The role of PDGF-A in lung development, injury and repair

  • Datum:
  • Plats: Rudbecksalen, Dag Hammarskjöls väg 20, Uppsala
  • Doktorand: Gouveia, Leonor
  • Om avhandlingen
  • Arrangör: Institutionen för immunologi, genetik och patologi
  • Kontaktperson: Gouveia, Leonor
  • Disputation

The developmental processes that take place during embryogenesis depend on a great number of proteins that are important for cell-to-cell communication. Platelet-derived growth factors are known to be important for epithelial-mesenchymal interactions during development and organogenesis.

However, many details are still lacking regarding organ-specific PDGF expression patterns and detailed cellular functions. This thesis aims to better describe the contribution of PDGF-A signaling to lung developmental and injury processes.

To study the cell-specific expression patterns of PDGF-A we generated a reporter mouse that show LacZ expression in all PDGF-A positive cells. This mouse model was used to characterize PDGF-A expression in embryonic and adult mouse tissues (paper I).

With the use of three different reporter mice, we described the cell type specific expression patterns of PDGF-A, PDGF-C and PDGFRα in mouse lungs, from embryonic day 10.5 (E10.5) when development is initiated, until adulthood (Postnatal day 60) when the lung is fully mature (paper II).

A lung-specific Pdgfa knockout mouse was generated and the impact of the deletion was studied during lung development and adulthood. Mice lacking Pdgfa expression in the lung survived until adulthood but exhibited abnormal alveolar development. This phenotype was caused by the inability of myofibroblasts to assemble alpha smooth muscle actin ring around the forming alveoli (paper III).

To investigate if PDGF-A is involved in the injury response mechanisms of the adult lung, we generated inducible lung-specific Pdgfa knockout mice. In homeostasis, adult Pdgfa deletion did not result in any apparent phenotype, whereas after hyperoxia-induced lung injury, preliminary data show that mutant mice exhibit substantially more alveolar damage and immune cell infiltration (paper IV).

In conclusion, this thesis reports novel insights into the expression and role of PDGF-A and PDGFRα for the lung, both in development and adulthood.