This proposal seeks to understand how spatial heterogeneity in the distribution of pulmonary blood flow and increased pulmonary capillary pressures interact to affect the development of pulmonary edema. High altitude pulmonary edema (HAPE), an acute potentially fatal edema is used as a disease model, to allow investigation of mechanisms of pulmonary edema without confounding variables such as sepsis or multi- organ failure. Mechanical stress injury of the pulmonary capillaries has been shown to be important in the development of HAPE, but how the pulmonary capillaries are exposed to high pressure is unresolved. The overall hypothesis of this proposal is that increased susceptibility to HAPE requires both a hypoxia-induced increase in perfusion heterogeneity and increased pulmonary vascular pressures, resulting in edema in the lung regions of increased flow and pressure. Using a quantitative functional magnetic resonance imaging (fMRI) technique known as arterial spin labeling (ASL) we have previously shown that regional pulmonary blood flow becomes less uniform in a single isogravitational plane during normobaric hypoxia in HAPE susceptible subjects, a finding which is not observed in HAPE resistant subjects, supporting this idea. The effects of hypoxia and exercise on the spatial distribution of pulmonary blood flow will be measured in the entire lung at sea level, using state of the art quantitative fMRI-ASL, and changes related to increased regional extravascular fluid measured with a non-contrast multi echo MR I technique. This will allow insights into the mechanism of the edema, since if the uneven hypoxic pulmonary vasoconstriction is pre-capillary constriction, then the high capillary pressures (and fluid accumulation) will occur in the high flow (less constricted) regions, exposed to the high pulmonary artery pressure due to low arteriolar resistance. A finding of edema in lung regions of low flow would conversely implicate post capillary venoconstriction. The anatomic reproducibility of the pulmonary vascular response will be evaluated to determine whether the pattern of perfusion changes with hypoxia are regionally stable, or whether the regions of high flow change their anatomic location over time. If they are regionally reproducible, this would suggest that there are inherent structural abnormalities in some lung regions, while an anatomically variable response would suggest a predominantly dynamic interdependent process. Finally the effects of acclimatization, and exercise (important modulating factors for HAPE) on the development of increased perfusion heterogeneity and resultant fluid accumulation will be evaluated. The results of these studies may offer insights into how fluid accumulates in the lung under conditions of stress when the pressure in the lung blood vessels is increased and available oxygen is reduced. In particular, by evaluating the relationship between blood flow and fluid formation in the lung, this work may allow the identification of a threshold for lung injury under certain conditions to be identified and the prediction of those who are at risk for pulmonary edema. ? ? ?
| Basaran, Kemal Erdem; Villongco, Michael; Ho, Baran et al. (2016) Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans. PLoS One 11:e0146087 |
| Sá, Rui Carlos; Asadi, Amran K; Theilmann, Rebecca J et al. (2014) Validating the distribution of specific ventilation in healthy humans measured using proton MR imaging. J Appl Physiol (1985) 116:1048-56 |
| Tedjasaputra, Vince; Sa, Rui Carlos; Arai, Tatsuya J et al. (2013) The heterogeneity of regional specific ventilation is unchanged following heavy exercise in athletes. J Appl Physiol (1985) 115:126-35 |
| Stickland, Michael K; Lindinger, Michael I; Olfert, I Mark et al. (2013) Pulmonary gas exchange and acid-base balance during exercise. Compr Physiol 3:693-739 |
| Asadi, Amran K; Cronin, Matthew V; Sá, Rui Carlos et al. (2013) Spatial-temporal dynamics of pulmonary blood flow in the healthy human lung in response to altered FI(O2). J Appl Physiol (1985) 114:107-18 |
| Arai, Tatsuya J; Villongco, Christopher T; Villongco, Michael T et al. (2012) Affine transformation registers small scale lung deformation. Conf Proc IEEE Eng Med Biol Soc 2012:5298-301 |
| Hopkins, Susan R; Wielputz, Mark O; Kauczor, Hans-Ulrich (2012) Imaging lung perfusion. J Appl Physiol 113:328-39 |
| Henderson, A C; Sa, R C; Barash, I A et al. (2012) Rapid intravenous infusion of 20 mL/kg saline alters the distribution of perfusion in healthy supine humans. Respir Physiol Neurobiol 180:331-41 |
| Arai, Tatsuya J; Prisk, G Kim; Holverda, Sebastiaan et al. (2011) Magnetic resonance imaging quantification of pulmonary perfusion using calibrated arterial spin labeling. J Vis Exp : |
| Holverda, Sebastiaan; Theilmann, Rebecca J; Sa, Rui C et al. (2011) Measuring lung water: ex vivo validation of multi-image gradient echo MRI. J Magn Reson Imaging 34:220-4 |
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