Mechanism of Neonatal Chronic Lung Disease (Hilgendorff Lab)

Our main goals are

  1. to define the specific role of shear stress and oxygen toxicity in alveolar and vascular development,
  2. to characterize the impact of extracellular matrix remodeling and impaired growth factor signaling in the pathophysiologic context of the disease and
  3. to translate these findings into clinical studies to identify biomarkers for disease monitoring and exploration of potential treatment options.

Rationale

Bronchopulmonary dysplasia (BPD) is a chronic pulmonary disorder affecting more than 30% of all very preterm infants that increases the risk for pulmonary and neurologic sequelae persisting into adulthood. While mechanical ventilation (MV) and oxygen therapy offer live saving treatment to this patient population, they mainly contribute to the development of this disease. The arrest of pulmonary development that characterizes BPD is accompanied by extensive extracellular matrix (ECM) remodeling that promotes the formation of simplified alveolar structures and dysmorphic capillaries, the recruitment of inflammatory cells to the lung, and (TGF-β) mediated fibroproliferation. A profound understanding of the molecular mechanisms regulating ECM remodeling in the context of a perpetuated inflammatory response and their specific contribution to impaired alveolar and vascular development still remains elusive. Furthermore, early markers that allow the prediction of BPD development and the progression of this disease in the preterm infant are urgently needed, as, the diagnosis and subsequent treatment decisions are currently solely based on clinical definitions derived from end-stage pulmonary function right before discharge but are not suitable for treatment decisions during the acute phase of lung damage. 

Scientific direction and aims

The overall aim of ongoing and future projects is to generate a profound understanding of the molecular mechanisms regulating ECM remodelling in the context of pulmonary inflammatory processes, thereby contributing to impaired alveolar and vascular development, by using a unique mouse model. This model of prolonged mechanical ventilation in newborn mice alongside with pulmonary function testing (PFT) in newborn mice was established in collaboration with Professor Richard Bland and Professor Carlos Milla at Stanford University. Experimental in vivo studies are complemented by in vitro experiments studying the effect of stretch on primary cell cultures under different culture conditions. Furthermore, we aim at identifying key molecules that can serve as early surrogate markers for the development of BPD in preterm infants. These projects will help to enable the early diagnosis of lung alterations that are suitable for treatment decisions aimed to prevent the development of BPD. This approach will be carried out in closest collaboration with the Department of Neonatology, Grosshadern as well as the Department for Clinical Radiology, Grosshadern, Ludwig-Maximilian University.

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