Table 1.

Unanswered questions about angiogenesis and lymphangiogenesis in COPD.

Are angiogenesis and lymphangiogenesis secondary to chronic inflammation and/or reparative processes, or an important early step in COPD? What do other members of the VEGF family (e.g., VEGF-B, -C, -D) besides VEGF-A do in COPD? Is the hyperproduction of VEGF induced by local hypoxia an adaptive phenomenon, or does it have a pathogenic role in COPD? What are the main immunologic stimuli that induce the release of angiogenic and lymphangiogenic factors from resident lung immune cells (macrophages, mast cells, neutrophils) in COPD? Could human inflammatory cells, under appropriate circumstances, produce anti-angiogenic factors (e.g., VEGF-A165b)? What are the roles of pro- and anti-angiogenic chemokines synthesized by human inflammatory cells in COPD? What part do alarmins (TSLP, IL-33, IL-25) play in angiogenesis in COPD? Are other angiogenic networks (e.g., ANGPT/Tie receptors) involved in COPD? What is the importance of lymphangiogenesis in COPD? What stimuli drive lymphangiogenesis during inflammation? MicroRNAs (miRNAs) regulate gene expression and specific miRNAs that regulate endothelial cell functions and angiogenesis have been described. Are specific miRNAs involved in angiogenesis/lymphangiogenesis in COPD?