Our
research focuses on alveolar fibroblasts during septation and bronchiolar
fibrosis after epithelial injury. Our projects strive to understand the
cellular and molecular mechanisms related to the pathology of lung diseases,
like bronchopulmonary dysplasia (BPD), emphysema, chronic obstructive pulmonary
disease (COPD) and bronchiolitis obliterans (BOS). We use state of the art
transgenic mouse models to provide novel and innovative tools to enable studies
of complex molecular pathways and lineage relationships, in lung development
and diseases. Jenna Green established immunofluorescence staining protocols for
adult mouse lung that allow 3d high resolution confocal imaging.
Our histological approach is complemented by sophisticated flow cytometry to
identify subpopulations of pulmonary fibroblasts, which was established by Leiling
Chen, PhD. We have
two major focuses in the lab:
- Role of
myofibroblast differentiation during alveolar septation: Arrest of alveolarization in
infants with BPD and loss of alveolar surface area in patients with COPD, pose
enormous public health burdens. Transgenic mice offer unique opportunities to
explore cellular and molecular mechanisms of compensatory lung growth that
might be useful in the future to increase the limited potential of adaptive
growth in human lungs. Our long-term goal is to identify the signaling pathways
that regulate the formation of new alveolar septae. We identified a critical
role for the interstitial myofibroblast in alveolar regeneration and are
currently funded by the NIH to study neo-alveolarization during compensatory
lung regrowth. We are in the course of 1) identifying roles of lung resident
fibroblast populations, 2) identifying genes that regulate fibroblast differentiation
and 3) determining the key pathways that are involved in alveolar regeneration.
- Epithelial
injury results in airway fibrosis and allograft rejection: Bronchiolitis obliterans is a
fatal lung syndrome responsible for graft failure in most lung transplant
recipients. BOS is characterized by loss of epithelial integrity and airway fibrosis.
The long-term goal of this project is to identify epithelial-mesenchymal
interactions that facilitate proper lung repair and prevention of airway wall
fibrosis. My laboratory has developed a conditional transgenic mouse model to
induce diphtheria toxin mediated cell death specifically in bronchiolar Clara
cells. We are using this mouse model to study 1) bronchiolar stem cells, 2)
molecular mechanisms responsible for bronchiolar regeneration after acute
injury and 3) airway wall fibrosis after chronic injury. Ourrecent studies demonstrated that
excessive Clara cell depletion results in neutrophil and dendritic cell
recruitment and subsequent chronic lung inflammation. In collaboration with Drs.
Gelman and Huang from Washington University in St Louis we are currently investigating
how established lung allografts undergo graft rejection after Clara cell injury. In collaboration with Drs. Klepetko
and Aigner from the Medical University in Vienna we are investigating how ex
vivo lung perfusion ameliorates graft function and decreases primary graft
dysfunction in human lung transplant patients.