KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

Andreas Günther

Prof. Dr. med. Andreas Günther

Justus Liebig University Giessen
Department of Internal Medicine
Klinikstrasse 31; 35392 Giessen

+49-641-99-42502
Saverio Bellusci

Prof. Dr. rer. nat. Saverio Bellusci

Justus Liebig University Giessen
Excellence Cluster „Cardiopulmonary System“ 
Aulweg 130, 35392 Giessen

+49-641-99-46730

Role of epithelial endoplasmic reticulum stress and epithelial FGF signaling in the initiation and aggravation of lung fibrosis by viral infection

Summary

Idiopathic Pulmonary Fibrosis (IPF) is an aggressive form of lung fibrosis with poor prognosis. Respiratory infections seem to trigger the initiation and aggravation of IPF; however, the detailed mechanisms underlying these processes are poorly understood. Proapoptotic ER-stress is observed in alveolar epithelial cells type II (AECII) of IPF patients and largely contributes to AECII apoptosis and lung fibrosis. Fibroblast growth factors (FGFs) play a key role during organogenesis and repair after lung injury, and we recently identified that FGF10 protects AECII and attenuates fibrosis induction in a murine model of lung fibrosis induced by bleomycin. 

We therefore hypothesize that maladaptive ER stress in IPF raises the susceptibility of AECII to viral infections and, at the same time, enhances the readiness to execute apoptosis thereby triggering the fibrotic response. We also hypothesize that exogenous FGF10 prevents maladaptive ER stress in the alveolar epithelium in viral infection, thereby protecting the cells from apoptosis, and that endogenous Fgf10 is critical to maintain the appropriate alveolar epithelial stem cell pool size mandatory for regeneration, thus rendering it a highly attractive candidate for therapy. We will therefore
i) assess the impact of respiratory virus infection on survival and pro-fibrotic signaling of AECs with different states of ER-stress in vitro and ex vivo, including primary cells or lung explants from IPF patients; . We will
ii) study the consequences of such pre-existing ER-stress conditions on viral replication and viral protein synthesis; and
iii) analyze which transcriptional programs in fibrotic AEC II are associated with impaired recruitment of endogenous (anti-fibrotic) FGF signaling.
Finally, using different transgenic mouse models with cell-specific gain- and loss-of-function, we will
iv) determine the impact of endogenous deletion or overexpression of components of the FGF10 signaling cascade on the AECII cell fate and on fibroproliferative events in response to primary ER stress induction in the context of secondary viral infection.

Ultimately, this project is envisioned to elucidate mechanisms of virus-induced aggravation of lung fibrosis, and to reveal novel putative treatment targets, including the FGF10 signaling pathway, to attenuate this process in IPF patients.

Publications

Origin and Characterization of Alpha Smooth Muscle Actin-Positive Cells During Murine Lung Development

Stem Cells 2017 35(6):1566-1578 dog:10.1002/stem.2615 Epub 2017 Apr 4

Principal Investigators

Andreas Günther

Prof. Dr. med. Andreas Günther

Justus Liebig University Giessen
Department of Internal Medicine
Klinikstrasse 31; 35392 Giessen

+49-641-99-42502
Saverio Bellusci

Prof. Dr. rer. nat. Saverio Bellusci

Justus Liebig University Giessen
Excellence Cluster „Cardiopulmonary System“ 
Aulweg 130, 35392 Giessen

+49-641-99-46730

Project group

  • Roxana Wasnick

    Dr. Roxana Wasnick

    Postdoc

  • Martina Korfei

    Dr. Martina Korfei

    Postdoc

  • Irina Shalashova

    Irina Shalashova

  • Cho-Ming Chao

    Dr. Cho-Ming Chao

  • Silke Händel

    Silke Händel

    Technician

  • Simone Becker

    Simone Becker

    Technician

  • Kerstin Goth

    Kerstin Goth

    Technician