Alveolar Epithelial Repair in Gram Negative Bacterial Pneumonia

Damaged alveolar barrier and impaired gas exchange are the major hallmarks of pulmonary infection. Consequently, epithelial repair processes are initiated to restore the normal lung homeostasis. In the present thesis it was investigated whether early activated alveolar macrophages (AMf) contribute to alveolar epithelial repair following infection. LPS-activated AMf stimulated alveolar epithelial cells (AEC) to express growth factors, particularly GM-CSF in co-culture, in a TNF-alpha dependent manner. GM-CSF in turn elicited autocrine proliferative signalling in AEC. Notably, intra-alveolar TNF-alpha neutralization impaired AEC proliferation in LPS-injured mice in vivo. GM-CSF-deficient mice displayed reduced AEC proliferation and sustained alveolar barrier dysfunction upon LPS injury. Similarly, K. pneumoniae lung infection resulted in early release of macrophage TNF-alpha and epithelial GM-CSF, and subsequent TNF-α-dependent AEC proliferation during alveolar repair. These findings indicate that TNF-alpha from activated AMf induces epithelial GM-CSF expression, which in turn initiates AEC proliferation and thus contributes to restore alveolar barrier function.