Warren Zapol - Academia.edu (original) (raw)

Papers by Warren Zapol

Research paper thumbnail of Autologous tansfusion of stored red blood cells increases pulmonary artery pressure

Research paper thumbnail of 5-Lipoxygenase Deficiency Prevents Respiratory Failure during Ventilator-induced Lung Injury

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Rationale: Mechanical ventilation with high tidal volumes (HV T ) progressively leads to lung inj... more Rationale: Mechanical ventilation with high tidal volumes (HV T ) progressively leads to lung injury and decreased efficiency of gas exchange. Hypoxic pulmonary vasoconstriction (HPV) directs blood flow to well-ventilated lung regions preserving systemic oxygenation during pulmonary injury. Recent experimental studies have revealed an important role for leukotriene (LT) biosynthesis by 5-lipoxygenase (5LO) in the impairment of HPV by endotoxin. Objectives: To investigate whether or not impairment of HPV contributes to the hypoxemia associated with HV T and to evaluate the role of LTs in ventilator-induced lung injury (VILI). Methods: We studied wild-type and 5LO-deficient mice ventilated for up to 10 hours with low tidal volumes (LV T ) or HV T . Results: In wild-type mice, HV T , but not LV T , increased pulmonary vascular permeability and edema formation, impaired systemic oxygenation, and reduced survival. HPV, as reflected by the increase in left pulmonary vascular resistance (LPVR) induced by left mainstem bronchus occlusion (LMBO), was markedly impaired in animals ventilated with HV T . HV T ventilation increased bronchoalveolar lavage levels of LTs and neutrophils. In 5LO-deficient mice, the HV Tinduced increase of pulmonary vascular permeability and worsening of respiratory mechanics were markedly attenuated, systemic oxygenation was preserved, and survival increased.

Research paper thumbnail of 99mTechnetium-Fibrinogen Lung Scanning in Canine Lung Contusion

Journal of Trauma and Acute Care Surgery, Jun 30, 1984

... In the center of contusion #2, the mean Tc activity per gram of contused lung tissue was 12.2... more ... In the center of contusion #2, the mean Tc activity per gram of contused lung tissue was 12.22 ± 1.95 (mean ± SE) times the Tc activity of a gram of normal lung tissue and was significantly greater than the activity of the pericontused region, which was 3.05 ± 0.50 times the ...

Research paper thumbnail of Pulmonary Hypertension after Prolonged Hypoxic Exposure in Mice with a Congenital Deficiency of Cyp2j

American Journal of Respiratory Cell and Molecular Biology, May 1, 2015

Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pul... more Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pulmonary vascular tone and hypoxic pulmonary vasoconstriction. We investigated whether the attenuated acute vasoconstrictor response to hypoxic exposure of Cyp2j(-/-) mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j(-/-) and Cyp2j(+/+) male and female mice continuously breathed an inspired oxygen fraction of 0.21 (normoxia) or 0.10 (hypoxia) in a normobaric chamber for six weeks. We assessed hemoglobin (Hb) concentrations, right ventricular systolic pressure (RVSP), and transthoracic echocardiographic parameters (pulmonary acceleration time (PAT) and right ventricular (RV) wall thickness). Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels were measured in Cyp2j(-/-) and Cyp2j(+/+) male mice At baseline Cyp2j(-/-) and Cyp2j(+/+) mice had similar Hb levels and RVSP while breathing air. After 6 weeks of hypoxia, circulating Hb concentration increased but did not differ between Cyp2j(-/-) and Cyp2j(+/+) mice. Chronic hypoxia increased RVSP in both Cyp2j(-/-) and Cyp2j(+/+) mice of either gender. Exposure to chronic hypoxia decreased PAT and increased RV wall thickness in both genotypes and genders to a similar extent. Prolonged exposure to hypoxia produced similar levels of RV hypertrophy in both genotypes of either gender. Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels did not differ between Cyp2j-/- and Cyp2j+/+ male mice after breathing at normoxia or hypoxia for 6 weeks. These results suggest that murine Cyp2j deficiency does not attenuate the development of murine pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia in mice of both genders.

Research paper thumbnail of Inhibition of Soluble Epoxide Hydrolase Augments Hypoxic Pulmonary Vasoconstriction and Improves Gas Exchange in Mice

The Faseb Journal, Apr 1, 2013

Research paper thumbnail of Inhaled Nitric Oxide Dilates Human Hypoxic Pulmonary Vasoconstriction Without Causing Systemic Vasodilation

Research paper thumbnail of Nitric Oxide Inhalation Decreases Pulmonary Artery Remodeling in the Injured Lungs of Rat Pups

Vascular injury causes the muscularization of peripheral pulmonary arteries, which is more pronou... more Vascular injury causes the muscularization of peripheral pulmonary arteries, which is more pronounced in the infant than in the adult lung. Although inhaled NO gas attenuates pulmonary artery remodeling in hypoxic rats, whether or not it protects the lung by mitigating vasoconstriction is unknown. This investigation tested whether inhaled NO decreases the muscularization of injured pulmonary arteries in rat pups by modulating vascular tone. One week after monocrotaline administration, the percentage of muscularized rat pup lung arteries was increased by Ͼ3-fold. Nevertheless, monocrotaline exposure did not cause right ventricular hypertrophy, pulmonary hypertension, or vasoconstriction. In addition, it did not increase the expression of markers of inflammation (interleukin-1␤, intercellular adhesion molecule-1, and E-selectin) or of platelet-mediated thrombosis (GPIb␣). Continuous inhalation of 20 ppm NO gas prevented the neomuscularization of the pulmonary arteries in pups with lung injury. Moreover, a 3-fold increase in cell proliferation and 30% decrease in cell numbers in pulmonary arteries caused by monocrotaline exposure was prevented by NO inhalation. These data indicate that inhaled NO protects infants against pulmonary remodeling induced by lung injury by mechanisms that are independent of pulmonary tone, inflammation, or thrombosis. (Circ Res. 2000;87:140-145.) Key Words: inhaled nitric oxide Ⅲ pulmonary hypertension Ⅲ proliferation Ⅲ congenital heart disease Ⅲ bronchopulmonary dysplasia

Research paper thumbnail of Differential Changes of Alveolar Gas Concentrations During Anesthetic Induction of a Patient with an Absent Right Pulmonary Artery

Anesthesia and Analgesia, Sep 1, 2006

A 38-yr-old man with congenital right pulmonary artery agenesis, whose right lung was perfused wi... more A 38-yr-old man with congenital right pulmonary artery agenesis, whose right lung was perfused with collateral systemic arterial blood, presented for right pneumonectomy. Because of a likely difference in gas exchange between the two lungs, we sampled end-tidal gases from each lung individually, as well as from the common gas outlet of a double-lumen endobronchial tube. Our results indicated a higher end-tidal CO 2 from the left, normally perfused, lung than from the right, systemically perfused, lung. We also determined uptake of sevoflurane from each lung, demonstrating a more rapid uptake in the left lung than in the right. In conclusion, we report the rare case of unilateral pulmonary artery agenesis with systemic arterial collateralization and characterize the differences in gas exchange.

Research paper thumbnail of Abstract 10990: Identification of a Critical Role for BMP Signaling in Atherogenesis

Circulation, Nov 23, 2010

Research paper thumbnail of BMP Type I Receptor ALK2 is Required for Angiotensin II-Induced Cardiac Hypertrophy

American Journal of Physiology - Heart and Circulatory Physiology, 2016

Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy.... more Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine (PE)-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 (LDN) or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of PE to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T-cells (NFAT), providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN attenuated angiotensin II-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2, but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/NFAT pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis.

Research paper thumbnail of Abstract 13617: Bone Morphogenetic Protein Signaling is a Regulator of Hepatic Cholesterol Biosynthesis in vitro and in vivo

Circulation, Nov 22, 2011

Research paper thumbnail of Pathophysiologic Pathways of the Adult Respiratory Distress Syndrome

Care of the Critically Ill Patient, 1983

Research paper thumbnail of Nitric oxide synthase 3 deficiency does not prevent the adverse effects of transfusing stored blood in murine hemorrhagic shock

Research paper thumbnail of Autologous transfusion of stored red blood cells increases pulmonary artery pressure

American journal of respiratory and critical care medicine, 2014

Transfusion of erythrocytes stored for prolonged periods is associated with increased mortality. ... more Transfusion of erythrocytes stored for prolonged periods is associated with increased mortality. Erythrocytes undergo hemolysis during storage and after transfusion. Plasma hemoglobin scavenges endogenous nitric oxide leading to systemic and pulmonary vasoconstriction. We hypothesized that transfusion of autologous blood stored for 40 days would increase the pulmonary artery pressure in volunteers with endothelial dysfunction (impaired endothelial production of nitric oxide). We also tested whether breathing nitric oxide before and during transfusion could prevent the increase of pulmonary artery pressure. Fourteen obese adults with endothelial dysfunction were enrolled in a randomized crossover study of transfusing autologous, leukoreduced blood stored for either 3 or 40 days. Volunteers were transfused with 3-day blood, 40-day blood, and 40-day blood while breathing 80 ppm nitric oxide. The age of volunteers was 41 ± 4 years (mean ± SEM), and their body mass index was 33.4 ± 1.3 k...

Research paper thumbnail of Pulmonary Hypertension After Prolonged Hypoxic Exposure In Mice With a Congenital Deficiency of Cyp2j

American Journal of Respiratory Cell and Molecular Biology, 2013

Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pul... more Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pulmonary vascular tone and hypoxic pulmonary vasoconstriction. We investigated whether the attenuated acute vasoconstrictor response to hypoxic exposure of Cyp2j(-/-) mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j(-/-) and Cyp2j(+/+) male and female mice continuously breathed an inspired oxygen fraction of 0.21 (normoxia) or 0.10 (hypoxia) in a normobaric chamber for six weeks. We assessed hemoglobin (Hb) concentrations, right ventricular systolic pressure (RVSP), and transthoracic echocardiographic parameters (pulmonary acceleration time (PAT) and right ventricular (RV) wall thickness). Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels were measured in Cyp2j(-/-) and Cyp2j(+/+) male mice At baseline Cyp2j(-/-) and Cyp2j(+/+) mice had similar Hb levels and RVSP while breathing air. After 6 weeks of hypoxia, circulating Hb concentration increased but did not differ between Cyp2j(-/-) and Cyp2j(+/+) mice. Chronic hypoxia increased RVSP in both Cyp2j(-/-) and Cyp2j(+/+) mice of either gender. Exposure to chronic hypoxia decreased PAT and increased RV wall thickness in both genotypes and genders to a similar extent. Prolonged exposure to hypoxia produced similar levels of RV hypertrophy in both genotypes of either gender. Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels did not differ between Cyp2j-/- and Cyp2j+/+ male mice after breathing at normoxia or hypoxia for 6 weeks. These results suggest that murine Cyp2j deficiency does not attenuate the development of murine pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia in mice of both genders.

Research paper thumbnail of Vascular Components of ARDS: Clinical Pulmonary Hemodynamics and Morphology

American Review of Respiratory Disease, 1987

Mild pulmonary artery hypertension (PAP, 29.6 +/- 10.6 mm Hg, mean +/- SD) due to a 3-fold elevat... more Mild pulmonary artery hypertension (PAP, 29.6 +/- 10.6 mm Hg, mean +/- SD) due to a 3-fold elevation of pulmonary vascular resistance (PVR, 2.2 +/- 1.1 mm Hg X L/min) is a common finding in severe ARDS. A vasodilator such as nitroprusside (151 micrograms/kg X min) can be administered in early ARDS and will lower PAP and PAOP (capillary wedge pressure) while increasing cardiac output (CO) from 6.9 to 8.75 L/min X M2 and venous admixture from 23% to 31.6%. This suggests diffuse vasoconstriction is present in early ARDS. In 19 patients with severe ARDS, 13 had vascular occlusions on balloon occlusion angiography, and these occlusions correlated with increased post mortem counts of PA thrombi. At autopsy, there was a considerable increase of PA medial thickness and a reduction of lumen diameter. This hemodynamic and morphologic evidence suggests both vasoconstrictor and anatomic changes play major roles elevating the PVR in ARDS.

Research paper thumbnail of Oxygen saturation in free-diving whales: optical sensor development

Biomedical Applications of Light Scattering VII, 2013

ABSTRACT Mass stranding of live whales has been explained by proposing many natural or human-rela... more ABSTRACT Mass stranding of live whales has been explained by proposing many natural or human-related causes. Recent necropsy reports suggest a link between the mass stranding of beaked whales and the use of naval mid-frequency sonar. Surprisingly, whales have experienced symptoms similar to those caused by inert gas bubbles in human divers. Our goal is to develop a compact optical sensor to monitor the consumption of the oxygen stores in the muscle of freely diving whales. To this end we have proposed the use of a near-infrared phase-modulated frequency-domain spectrophotometer, in reflectance mode, to probe tissue oxygenation. Our probe consists of three main components: radiofrequency (RF) modulated light sources, a high-bandwidth avalanche photodiode with transimpedance amplifier, and a RF gain and phase detector. In this work, we concentrate on the design and performance of the light sensor, and its corresponding amplifier unit. We compare three state-of-the-art avalanche photodiodes: one through-hole device and two surface-mount detectors. We demonstrate that the gain due to the avalanche effect differs between sensors. The avalanche gain near maximum bias of the through-hole device exceeds by a factor of 2.5 and 8.3 that of the surface-mount detectors. We present the behavior of our assembled through-hole detector plus high-bandwidth transimpedance amplifier, and compare its performance to that of a commercially available module. The assembled unit enables variable gain, its phase noise is qualitatively lower, and the form factor is significantly smaller. Having a detecting unit that is compact, flexible, and functional is a milestone in the development of our tissue oxygenation tag.

Research paper thumbnail of Diabetes augments and inhaled nitric oxide prevents the adverse hemodynamic effects of transfusing syngeneic stored blood in mice

Transfusion, 2012

BACKGROUND: Stored red blood cells (RBCs) undergo progressive deleterious functional, biochemical... more BACKGROUND: Stored red blood cells (RBCs) undergo progressive deleterious functional, biochemical, and structural changes. The mechanisms responsible for the adverse effects of transfusing stored RBCs remain incompletely elucidated. STUDY DESIGN AND METHODS: Awake wild-type (WT) mice, WT mice fed a high-fat diet (HFD-fed WT) for 4 to 6 weeks, and diabetic (db/db) mice were transfused with syngeneic leukoreduced RBCs or supernatant with or without oxidation (10% of total blood volume) after storage for not more than 24 hours (FRBCs) or 2 weeks (SRBCs). Inhaled nitric oxide (NO) at 80 parts per million was administered to a group of mice transfused with SRBCs. Blood and tissue samples were collected 2 hours after transfusion to measure iron and cytokine levels. RESULTS: SRBCs had altered RBC morphology and a reduced P50. Transfusion of SRBCs into WT or HFD-fed WT mice did not produce systemic hemodynamic changes. In contrast, transfusion of SRBCs or supernatant from SRBCs into db/db mice induced systemic hypertension that was prevented by concurrent inhalation of NO. Infusion of washed SRBCs or oxidized SRBC supernatant into db/db mice did not induce hypertension. Two hours after SRBC transfusion, plasma hemoglobin (Hb), interleukin-6, and serum iron levels were increased. CONCLUSION: Transfusion of syngeneic SRBCs or the supernatant from SRBCs produces systemic hypertension and vasoconstriction in db/db mice. It is likely that RBC storage, by causing in vitro hemolysis and posttransfusion hemoglobinemia, produces sustained NO scavenging and vasoconstriction in mice with endothelial dysfunction. Vasoconstriction is prevented by oxidizing the supernatant of SRBCs or breathing NO during SRBC transfusion.

Research paper thumbnail of Hemodynamic responses to a hemoglobin bis-tetramer and its polyethylene glycol conjugate

Transfusion, 2012

The design of hemoglobin-based oxygen carriers (HBOCs) poses a significant challenge as clinical ... more The design of hemoglobin-based oxygen carriers (HBOCs) poses a significant challenge as clinical trials of many materials have reported adverse side effects that may come from the scavenging of the vasodilator nitric oxide (NO). A compensating reaction, reduction of endogenous nitrite by hemoglobin (Hb) and its derivatives, generates NO. Polyethylene glycol (PEG) conjugation of Hb enhances the rate of the reaction. STUDY DESIGN AND METHODS: Hemoglobin bistetramers (BT) and their PEGylated derivative (BT-PEG) bind oxygen with a degree of cooperativity and also have significantly enhanced nitrite reductase activity compared to the native protein. Circulatory evaluation will test if the properties of BT and BT-PEG are reflected in their effects in vivo. BT and BT-PEG were evaluated as infusions into healthy wild-type (WT) and diabetic (db/db) mouse models. The effects were compared to infusions of murine Hb. RESULTS: The materials were found not to cause significant increases in systemic blood pressure in either WT mice or db/db mice. The latter are highly sensitive to NO scavenging. Further hemodynamic measurements in WT mice indicate that while a slight increase in systemic vascular resistance (SVR) was observed after infusion of BT, the extent is not significant. No change in SVR from baseline was observed after infusion of BT-PEG. CONCLUSION: The enlarged Hb derivatives do not evoke unfavorable circulatory responses that have been noted to result from infusion of Hb derivatives. These results suggest that a compromise between the P50, n50, and nitrite reductase activity of a Hb derivative can serve as the basis for producing HBOCs that can be tested for vasoactivity.

Research paper thumbnail of Inhaled nitric oxide

Seminars in Perinatology, 2000

Nitric oxide (NO) is a free-radical gas that is an important signaling molecule in pulmonary vess... more Nitric oxide (NO) is a free-radical gas that is an important signaling molecule in pulmonary vessels.

Research paper thumbnail of Autologous tansfusion of stored red blood cells increases pulmonary artery pressure

Research paper thumbnail of 5-Lipoxygenase Deficiency Prevents Respiratory Failure during Ventilator-induced Lung Injury

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Rationale: Mechanical ventilation with high tidal volumes (HV T ) progressively leads to lung inj... more Rationale: Mechanical ventilation with high tidal volumes (HV T ) progressively leads to lung injury and decreased efficiency of gas exchange. Hypoxic pulmonary vasoconstriction (HPV) directs blood flow to well-ventilated lung regions preserving systemic oxygenation during pulmonary injury. Recent experimental studies have revealed an important role for leukotriene (LT) biosynthesis by 5-lipoxygenase (5LO) in the impairment of HPV by endotoxin. Objectives: To investigate whether or not impairment of HPV contributes to the hypoxemia associated with HV T and to evaluate the role of LTs in ventilator-induced lung injury (VILI). Methods: We studied wild-type and 5LO-deficient mice ventilated for up to 10 hours with low tidal volumes (LV T ) or HV T . Results: In wild-type mice, HV T , but not LV T , increased pulmonary vascular permeability and edema formation, impaired systemic oxygenation, and reduced survival. HPV, as reflected by the increase in left pulmonary vascular resistance (LPVR) induced by left mainstem bronchus occlusion (LMBO), was markedly impaired in animals ventilated with HV T . HV T ventilation increased bronchoalveolar lavage levels of LTs and neutrophils. In 5LO-deficient mice, the HV Tinduced increase of pulmonary vascular permeability and worsening of respiratory mechanics were markedly attenuated, systemic oxygenation was preserved, and survival increased.

Research paper thumbnail of 99mTechnetium-Fibrinogen Lung Scanning in Canine Lung Contusion

Journal of Trauma and Acute Care Surgery, Jun 30, 1984

... In the center of contusion #2, the mean Tc activity per gram of contused lung tissue was 12.2... more ... In the center of contusion #2, the mean Tc activity per gram of contused lung tissue was 12.22 ± 1.95 (mean ± SE) times the Tc activity of a gram of normal lung tissue and was significantly greater than the activity of the pericontused region, which was 3.05 ± 0.50 times the ...

Research paper thumbnail of Pulmonary Hypertension after Prolonged Hypoxic Exposure in Mice with a Congenital Deficiency of Cyp2j

American Journal of Respiratory Cell and Molecular Biology, May 1, 2015

Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pul... more Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pulmonary vascular tone and hypoxic pulmonary vasoconstriction. We investigated whether the attenuated acute vasoconstrictor response to hypoxic exposure of Cyp2j(-/-) mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j(-/-) and Cyp2j(+/+) male and female mice continuously breathed an inspired oxygen fraction of 0.21 (normoxia) or 0.10 (hypoxia) in a normobaric chamber for six weeks. We assessed hemoglobin (Hb) concentrations, right ventricular systolic pressure (RVSP), and transthoracic echocardiographic parameters (pulmonary acceleration time (PAT) and right ventricular (RV) wall thickness). Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels were measured in Cyp2j(-/-) and Cyp2j(+/+) male mice At baseline Cyp2j(-/-) and Cyp2j(+/+) mice had similar Hb levels and RVSP while breathing air. After 6 weeks of hypoxia, circulating Hb concentration increased but did not differ between Cyp2j(-/-) and Cyp2j(+/+) mice. Chronic hypoxia increased RVSP in both Cyp2j(-/-) and Cyp2j(+/+) mice of either gender. Exposure to chronic hypoxia decreased PAT and increased RV wall thickness in both genotypes and genders to a similar extent. Prolonged exposure to hypoxia produced similar levels of RV hypertrophy in both genotypes of either gender. Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels did not differ between Cyp2j-/- and Cyp2j+/+ male mice after breathing at normoxia or hypoxia for 6 weeks. These results suggest that murine Cyp2j deficiency does not attenuate the development of murine pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia in mice of both genders.

Research paper thumbnail of Inhibition of Soluble Epoxide Hydrolase Augments Hypoxic Pulmonary Vasoconstriction and Improves Gas Exchange in Mice

The Faseb Journal, Apr 1, 2013

Research paper thumbnail of Inhaled Nitric Oxide Dilates Human Hypoxic Pulmonary Vasoconstriction Without Causing Systemic Vasodilation

Research paper thumbnail of Nitric Oxide Inhalation Decreases Pulmonary Artery Remodeling in the Injured Lungs of Rat Pups

Vascular injury causes the muscularization of peripheral pulmonary arteries, which is more pronou... more Vascular injury causes the muscularization of peripheral pulmonary arteries, which is more pronounced in the infant than in the adult lung. Although inhaled NO gas attenuates pulmonary artery remodeling in hypoxic rats, whether or not it protects the lung by mitigating vasoconstriction is unknown. This investigation tested whether inhaled NO decreases the muscularization of injured pulmonary arteries in rat pups by modulating vascular tone. One week after monocrotaline administration, the percentage of muscularized rat pup lung arteries was increased by Ͼ3-fold. Nevertheless, monocrotaline exposure did not cause right ventricular hypertrophy, pulmonary hypertension, or vasoconstriction. In addition, it did not increase the expression of markers of inflammation (interleukin-1␤, intercellular adhesion molecule-1, and E-selectin) or of platelet-mediated thrombosis (GPIb␣). Continuous inhalation of 20 ppm NO gas prevented the neomuscularization of the pulmonary arteries in pups with lung injury. Moreover, a 3-fold increase in cell proliferation and 30% decrease in cell numbers in pulmonary arteries caused by monocrotaline exposure was prevented by NO inhalation. These data indicate that inhaled NO protects infants against pulmonary remodeling induced by lung injury by mechanisms that are independent of pulmonary tone, inflammation, or thrombosis. (Circ Res. 2000;87:140-145.) Key Words: inhaled nitric oxide Ⅲ pulmonary hypertension Ⅲ proliferation Ⅲ congenital heart disease Ⅲ bronchopulmonary dysplasia

Research paper thumbnail of Differential Changes of Alveolar Gas Concentrations During Anesthetic Induction of a Patient with an Absent Right Pulmonary Artery

Anesthesia and Analgesia, Sep 1, 2006

A 38-yr-old man with congenital right pulmonary artery agenesis, whose right lung was perfused wi... more A 38-yr-old man with congenital right pulmonary artery agenesis, whose right lung was perfused with collateral systemic arterial blood, presented for right pneumonectomy. Because of a likely difference in gas exchange between the two lungs, we sampled end-tidal gases from each lung individually, as well as from the common gas outlet of a double-lumen endobronchial tube. Our results indicated a higher end-tidal CO 2 from the left, normally perfused, lung than from the right, systemically perfused, lung. We also determined uptake of sevoflurane from each lung, demonstrating a more rapid uptake in the left lung than in the right. In conclusion, we report the rare case of unilateral pulmonary artery agenesis with systemic arterial collateralization and characterize the differences in gas exchange.

Research paper thumbnail of Abstract 10990: Identification of a Critical Role for BMP Signaling in Atherogenesis

Circulation, Nov 23, 2010

Research paper thumbnail of BMP Type I Receptor ALK2 is Required for Angiotensin II-Induced Cardiac Hypertrophy

American Journal of Physiology - Heart and Circulatory Physiology, 2016

Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy.... more Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine (PE)-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 (LDN) or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of PE to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T-cells (NFAT), providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN attenuated angiotensin II-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2, but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/NFAT pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis.

Research paper thumbnail of Abstract 13617: Bone Morphogenetic Protein Signaling is a Regulator of Hepatic Cholesterol Biosynthesis in vitro and in vivo

Circulation, Nov 22, 2011

Research paper thumbnail of Pathophysiologic Pathways of the Adult Respiratory Distress Syndrome

Care of the Critically Ill Patient, 1983

Research paper thumbnail of Nitric oxide synthase 3 deficiency does not prevent the adverse effects of transfusing stored blood in murine hemorrhagic shock

Research paper thumbnail of Autologous transfusion of stored red blood cells increases pulmonary artery pressure

American journal of respiratory and critical care medicine, 2014

Transfusion of erythrocytes stored for prolonged periods is associated with increased mortality. ... more Transfusion of erythrocytes stored for prolonged periods is associated with increased mortality. Erythrocytes undergo hemolysis during storage and after transfusion. Plasma hemoglobin scavenges endogenous nitric oxide leading to systemic and pulmonary vasoconstriction. We hypothesized that transfusion of autologous blood stored for 40 days would increase the pulmonary artery pressure in volunteers with endothelial dysfunction (impaired endothelial production of nitric oxide). We also tested whether breathing nitric oxide before and during transfusion could prevent the increase of pulmonary artery pressure. Fourteen obese adults with endothelial dysfunction were enrolled in a randomized crossover study of transfusing autologous, leukoreduced blood stored for either 3 or 40 days. Volunteers were transfused with 3-day blood, 40-day blood, and 40-day blood while breathing 80 ppm nitric oxide. The age of volunteers was 41 ± 4 years (mean ± SEM), and their body mass index was 33.4 ± 1.3 k...

Research paper thumbnail of Pulmonary Hypertension After Prolonged Hypoxic Exposure In Mice With a Congenital Deficiency of Cyp2j

American Journal of Respiratory Cell and Molecular Biology, 2013

Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pul... more Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pulmonary vascular tone and hypoxic pulmonary vasoconstriction. We investigated whether the attenuated acute vasoconstrictor response to hypoxic exposure of Cyp2j(-/-) mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j(-/-) and Cyp2j(+/+) male and female mice continuously breathed an inspired oxygen fraction of 0.21 (normoxia) or 0.10 (hypoxia) in a normobaric chamber for six weeks. We assessed hemoglobin (Hb) concentrations, right ventricular systolic pressure (RVSP), and transthoracic echocardiographic parameters (pulmonary acceleration time (PAT) and right ventricular (RV) wall thickness). Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels were measured in Cyp2j(-/-) and Cyp2j(+/+) male mice At baseline Cyp2j(-/-) and Cyp2j(+/+) mice had similar Hb levels and RVSP while breathing air. After 6 weeks of hypoxia, circulating Hb concentration increased but did not differ between Cyp2j(-/-) and Cyp2j(+/+) mice. Chronic hypoxia increased RVSP in both Cyp2j(-/-) and Cyp2j(+/+) mice of either gender. Exposure to chronic hypoxia decreased PAT and increased RV wall thickness in both genotypes and genders to a similar extent. Prolonged exposure to hypoxia produced similar levels of RV hypertrophy in both genotypes of either gender. Pulmonary Cyp2c29, Cyp2c38 and sEH mRNA levels did not differ between Cyp2j-/- and Cyp2j+/+ male mice after breathing at normoxia or hypoxia for 6 weeks. These results suggest that murine Cyp2j deficiency does not attenuate the development of murine pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia in mice of both genders.

Research paper thumbnail of Vascular Components of ARDS: Clinical Pulmonary Hemodynamics and Morphology

American Review of Respiratory Disease, 1987

Mild pulmonary artery hypertension (PAP, 29.6 +/- 10.6 mm Hg, mean +/- SD) due to a 3-fold elevat... more Mild pulmonary artery hypertension (PAP, 29.6 +/- 10.6 mm Hg, mean +/- SD) due to a 3-fold elevation of pulmonary vascular resistance (PVR, 2.2 +/- 1.1 mm Hg X L/min) is a common finding in severe ARDS. A vasodilator such as nitroprusside (151 micrograms/kg X min) can be administered in early ARDS and will lower PAP and PAOP (capillary wedge pressure) while increasing cardiac output (CO) from 6.9 to 8.75 L/min X M2 and venous admixture from 23% to 31.6%. This suggests diffuse vasoconstriction is present in early ARDS. In 19 patients with severe ARDS, 13 had vascular occlusions on balloon occlusion angiography, and these occlusions correlated with increased post mortem counts of PA thrombi. At autopsy, there was a considerable increase of PA medial thickness and a reduction of lumen diameter. This hemodynamic and morphologic evidence suggests both vasoconstrictor and anatomic changes play major roles elevating the PVR in ARDS.

Research paper thumbnail of Oxygen saturation in free-diving whales: optical sensor development

Biomedical Applications of Light Scattering VII, 2013

ABSTRACT Mass stranding of live whales has been explained by proposing many natural or human-rela... more ABSTRACT Mass stranding of live whales has been explained by proposing many natural or human-related causes. Recent necropsy reports suggest a link between the mass stranding of beaked whales and the use of naval mid-frequency sonar. Surprisingly, whales have experienced symptoms similar to those caused by inert gas bubbles in human divers. Our goal is to develop a compact optical sensor to monitor the consumption of the oxygen stores in the muscle of freely diving whales. To this end we have proposed the use of a near-infrared phase-modulated frequency-domain spectrophotometer, in reflectance mode, to probe tissue oxygenation. Our probe consists of three main components: radiofrequency (RF) modulated light sources, a high-bandwidth avalanche photodiode with transimpedance amplifier, and a RF gain and phase detector. In this work, we concentrate on the design and performance of the light sensor, and its corresponding amplifier unit. We compare three state-of-the-art avalanche photodiodes: one through-hole device and two surface-mount detectors. We demonstrate that the gain due to the avalanche effect differs between sensors. The avalanche gain near maximum bias of the through-hole device exceeds by a factor of 2.5 and 8.3 that of the surface-mount detectors. We present the behavior of our assembled through-hole detector plus high-bandwidth transimpedance amplifier, and compare its performance to that of a commercially available module. The assembled unit enables variable gain, its phase noise is qualitatively lower, and the form factor is significantly smaller. Having a detecting unit that is compact, flexible, and functional is a milestone in the development of our tissue oxygenation tag.

Research paper thumbnail of Diabetes augments and inhaled nitric oxide prevents the adverse hemodynamic effects of transfusing syngeneic stored blood in mice

Transfusion, 2012

BACKGROUND: Stored red blood cells (RBCs) undergo progressive deleterious functional, biochemical... more BACKGROUND: Stored red blood cells (RBCs) undergo progressive deleterious functional, biochemical, and structural changes. The mechanisms responsible for the adverse effects of transfusing stored RBCs remain incompletely elucidated. STUDY DESIGN AND METHODS: Awake wild-type (WT) mice, WT mice fed a high-fat diet (HFD-fed WT) for 4 to 6 weeks, and diabetic (db/db) mice were transfused with syngeneic leukoreduced RBCs or supernatant with or without oxidation (10% of total blood volume) after storage for not more than 24 hours (FRBCs) or 2 weeks (SRBCs). Inhaled nitric oxide (NO) at 80 parts per million was administered to a group of mice transfused with SRBCs. Blood and tissue samples were collected 2 hours after transfusion to measure iron and cytokine levels. RESULTS: SRBCs had altered RBC morphology and a reduced P50. Transfusion of SRBCs into WT or HFD-fed WT mice did not produce systemic hemodynamic changes. In contrast, transfusion of SRBCs or supernatant from SRBCs into db/db mice induced systemic hypertension that was prevented by concurrent inhalation of NO. Infusion of washed SRBCs or oxidized SRBC supernatant into db/db mice did not induce hypertension. Two hours after SRBC transfusion, plasma hemoglobin (Hb), interleukin-6, and serum iron levels were increased. CONCLUSION: Transfusion of syngeneic SRBCs or the supernatant from SRBCs produces systemic hypertension and vasoconstriction in db/db mice. It is likely that RBC storage, by causing in vitro hemolysis and posttransfusion hemoglobinemia, produces sustained NO scavenging and vasoconstriction in mice with endothelial dysfunction. Vasoconstriction is prevented by oxidizing the supernatant of SRBCs or breathing NO during SRBC transfusion.

Research paper thumbnail of Hemodynamic responses to a hemoglobin bis-tetramer and its polyethylene glycol conjugate

Transfusion, 2012

The design of hemoglobin-based oxygen carriers (HBOCs) poses a significant challenge as clinical ... more The design of hemoglobin-based oxygen carriers (HBOCs) poses a significant challenge as clinical trials of many materials have reported adverse side effects that may come from the scavenging of the vasodilator nitric oxide (NO). A compensating reaction, reduction of endogenous nitrite by hemoglobin (Hb) and its derivatives, generates NO. Polyethylene glycol (PEG) conjugation of Hb enhances the rate of the reaction. STUDY DESIGN AND METHODS: Hemoglobin bistetramers (BT) and their PEGylated derivative (BT-PEG) bind oxygen with a degree of cooperativity and also have significantly enhanced nitrite reductase activity compared to the native protein. Circulatory evaluation will test if the properties of BT and BT-PEG are reflected in their effects in vivo. BT and BT-PEG were evaluated as infusions into healthy wild-type (WT) and diabetic (db/db) mouse models. The effects were compared to infusions of murine Hb. RESULTS: The materials were found not to cause significant increases in systemic blood pressure in either WT mice or db/db mice. The latter are highly sensitive to NO scavenging. Further hemodynamic measurements in WT mice indicate that while a slight increase in systemic vascular resistance (SVR) was observed after infusion of BT, the extent is not significant. No change in SVR from baseline was observed after infusion of BT-PEG. CONCLUSION: The enlarged Hb derivatives do not evoke unfavorable circulatory responses that have been noted to result from infusion of Hb derivatives. These results suggest that a compromise between the P50, n50, and nitrite reductase activity of a Hb derivative can serve as the basis for producing HBOCs that can be tested for vasoactivity.

Research paper thumbnail of Inhaled nitric oxide

Seminars in Perinatology, 2000

Nitric oxide (NO) is a free-radical gas that is an important signaling molecule in pulmonary vess... more Nitric oxide (NO) is a free-radical gas that is an important signaling molecule in pulmonary vessels.