Cardiovascular & Respiratory Physiology

Updated 11/26/07

1. Hemoglobin, Nitric Oxide and the Pulmonary Circulation

S.A. Deem, M.D., E.R. Swenson, M.D., M.T. Gladwin, M.D.

Red blood cells (RBCs) have generally been thought to serve as mere carriers of oxygen and carbon dioxide between the lung and systemic tissues. However, recent studies indicate that RBCs are actively involved in the regulation of vascular tone, largely through their capacity to stimulate production of, inactivate, and transport the vasodilator substance nitric oxide (NO). In particular, the irreversible oxidation of NO to form metHb and nitrate, and the reversible reactions of NO with hemoglobin (Hb) to form S-nitrosoHb (SNO-Hb) and nitrosyl(heme)Hb are of potential major import. The interactions between RBCs and vascular tone appear to be particularly important during hypoxic conditions, wherein RBCs augment hypoxic pulmonary vasoconstriction and optimize regional ventilation-perfusion matching in the lung, and optimize oxygen delivery to systemic tissues. The Targeted Goals of the project are to: IA. Determine the effects of free and intraerythrocytic nitrosyl(heme)Hb and SNO-Hb on pulmonary pressure, HPV, and NO kinetics in an isolated lung model IB. Determine whether SNO-Hb and nitrosyl(heme)Hb have effects on pulmonary and systemic vascular resistance and HPV in vivo, using live anesthetized rats as a model.  IC. Determine whether nitrite protects NO from oxidation by Hb and whether nitrite modulates HPV. IIA. Determine whether SNO-Hb and nitrosyl(heme)Hb relax pulmonary vascular smooth muscle (VSM) in vitro, and explore the mechanism of any different effects of these mediators on pulmonary vs. systemic VSM. In particular, we will determine effects on pulmonary VSM of the SNO-Hb/NO intermediate nitroxyl anion. IIB. Determine whether nitroxyl anion inhibits HPV in an isolated, perfused lung model, and determine whether nitroxyl may be produced from SNO-Hb in this model. Techniques used for all Targeted Goals will include measurement of physiologic variables and biomolecular markers of NO production and inactivation, including exhaled NO. The ultimate objectives of this project are to increase the understanding of how RBCs, Hb, and by extension anemia affect pulmonary and systemic oxygen exchange in health and disease. Ultimately, the information gained will allow refinement of blood transfusion practice during surgery and in critical illness. The potential clinical impact is large given the risk and cost associated with blood transfusion and world-wide shortage of blood products.

2. Red Blood Cells, Nitric Oxide and Pulmonary Circulation

S.A. Deem, M.D.

The long term objectives of this project are to elucidate the role of red blood cells (RBCs), hemoglobin (Hb), and nitric oxide (NO) in modulating pulmonary blood flow at the microvascular and macrovascular levels, and to thereby provide insight into the mechanisms by which RBCs affect pulmonary gas exchange. 

The knowledge gained from this project will have health-related ramifications, in that it will allow more informed understanding and treatment of anemia, a common accompaniment of illness, and ultimately lead to improvements in patient care through the optimization of transfusion strategies and the development of hemoglobin-based oxygen carriers. 

Dr. Deem has previously described the importance of RBCs in augmenting hypoxic pulmonary vasoconstriction through inactivation of NO by Hb, and has delineated the enhancement of pulmonary gas exchange by anemia under certain conditions. The current project will build on these findings in the following Specific Aims: I. Determine whether NO that is "biopreserved in the form of the oxidation product nitrite, or the NO-Hb products nitrosyl(heme)Hb and S-nitrosoHb can be released in the pulmonary circulation and result in vasodilation. The effect of these products on pulmonary artery pressure and NO production will be studied during normoxic and hypoxic conditions in an isolated, perfused rat lung model and in anesthetized rats. In addition, this aim will explore whether encapsulation of Hb within the red blood cell membrane alters the vasoactive properties of NO-Hb products. II. Determine the role of RBCs in determining microvascular hemodynamics using intravital microscopy in isolated, perfused rat lungs. This Aim will directly explore the rheology of the pulmonary microcirculation, help determine whether the RBC plays an active or passive role in determining pulmonary microvascular hemodynamics, and provide insights into the mechanisms by which RBCs alter pulmonary blood flow distribution and gas exchange.

3. Oxidative Inflammatory Mechanisms of Hypercapnia

J.D. Lang, Jr, M.D.

This project will define how hypercapnia (increased carbon dioxide concentrations) modifies oxidant-mediated inflammatory pathways with in vitro and in vivo models of inflammatory lung injury. Inflammatory-mediated lung injury often damages the air-blood barrier, impairing gas exchange and inducing hypoxemia. Recent innovative clinical strategies for resolving this pathologic process include the use of "protective" low tidal volume ventilatory strategies to retard ventilator-associated lung injury (VALI). There is an increasingly pervasive clinical perception that the allowance of hypercapnia is desirable and may be utilized as a strategy unto itself to retard lung injury. While there is modest clinical evidence that supports this approach, it remains biochemically unsubstantiated. In contrast, there is expanding evidence that CO2 actively reacts with inflammatory oxidants, yielding products with altered oxidizing and nitrating capabilities. We have observed that carbon dioxide rapidly reacts with reactive oxygen species generated during systemic inflammation, forming reactive nitrating and oxidizing species, specifically nitrosoperoxocarbonate (ONOOCO2-) a species capable of mediating further potent oxidation and nitration reactions. From this foundation of knowledge, it is hypothesized that hypercapnia amplifies inflammatory lung cell injury via modulation of oxidative injury and signaling pathways. To test this hypothesis, the following Specific Aims will be pursued: #1: Define the influence of hypercapnia on oxidant generation and cell signaling pathways in an in vitro model of lung epithelial and endothelial cell inflammation. #2: Investigate the contribution of mechanical stress, in conjunction with hypercapnia, on oxidative inflammatory and cell signaling events in an in vitro model of lung injury. #3: Delineate the consequences of concurrent hypercapnia, lung cell mechanical stress, and inhaled .NO in an in vivo model of critical illness. This proposed experimental plan advances recent investigation of CO 2interactions with NO-derived species by examining the influence of CO2 on in vitro and in vivo models of inflammatory and ventilator-induced lung injury. The proposed research plan also provides a key element of the training platform that has been devised for the further development of the candidate as a physician-scientist and his pursuit to understand and improve issues of relevance to critical care medicine.

4. Early Antipseudomonal Therapy in Cyctic Fibrosis

B. Ramsey, M.D.,  M. Treggiari,  M.D.

 The purpose of the present study is to determine the long-term microbiologic efficacy and safety of early intervention with antimicrobial therapy in infants and young children with cystic fibrosis (CF) and documented Pseudomonas aeruginosa (Pa) airway infection.

There is growing interest in investigating anti-pseudomonal therapies in very young children with the long-term goal of delaying or preventing chronic infection that contributes to irreversible lung disease. There has been minimal evaluation of either the clinical efficacy or safety of aggressive early intervention (i.e., intervention based on first isolation of Pa alone, in the absence of symptoms). While anti-pseudomonal therapy for first isolation of Pa will likely result in short-term eradication of Pa from respiratory cultures, it is not known whether it will improve clinical outcomes, be associated with unacceptable toxicities, or increase the rate of acquisition of resistant organisms. Young children with CF ranging in age from 6 months to 12 years will be enrolled at one of over 100 clinical centers nationwide to either a clinical trial (CT) that will include about 500 patients and/or an observational study (OS) that will include a total of about 3,500 CF children. The clinical trial is designed to allow randomized controlled evaluation of early intervention with inhaled antipseudomonal therapy in young patients with CF at first isolation of Pa from respiratory cultures. The observational study component will complement the clinical trial by assessing new risk indicators and biomarkers for disease, and observing the history of airway colonization with Pa in a large prospective cohort.

The primary outcome of the clinical trial is time to occurrence of a pulmonary exacerbation, comparing patients assigned to the three different treatment algorithms. The secondary outcomes will evaluate the effect of antibiotic therapy on safety (adverse events profile with particular reference to masculo-skeletal symptoms, renal function as measured by serum creatinine, hearing acuity, liver function tests, and complete blood count with differential), clinical variables (proportion of patients with pulmonary exacerbations, number of pulmonary exacerbations, linear growth, weight gain, FEV1, total inpatient days, cough scores, and treatment failure), microbiology findings (time to first recurrence of Pa from oropharyngeal or sputum cultures, proportion of participants with respiratory cultures positive for Pa at the end of the study, presence and pattern of mucoid Pa isolates identified by colony morphology, changes in MICs of Pa isolates from oropharyngeal cultures, and changes in the genotype of Pa isolates from baseline to the end of the study), and Pa serology (changes and patterns in anti-pseudomonal antibody titers against exotoxin A, exotoxin S and elastase, and in inflammatory markers in blood from baseline to the end of study).

5. Does the vestibular organ play a role in theventilatory response to hypercapnia during sleep?

D. Rubens, M.D., 

 The purpose of the present study is to evaluate the role of the vestibular organ in the mediation of the ventilatory response to systemic hypercapnia during sleep.  The ventilatory response of sleeping rodents with and without vestibular hair cell (vhc) impairment will be compared when both groups are exposed to increasing levels of carbon dioxide.

The primary goal of this study is to further the understanding of the relationship between vestibular function and ventilatory control.  It may also help to establish a possible association between vestibular hair cell dysfunction and SIDS.

* (C) denotes clinical investigation.

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