Figure 1

Schematic representation of the two major pathogenetic pathways regulating angiogenesis in pulmonary fibrosis. Under normal oxygen conditions HIF-1a is subject to ubiquitination and proteasomal degradation. Under hypoxic conditions, its ubiquitination is inhibited and HIF-1a is activated through the same kinase pathways with NF-κB and translocates to the nucleus. There it dimerizes with HIF-1b and the heterodimer recognizes specific allelic sequences located within the hypoxia response element found in the promoter region of several target genes (i.e VEGF). In addition, VEGF may directly promote the expression of angiogenic chemokines (i.e CXCL8) from endothelial cells in an autocrine and paracrine way. Generation of reactive oxygen species and activation of kinase pathogenetic pathways converges and activates NF-κB and sets in motion a process that releases NF-κB in the cytoplasm and leads to its translocation into the nucleus. There, all the promoters of angiogenic CXC chemokines contain a putative cis-element that recognizes and binds the transcriptional factor resulting to the activation of target genes and ultimately to protein synthesis.