We previously found increased expression of erythropoietin receptor (EPO-R) in peripheral dog lung during postnatal and post-pneumonectomy (PNX) lung growth. To study the upstream regulation of EPO-R, we analyzed the expression of hypoxia inducible factors (HIF)-1, -2 and -3 during postnatal lung growth in immature and mature (2.5 and 12 mo old, respectively) dogs, and during compensatory lung growth 3 wk and 10 mo following right PNX. Relative to their respective controls, HIF-1 transcript was 52-95% higher in immature lungs and 284% higher in the remaining lung 3-wk post-PNX. HIF-2 transcript did not change during maturation but was 42% lower 3-wk post-PNX. HIF-3 transcript was 53-65% lower in both the immature lung and 3-wk post-PNX. Changes were no longer detectable 10-mo post-PNX. No change in HIF transcripts was observed in kidney and liver post-PNX. Consistent with the mRNA changes, HIF-1protein was 120% and 196% higher in growing lungs and 3-wk post-PNX relative to their respective controls. Over-expression of HIF-1 in cultured HEK-293 cells increased endogenous expression of EPO-R protein. These results demonstrate regulated expression of the HIF system as well as parallel changes in HIF-1 and EPO-R expression during two types of lung growth. Since the normal growing lung is not hypoxic, the HIF system likely responds to other signals such encountered during sustained lung strain.