair and fibrotic diseases. Recent studies from our laboratory have shown that both FAK and AKT activation are increased in areas of active fibrogenesis following acute lung injury in mice [46]. Treatment with a protein tyrosine kinase inhibitor that blocks TGF-β1-activation of FAK and AKT in lung fibroblasts is protective against the development of fibrosis in this animal model [46].…”

Section: Discussionmentioning

confidence: 82%

“…Recent studies from our laboratory have shown that both FAK and AKT activation are increased in areas of active fibrogenesis following acute lung injury in mice [46]. Treatment with a protein tyrosine kinase inhibitor that blocks TGF-β1-activation of FAK and AKT in lung fibroblasts is protective against the development of fibrosis in this animal model [46]. Additionally, we have shown that alveolar mesenchymal cells isolated from patients with non-resolving (fibrotic/persistent) acute respiratory distress syndrome (ARDS) demonstrate high levels of AKT activation and resistance to apoptosis compared to mesenchymal cells from patients with resolving ARDS [47].…”

Section: Discussionmentioning

confidence: 99%

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

Self Cite

224

177

View full text Add to dashboard Cite

Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

show abstract

“…It is not known if restoration of fibroblast apoptosis can mitigate fibrotic lung disease in vivo, but several studies provide proof of principal that modulation of signaling pathways involved in fibroblast resistance to apoptosis can attenuate fibrogenesis in murine models (53)(54)(55)(56)(57). Our findings suggest that XIAP antagonists may have therapeutic potential in disease processes characterized by fibroblast accumulation and fibrosis, although it will be critical to determine the impact of these antagonists on other cell populations before translating this strategy to patient care.…”

Section: Discussionmentioning

confidence: 83%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E 2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fasmediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.Keywords: myofibroblast; idiopathic pulmonary fibrosis; inhibitor of apoptosis; lung fibrosis; apoptosis Mesenchymal cells display a dynamic spectrum of phenotypes ranging between an undifferentiated state (fibroblast) and a differentiated state (myofibroblast) (1, 2). Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3, 4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5, 6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7-12).Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology that is characterized by progressive alveolar fibrosis (13,14). The overall prognosis of patie...

show abstract

Modulation of Prosurvival Signaling in Fibroblasts by a Protein Kinase Inhibitor Protects against Fibrotic Tissue Injury

Abstract: Inflammation and repair are stereotypical host responses to injury of adult mammalian tissues. Dysregulation of either of these processes may lead to pathological outcomes resulting in varying degrees of chronic inflammation and fibrosis.

Cited by 116 publications

References 49 publications

Lipoxin A4 Modifies Platelet-Derived Growth Factor-Induced Profibrotic Gene Expression in Human Renal Mesangial Cells

Lipoxin A4 Modifies Platelet-Derived Growth Factor-Induced Profibrotic Gene Expression in Human Renal Mesangial Cells

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Contact Info

Product

Resources

About