Inhibition of activin receptor-like kinase 5 attenuates Bleomycin-induced pulmonary fibrosis

Higashiyama, Hiroyuki; Yoshimoto, Daisuke; Kaise, Toshihiko; Matsubara, Shigeki; Fujiwara, Masatoshi; Kikkawa, Hideo; Asano, Shigetaka; Kinoshita, Mine

doi:10.1016/j.yexmp.2006.12.003

Cited by 88 publications

(61 citation statements)

References 35 publications

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“…In accordance to the computational models discussed above, this is indicative of a heterogenous pattern of constriction that includes randomly distributed airway closures or near closures (138). These observations are supported by ventilation imaging studies such as hyperpolarized 3 He MRI (39,207,234), single-photon emission computed tomography (116) and positron emission tomography (169). These studies showed that asthmatics have increased ventilation heterogeneity at baseline and, even if heterogeneous airway response to a spamogen is also observed in non-asthmatics, the level of ventilation heterogeneity achieved is greater in asthmatics (39,207,234).…”

Section: Non-uniform Ventilation With Air Trapping and Ahrsupporting

confidence: 63%

“…[59] Douglas JS, Dennis MW, Ridgway P, and Bouhuys A. Airway constriction in guinea pigs: interaction of histamine and autonomic drugs. J Pharmacol Exp Ther 184: [169][170][171][172][173][174][175][176][177][178][179]1973. [60] Downie SR, Salome CM, Verbanck S, Thompson B, Berend N, and King GG.…”

Section: Referencesmentioning

confidence: 99%

“…These apparent chronic differences may be due to the initial extent of acute lung injury immediately following TGF overexpression, in that transgenic mediated TGF induces extensive apoptosis, whereby blocking apoptosis inhibits subsequent fibrosis 165 . Blockade of TGF in experimental models of lung fibrosis through either antibody neutralization, receptor inhibition of TGF activation has been shown to attenuate lung remodelling 99,100,[168][169][170] . However, TGF1 gene deficient mice die within 3-4 weeks of age and demonstrate significant autoimmune pathologies, potentially due to the lack of immunoregulation in the absence of TGF 171,172 .…”

Section: Therapeutic Options For Targeting Pro-fibrotic Cellsmentioning

confidence: 99%

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Lung Diseases - Selected State of the Art Reviews

Irusen¹

2012

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Section: Non-uniform Ventilation With Air Trapping and Ahrsupporting

confidence: 63%

Section: Referencesmentioning

confidence: 99%

Section: Therapeutic Options For Targeting Pro-fibrotic Cellsmentioning

confidence: 99%

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Lung Diseases - Selected State of the Art Reviews

Irusen¹

2012

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“…It is established that fibroblasts transdifferentiate to myofibroblasts that express elevated levels of ␣-smooth muscle actin and, consequently, display a markedly enhanced ability to secrete extracellular matrix proteins (57)(58)(59). Among several mediators, TGF-␤ is the major cytokine associated with pulmonary fibrosis; it is involved in the transition of fibroblasts into myofibroblasts (60), the synthesis of matrix proteins, and collagen degradation inhibition (61,62). Our results show that ATLa reduced BLM-induced myofibroblast accumulation/differentiation in the lung.…”

Section: Discussionmentioning

confidence: 99%

ATLa, an Aspirin-Triggered Lipoxin A4 Synthetic Analog, Prevents the Inflammatory and Fibrotic Effects of Bleomycin-Induced Pulmonary Fibrosis

Martins¹,

Farias-Filho

Molinaro³

et al. 2009

The Journal of Immunology

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Despite an increase in the knowledge of mechanisms and mediators involved in pulmonary fibrosis, there are no successful therapeutics available. Lipoxins (LX) and their 15-epimers, aspirin-triggered LX (ATL), are endogenously produced eicosanoids with potent anti-inflammatory and proresolution effects. To date, few studies have been performed regarding their effect on pulmonary fibrosis. In the present study, using C57BL/6 mice, we report that bleomycin (BLM)-induced lung fibrosis was prevented by the concomitant treatment with an ATL synthetic analog, ATLa, which reduced inflammation and matrix deposition. ATLa inhibited BLM-induced leukocyte accumulation and alveolar collapse as evaluated by histology and morphometrical analysis. Moreover, Sirius red staining and lung hydroxyproline content showed an increased collagen deposition in mice receiving BLM alone that was decreased upon treatment with the analog. These effects resulted in benefits to pulmonary mechanics, as ATLa brought to normal levels both lung resistance and compliance. Furthermore, the analog improved mouse survival, suggesting an important role for the LX pathway in the control of disease establishment and progression. One possible mechanism by which ATLa restrained fibrosis was suggested by the finding that BLM-induced myofibroblast accumulation/differentiation in the lung parenchyma was also reduced by both simultaneous and posttreatment with the analog (α-actin immunohistochemistry). Interestingly, ATLa posttreatment (4 days after BLM) showed similar inhibitory effects on inflammation and matrix deposition, besides the TGF-β level reduction in the lung, reinforcing an antifibrotic effect. In conclusion, our findings show that LX and ATL can be considered as promising therapeutic approaches to lung fibrotic diseases.

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“…bleomycin-induced lung injury and fibrosis, which is known to be TGF-b1/SMAD3 dependent (36,37). We achieved in vivo knockdown of CCN1 in the lung utilizing intranasal delivery of CCN1 siRNA, as previously described by our group (20) and others (38).…”

Section: Ccn1 Knockdown Attenuates Smad3 Signalingmentioning

confidence: 99%

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Kurundkar

Rangarajan

et al. 2016

FASEB j.

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Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-b1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-b1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-b1/SMAD3 signaling that promotes lung

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Inhibition of activin receptor-like kinase 5 attenuates Bleomycin-induced pulmonary fibrosis

Cited by 88 publications

References 35 publications

Lung Diseases - Selected State of the Art Reviews

Lung Diseases - Selected State of the Art Reviews

ATLa, an Aspirin-Triggered Lipoxin A4 Synthetic Analog, Prevents the Inflammatory and Fibrotic Effects of Bleomycin-Induced Pulmonary Fibrosis

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

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