SummaryIn spontaneously breathing newborn lambs, alveolar hypoxia increases lung microvascular pressure, which causes lung lymph flow to increase and the concentration of protein in lymph to decrease. To see if this response derives from hypoxia itself rather than from the change in breathing pattern that occurs during hypoxia, we measured lung vascular pressures, pleural pressure, cardiac output, and lung lymph flow in 12 anesthetized lambs that were ventilated at a fixed rate and tidal volume, first with air, then with 10-14% O2in nitrogen. Alveolar hypoxia did not affect pleural pressure, but pulmonary arterial pressure increased from 19 to 32 torr, lung lymph flow increased from 2.20 to 3.83 ml/h and lymph protein concentration decreased from 3.4 to 2.8 g/dl. To be certain that the increased lymph flow associated with hypoxia is not simply the result of an acute release of fluid from the lungs and to assess the effects of carbon dioxide on lymph flow during hypoxia, we next studied six unanesthetized lambs kept hypoxic for a total of 12 h. After a 2-4-h period in air the lambs breathed 9-11% O2in nitrogen for 2-4 h, then 8- 11% O2and 3-5% CO2in nitrogen for 8-10 h. In these lambs we injected intravenously radioactive albumin and measured its uptake in lymph to see if sustained hypoxia alters microvascular permeability to protein in the lungs. In these experiments pulmonary arterial pressure increased from 17 to 37 torr, lung lymph flow increased from 1.74 to 3.28 ml/h, and lymph protein concentration decreased from 3.8 to 3.1 g/dl during hypoxia. Addition of CO2to the inspired gas did not affect steady state lung lymph flow. Lymph flow remained elevated throughout the 12 h of alveolar hypoxia, and postmortem lung water determinations were not different from those of controls (4.65 ± 0.28 versus 4.72 ± 0.14 g/g dry bloodless lung). The time required for radioactive albumin to equilibrate in lymph at one-half the specific activity of plasma was no different before and during hypoxia (130 ± 7 versus 125 ± 11 min). We conclude that in the newborn lamb, alveolar hypoxia increases transvascular fluid filtration by increasing microvascular hydraulic pressure without altering microvascular permeability to protein. This response is independent of changes in pleural pressure or inspired carbon dioxide.