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. 2021 Apr;64(4):465-476.
doi: 10.1165/rcmb.2020-0516OC.

Notch3 Deficiency Attenuates Pulmonary Fibrosis and Impedes Lung-Function Decline

Laura Vera  1 , Paula Garcia-Olloqui  1 , Eva Petri  1 , Ana Cristina Viñado  2 , Pablo S Valera  1 , Zuriñe Blasco-Iturri  3 , Isabel A Calvo  2 , Itziar Cenzano  2 , Clemens Ruppert  4 , Javier J Zulueta  5 , Felipe Prosper  1   2 , Borja Saez  2 , Ana Pardo-Saganta  1
Affiliations

Notch3 Deficiency Attenuates Pulmonary Fibrosis and Impedes Lung-Function Decline

Laura Vera et al. Am J Respir Cell Mol Biol. 2021 Apr.

Abstract

Fibroblast activation includes differentiation to myofibroblasts 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. After injury, this activation increases, being found in αSMA-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 remains unknown. In this study, we examine the effects of Notch3 deletion in pulmonary fibrosis and demonstrate that Notch3-deficient lungs are protected from lung injury with significantly reduced collagen deposition after bleomycin administration. The induction of profibrotic genes is reduced in bleomycin-treated Notch3-knockout lungs that consistently present fewer αSMA-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 because of 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.

Keywords: Notch3 signaling; fibroblast activation; lung function; myofibroblast differentiation; pulmonary fibrosis.

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Comment in

  • Notch3: A New Culprit in Fibrotic Lung Disease.
    Gajjala PR, Madala SK. Gajjala PR, et al. Am J Respir Cell Mol Biol. 2021 Apr;64(4):403-404. doi: 10.1165/rcmb.2021-0024ED. Am J Respir Cell Mol Biol. 2021. PMID: 33591242 Free PMC article. No abstract available.

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