The overall objectives of the proposed studies will be to define the biomechanical functions of the pulmonary vascular bed by using its measured geometric and mechanical characteristics, including how these characteristics are influenced by passive and vasoactive phenomena, and, by using more comprehensive deterministic models to evaluate hypotheses used to explain how the structure-function interactions produce the integrated behavior of the pulmonary vascular bed. These objectives will be achieved by addressing Specific Aims 1-5, which will be to: 1) fill in specific gaps in our knowledge of pulmonary vascular mechanics by measuring the influence of lung volume on the longitudinal distribution of pulmonary vascular resistance and the arterial:capillary:venous distribution of blood volume, the influence of hematocrit on the longitudinal distribution of vascular resistance, and the distribution of intravascular pressure as a function of vessel diameter; 2) determine the relative contributions of the dispersion of transit times along individual pathways and between parallel pathways through the pulmonary circulation to the total heterogeneity in pulmonary transit times; 3) determine how inspired nitric oxide concentration, blood flow rate, ventilation:perfusion ratio, and perfusate composition affect the size of the pulmonary arteries and veins accessible to vasodilator concentrations of NO when NO is added to the inspired gas; 4) determine whether increased shear stress on the endothelium is an NO mediated vasodilator stimulus in pulmonary arteries; and 5) continue to construct a deterministic mathematical model of the pulmonary vascular bed using data obtained in the accomplishment of the other Specific Aims. The model will be used to evaluate the ability of extant hypotheses to explain how the pulmonary vasculature functions by determining whether their predictions are quantitatively consistent with experimental observations, and to help guide experimental and theoretical investigations when they are not. The experiments will be carried out using isolated lungs from dogs and ferrets. These preparations will allow for the necessary control over the relevant variables. The methods will include the application of various indicator dilution concepts for evaluating pulmonary vascular function from measurements made outside the lungs, and they will include direct observations using microfocal angiography and dynamic image analysis. Some of the methods to be employed are new and/or unique to studies like those proposed. The expectation is that these methods will provide the means to solve significant problems that are as yet unresolved because available methods have not been applicable to the specific problems or because previous methods have provided apparently inconsistent results. Accomplishment of Specific Aims 1-5 will provide fundamental information necessary for a rational approach to evaluation and treatment of pulmonary vascular disease. In addition, Specific Aim 3 will provide specific information regarding the efficacy of NO inhalation as a pulmonary vasodilator therapy.
Specific Aim 4 will evaluate the potential role of a physiological pulmonary vasodilator mechanism that may help to maintain normally low pulmonary vascular tone in the face of normally present vasoconstrictor stimuli. The malfunction of such a mechanism may contribute to pulmonary hypertension of otherwise unknown etiology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL019298-22
Application #
2028000
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1976-06-01
Project End
2002-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
22
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Rajaram, Satwik; Heinrich, Louise E; Gordan, John D et al. (2017) Sampling strategies to capture single-cell heterogeneity. Nat Methods 14:967-970
Lang, Ivan M; Haworth, Steven T; Medda, Bidyut K et al. (2016) Mechanisms of airway responses to esophageal acidification in cats. J Appl Physiol (1985) 120:774-83
Shingrani, Rahul; Krenz, Gary; Molthen, Robert (2010) Automation process for morphometric analysis of volumetric CT data from pulmonary vasculature in rats. Comput Methods Programs Biomed 97:62-77
Hirenallur-S, Dinesh K; Haworth, Steven T; Leming, Jeaninne T et al. (2008) Upregulation of vascular calcium channels in neonatal piglets with hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 295:L915-24
Lang, Ivan M; Haworth, Steven T; Medda, Bidyut K et al. (2008) Airway responses to esophageal acidification. Am J Physiol Regul Integr Comp Physiol 294:R211-9
Wietholt, Christian; Roerig, David L; Gordon, John B et al. (2008) Bronchial circulation angiogenesis in the rat quantified with SPECT and micro-CT. Eur J Nucl Med Mol Imaging 35:1124-32
Molthen, Robert C (2006) A simple, inexpensive, and effective light- carrying laryngoscopic blade for orotracheal intubation of rats. J Am Assoc Lab Anim Sci 45:88-93
Hu, Jicun; Haworth, Steve T; Molthen, Robert C et al. (2004) Dynamic small animal lung imaging via a postacquisition respiratory gating technique using micro-cone beam computed tomography. Acad Radiol 11:961-70
Molthen, Robert C; Karau, Kelly L; Dawson, Christopher A (2004) Quantitative models of the rat pulmonary arterial tree morphometry applied to hypoxia-induced arterial remodeling. J Appl Physiol 97:2372-84; discussion 2354
Hu, Jicun; Tam, Kwok; Johnson, Roger H (2004) A simple derivation and analysis of a helical cone beam tomographic algorithm for long object imaging via a novel definition of region of interest. Phys Med Biol 49:205-25

Showing the most recent 10 out of 62 publications