by Vera, Laura, Garcia-Olloqui, Paula, Petri, Eva, Viñado, Ana Cristina, Valera, Pablo S., Blasco-Iturri, Zuriñe, Calvo, Isabel A., Cenzano, Itziar, Ruppert, Clemens, Zulueta, Javier J., Prosper, Felipe, Saez, Borja and Pardo-Saganta, Ana
Abstract:
Fibroblast activation includes differentiation to myofibroblast and is a key feature of organ fibrosis. The Notch pathway has been involved in myofibroblast differentiation in several tissues including the lung. Here, we identify a subset of collagen-expressing cells in the lung that exhibit Notch3 activity at homeostasis. Following injury, this activation increases, being found in $alpha$SMA-expressing myofibroblasts in the mouse and human fibrotic lung. Although previous studies suggest a contribution of Notch3 in stromal activation, in vivo evidence of the role of Notch3 in lung fibrosis remained unknown. In this study, we examine the effects of Notch3 deletion in pulmonary fibrosis and we demonstrate that Notch3-deficient lungs are protected from lung injury with significant reduced collagen deposition post-bleomycin administration. The induction of profibrotic genes is reduced in bleomycin-treated Notch3 Knock-out lungs that consistently present fewer $alpha$SMA-positive myofibroblasts. As a result, the volume of healthy lung tissue is higher and lung function is improved in the absence of Notch3. Using in vitro cultures of lung primary fibroblasts, we confirmed that Notch3 participates in their survival and differentiation. Thus, Notch3 deficiency mitigates the development of lung fibrosis due to its role in mediating fibroblast activation. Our findings reveal a previously unidentified mechanism underlying lung fibrogenesis and provide a potential novel therapeutic approach to target pulmonary fibrosis.
Reference:
Notch3 Deficiency Attenuates Pulmonary Fibrosis and Impedes Lung Function Decline (Vera, Laura, Garcia-Olloqui, Paula, Petri, Eva, Viñado, Ana Cristina, Valera, Pablo S., Blasco-Iturri, Zuriñe, Calvo, Isabel A., Cenzano, Itziar, Ruppert, Clemens, Zulueta, Javier J., Prosper, Felipe, Saez, Borja and Pardo-Saganta, Ana), In American Journal of Respiratory Cell and Molecular Biology, 2021.
Bibtex Entry:
@article{vera_notch3_2021,
	title = {Notch3 {Deficiency} {Attenuates} {Pulmonary} {Fibrosis} and {Impedes} {Lung} {Function} {Decline}},
	issn = {1535-4989},
	doi = {10.1165/rcmb.2020-0516OC},
	abstract = {Fibroblast activation includes differentiation to myofibroblast and is a key feature of organ fibrosis. The Notch pathway has been involved in myofibroblast differentiation in several tissues including the lung. Here, we identify a subset of collagen-expressing cells in the lung that exhibit Notch3 activity at homeostasis. Following injury, this activation increases, being found in $alpha$SMA-expressing myofibroblasts in the mouse and human fibrotic lung. Although previous studies suggest a contribution of Notch3 in stromal activation, in vivo evidence of the role of Notch3 in lung fibrosis remained unknown. In this study, we examine the effects of Notch3 deletion in pulmonary fibrosis and we demonstrate that Notch3-deficient lungs are protected from lung injury with significant reduced collagen deposition post-bleomycin administration. The induction of profibrotic genes is reduced in bleomycin-treated Notch3 Knock-out lungs that consistently present fewer $alpha$SMA-positive myofibroblasts. As a result, the volume of healthy lung tissue is higher and lung function is improved in the absence of Notch3. Using in vitro cultures of lung primary fibroblasts, we confirmed that Notch3 participates in their survival and differentiation. Thus, Notch3 deficiency mitigates the development of lung fibrosis due to its role in mediating fibroblast activation. Our findings reveal a previously unidentified mechanism underlying lung fibrogenesis and provide a potential novel therapeutic approach to target pulmonary fibrosis.},
	language = {eng},
	journal = {American Journal of Respiratory Cell and Molecular Biology},
	author = {Vera, Laura and Garcia-Olloqui, Paula and Petri, Eva and Vi{~n}ado, Ana Cristina and Valera, Pablo S. and Blasco-Iturri, Zuri{~n}e and Calvo, Isabel A. and Cenzano, Itziar and Ruppert, Clemens and Zulueta, Javier J. and Prosper, Felipe and Saez, Borja and Pardo-Saganta, Ana},
	month = jan,
	year = {2021},
	pmid = {33493092},
	keywords = {Fibroblast activation, Lung function, Myofibroblast differentiation, Notch3 signaling, Pulmonary fibrosis},
}