From atmosphere to arteries: Investigating paracrine mediators in air pollution-induced pulmonary arterial hypertension

• Applicant: Dr. Gerrit Bredeck
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555526653

Pulmonary arterial hypertension is a devastating disease that involves cellular remodelling of blood vessels. Changes in the pulmonary blood vessels have been linked to inflammatory signalling induced by exposure to air pollutants, especially fine particulate matter (PM2.5) which deposits in the deep regions of the lungs, the alveoli. However, the molecular mediators released from the alveoli that contribute to pulmonary arterial remodelling remain largely unknown. Despite the striving to reduce animal (in vivo) trials, alternative (in vitro) methods for the identification of such molecular mediators are still scarce. One aim of this project is to identify PM2.5-induced molecules that mediate pulmonary arterial hypertension. Another objective is to establish a cell culture-based in vitro method which can aid the identification of these molecular mediators. As a PM2.5 sample, diesel exhaust particles commercially available from the U.S. National Institute of Standards and Technology as standard reference material 2975 will be used. As in vitro approach, a primary human alveolar model and a pulmonary artery-on-a-chip model will be combined. The alveolar model will be exposed to PM2.5 and the conditioned culture medium enriched with molecular mediators will be collected. This conditioned medium will be applied to the pulmonary artery-on-a-chip model. Cellular and molecular markers of inflammation and pulmonary arterial remodelling will be evaluated. As in vivo approach, mice will be exposed to PM2.5. Concentrations of PM2.5 causing inflammatory responses will be applied. In addition to the same molecular and cellular indicators examined in the in vitro investigations, haemodynamic and macroscopic indicators will be assessed in mice. To identify molecular mediators connecting PM2.5 exposed alveolar cells and pulmonary arterial cells, i.e. alveolar ligands with a matching pulmonary arterial receptor, bulk transcriptomes (in vitro) and single-cell transcriptomes (in vivo) will be screened against a ligand-receptor database. The role of the identified molecular mediators will be confirmed by performing in vitro and in vivo intervention studies. As interventions, neutralising antibodies, antagonists or downstream inhibitors will be applied and evaluated for their ability to inhibit the effects of PM2.5. The in vitro and in vivo experiments will be as parallel in design as possible to allow for a direct comparison of both models. One expected outcome is identifying a molecular mediator implicated in pulmonary arterial hypertension, that might serve as a drug target in future. Another expected outcome is determining whether the suggested in vitro method can mimic the indirect effects of PM2.5 on the pulmonary artery and, thus, help to reduce animal trials in the future.

• DFG Programme: WBP Position