FETAL LUNG FIBROBLASTS SELECTIVELY DOWN-REGULATE PROTEOGLYCAN SYNTHESIS IN RESPONSE TO ELEVATED OXYGEN

Cell proliferation is in part regulated by extracellular matrix, There fore, it is possible that elevated O-2 may indirectly affect lung fibr oblast growth via modulation of extracellular matrix, In the present s tudy, we investigated the effect of elevated O-2 on the synthesis of g lycosaminoglycans (GrAGs) and proteoglycans (PGs) by fetal lung fibrob lasts. A 48-h exposure to greater than or equal to 50% O-2 reduced the incorporation of [H-3]glucosamine and (SO4)-S-35 into GAGs by fetal l ung fibroblasts. The relative proportion of the individual GAG molecul es was not altered by elevated O-2, Fibroblasts exposed to 50% O-2 sec reted less [S-35]proteoglycans into the medium than controls. Specific ally, the synthesis of the small soluble PG, biglycan, was decreased b y exposure to 50% O-2. Fetal lung fibroblasts did not synthesize the s mall chondroitin/dermatan sulfate FG decorin, Elevated O-2 concentrati ons also reduced the synthesis of membrane- and matrix-associated PGs, Furthermore, exposure of fetal lung fibroblasts to greater than or eq ual to 50% O-2 resulted in a decreased mRNA expression for biglycan an d versican core protein sequences, Ttl contrast, elevated O, increased the message for type I collagen and fibronectin without affecting tha t of p-actin. The inhibitory effect of elevated O-2 on biglycan mRNA a nd protein expression was overcome by incubating the cells in 3% O-2 a fter the 48-h exposure to 50% O-2. The latter treatment also reversed the increased mRNA expression of type I collagen associated with eleva ted O-2 but not that of fibronectin, These results demonstrate that fe tal lung fibroblasts, in response to elevated oxygen concentrations, s electively down-regulate their GAG and PG synthesis and that this O-2 effect is reversible.