Large diameter (>50?m) intrapulmonary arteriovenous (IPAV) anastomoses are well known to exist in multiple mammalian species (22, 23), including healthy humans (1, 24, 25). Because the conditions under which these pathways are functional in health are not known, a role for these vessels in either health or disease has not been established. Our published data (26) provides strong evidence that these shunt pathways are inducible in healthy humans during hyper-dynamic conditions such as exercise and our preliminary data provides further evidence suggesting that these vascular pathways are modulated by oxygen tension (27). Accordingly, this proposal is designed to provide direct evidence that these anastomoses are inducible in multiple mammalian species under physiologic conditions and to define the mechanisms that regulate the recruitment of these important yet poorly understood intrapulmonary shunt pathways. We postulate that these anastomoses are dynamically regulated intrapulmonary arteriovenous shunt pathways that become functional under hyperdynamic states, thus allowing these unconventional vessels to provide an alternative/collateral pathway for pulmonary blood flow. The active recruitment of these intrapulmonary shunt pathways will result in physiological consequences with measurable outcomes. We further postulate that these shunt pathways are regulated opposite that of the conventional pulmonary arteries and are actively regulated by oxygen tension, in that hypoxia opens and hyperoxia closes them. Furthermore, we postulate that these inducible pathways are remnant fetal vessels that would divert pulmonary blood flow away from alveolar capillaries. To test these hypotheses we propose the following specific aims:
Aim A. Developmental influences on functional regulation of inducible intrapulmonary arteriovenous shunt pathways in an isolated piglet heart-lung model.
Aim B: Functional regulation and consequences of inducible intrapulmonary shunt pathways in the chronically instrumented exercising canine model.
Aim C. Role, regulation and consequences of inducible intrapulmonary shunt pathways in health, bronchopulmonary dysplasia (BPD) and high altitude pulmonary edema (HAPE).

Public Health Relevance

We have identified, in healthy humans, large pore pathways within the lung circulation that open to by-pass the lung gas exchange area. The discovery of these dynamically regulated lung pathways may have far reaching impact on how we view the lung in health and disease. When open, these pathways have the potential to allow dangerous emboli to by-pass the lung filter and enter the circulation of the brain and heart to cause strokes and heart attacks. Furthermore, the recruitment of these unique lung blood vessels may contribute to inefficiencies in breathing. The goal of this proposal is to better define the function regulation and consequences of these newly identified lung blood vessels in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086897-05
Application #
8318262
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Blaisdell, Carol J
Project Start
2008-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$363,214
Indirect Cost
$115,714
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Duenwald-Kuehl, Sarah; Bates, Melissa L; Cortes, Sonia Y et al. (2014) Ultrasound assessment of ex vivo lung tissue properties using a fluid-filled negative pressure bath. J Biomech Eng 136:
Bates, Melissa L; Jacobson, Joseph E; Eldridge, Marlowe W (2014) Transient intrapulmonary shunting in a patient treated with ??-adrenergic agonists for status asthmaticus. Pediatrics 133:e1087-91
Bates, Melissa L; Farrell, Emily T; Eldridge, Marlowe W (2014) Abnormal ventilatory responses in adults born prematurely. N Engl J Med 370:584-5
Bates, Melissa L; Farrell, Emily T; Drezdon, Alyssa et al. (2014) Hypoxia and exercise increase the transpulmonary passage of 99mTc-labeled albumin particles in humans. PLoS One 9:e101146
Bates, Melissa L; Pillers, De-Ann M; Palta, Mari et al. (2013) Ventilatory control in infants, children, and adults with bronchopulmonary dysplasia. Respir Physiol Neurobiol 189:329-37
Bates, Melissa L; Fulmer, Brendan R; Farrell, Emily T et al. (2012) Hypoxia recruits intrapulmonary arteriovenous pathways in intact rats but not isolated rat lungs. J Appl Physiol 112:1915-20
Lovering, Andrew T; Stickland, Michael K; Amann, Markus et al. (2011) Effect of a patent foramen ovale on pulmonary gas exchange efficiency at rest and during exercise. J Appl Physiol 110:1354-61
Lovering, Andrew T; Eldridge, Marlowe W; Stickland, Michael K (2009) Counterpoint: Exercise-induced intrapulmonary shunting is real. J Appl Physiol 107:994-7
Lovering, Andrew T; Eldridge, Marlowe W; Stickland, Michael K (2009) Last Word on Point:Counterpoint: Exercise-induced intrapulmonary shunting is imaginary vs. real. J Appl Physiol 107:1003
Lovering, Andrew T; Haverkamp, Hans C; Romer, Lee M et al. (2009) Transpulmonary passage of 99mTc macroaggregated albumin in healthy humans at rest and during maximal exercise. J Appl Physiol 106:1986-92