Structure Function Correlates in the Pulmonary Vasculature during Acute Lung Injury and Chronic Pulmonary Hypertension

1991 ◽  
Vol 19 (4_part_1) ◽  
pp. 447-457 ◽  
Author(s):  
Barbara Meyrick
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Edema ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Capillary Endothelium ◽  
Functional Changes ◽  
Structural Types ◽  
Chronic Pulmonary Hypertension ◽  
Hemodynamic Measurements

Arteries, veins, and capillaries comprise the pulmonary vasculature. Three structural types of artery and vein are identified, the most muscular vessels being the largest. For example, arteries that accompany the preacinar arteries are muscular in structure while those within the acinus may be either, muscular, partially muscular or non-muscular. These small intraacinar arteries contribute much to the hemodynamic behavior of the lung. Pulmonary edema results from damage to the capillary endothelium while chronic pulmonary hypertension is characterized by structural alterations in the pulmonary arteries. Correlation of the structural and functional changes of chronic pulmonary hypertension suggest that the increases in medial and adventitial thickness of the muscular preacinar arteries are secondary to the onset of this disease, while the changes in the peripheral arteries—appearance of muscle in smaller intraacinar arteries than normal and reduction in arterial volume—contribute to the rise in pulmonary artery pressure and pulmonary vascular resistance. Such correlations of structure and hemodynamic measurements demand that the lung be fixed in a simple and standardized manner. Available methodology to evaluate the structural changes that occur during the development of pulmonary edema and chronic pulmonary hypertension are described.

Secretory leukoprotease inhibitor attenuates lung injury induced by continuous air embolization into sheep

1995 ◽  
Vol 79 (4) ◽  
pp. 1163-1172 ◽  
Author(s):  
J. R. Gossage ◽  
E. A. Perkett ◽  
J. M. Davidson ◽  
B. C. Starcher ◽  
D. Carmichael ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Neutrophil Elastase ◽  
Serine Proteases ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor ◽  
Arterial Circulation ◽  
Chronic Pulmonary Hypertension ◽  
Lung Lymph

Continuous air embolization (CAE) into the pulmonary arterial circulation of sheep results in functional and structural changes of chronic pulmonary hypertension. Release of elastin peptides into lung lymph during CAE and attenuation of CAE-induced pulmonary hypertension by neutrophil depletion suggest that neutrophil elastase may contribute to these changes. To investigate this notion, we treated awake sheep with a potent neutrophil elastase inhibitor, recombinant secretory leukoprotease inhibitor (SLPI) (100 mg/day by aerosol), during 12 days of CAE (CAE+SLPI; n = 7). Controls included sheep receiving CAE + vehicle (VEH) (n = 6), VEH alone (n = 3), and SLPI alone (n = 3). SLPI significantly attenuated the CAE-induced increases in lung lymph flow (day 8; 2.3 +/- 0.5 vs. 5.6 +/- 1.7 ml/15 min), protein clearance (day 8; 1.36 +/- 0.32 vs. 3.08 +/- 0.84 ml/15 min), and elastin peptide concentration (day 8; 243 +/- 41 vs. 398 +/- 44 ng/ml). SLPI delayed the onset of sustained pulmonary hypertension from day 8 to day 12. Both CAE groups showed similar structural changes in the pulmonary arteries. SLPI was well tolerated in control sheep and did not affect hemodynamics or structure. We conclude that serine proteases may contribute to the early initiation of chronic pulmonary hypertension but do not play a striking role in its eventual development.

Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension

2007 ◽  
Vol 293 (1) ◽  
pp. L1-L8 ◽  
Author(s):  
Enrique Arciniegas ◽  
Maria G. Frid ◽  
Ivor S. Douglas ◽  
Kurt R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Serine Proteases ◽  
Structural Changes ◽  
Transforming Growth Factor ◽  
Pulmonary Arteries ◽  
Potential Contribution ◽  
Mesenchymal Transition ◽  
Endothelial Mesenchymal Transition

All forms of pulmonary hypertension are characterized by structural changes in pulmonary arteries. Increased numbers of cells expressing α-smooth muscle (α-SM) actin is a nearly universal finding in the remodeled artery. Traditionally, it was assumed that resident smooth muscle cells were the exclusive source of these newly appearing α-SM actin-expressing cells. However, rapidly emerging experimental evidence suggests other, alternative cellular sources of these cells. One possibility is that endothelial cells can transition into mesenchymal cells expressing α-SM actin and that this process contributes to the accumulation of SM-like cells in vascular pathologies. We review the evidence that endothelial-mesenchymal transition is an important contributor to cardiac and vascular development as well as to pathophysiological vascular remodeling. Recent work has provided evidence for the role of transforming growth factor-β, Wnt, and Notch signaling in this process. The potential roles of matrix metalloproteinases and serine proteases are also discussed. Importantly, endothelial-mesenchymal transition may be reversible. Thus insights into the mechanisms controlling endothelial-mesenchymal transition are relevant to vascular remodeling and are important as we consider new therapies aimed at reversing pulmonary vascular remodeling.

scholarly journals Pulmonary vessel casting in a rat model of monocrotaline-mediated pulmonary hypertension

2020 ◽  
Vol 10 (3) ◽  
pp. 204589402092212
Author(s):  
Zhongkai Zhu ◽  
Yifan Wang ◽  
Amy Long ◽  
Tianyu Feng ◽  
Maria Ocampo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Rat Model ◽  
Vascular System ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Control Group ◽  
Wall Thickening ◽  
Arterial Remodeling ◽  
Pulmonary Vessel ◽  
Pulmonary Arterial

Pulmonary hypertension is a chronic vascular disease characterized by pulmonary vasoconstriction and pulmonary arterial remodeling. Pulmonary arterial remodeling is mainly due to small pulmonary arterial wall thickening and lumen occlusion. Previous studies have described intravascular changes in lung sections using histopathology, but few were able to obtain a fine detailed image of the pulmonary vascular system. In this study, we used Microfil compounds to cast the pulmonary arteries in a rat model of monocrotaline-induced pulmonary hypertension. High-quality images that enabled quantification of distal pulmonary arterial branching based on the number of vessel bifurcations/junctions were demonstrated in this model. The branch and junction counts of distal pulmonary arteries significantly decreased in the monocrotaline group compared to the control group, and this effect was inversely proportional to the mean pulmonary artery pressure observed in each group. The patterns of pulmonary vasculature and the methods for pulmonary vessel casting are presented to provide a basis for future studies of pulmonary arterial remodeling due to pulmonary hypertension and other lung diseases that involve the remodeling of vasculature.

scholarly journals Update on the Use of Inhaled Nitric Oxide

1996 ◽  
Vol 3 (6) ◽  
pp. 373-376 ◽  
Author(s):  
Robert M Kacmarek
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Inhaled Nitric Oxide ◽  
Pulmonary Vasculature ◽  
Vascular Effects ◽  
The Past ◽  
Chronic Pulmonary Hypertension ◽  
Transplant Candidates ◽  
Nitric Oxide Therapy ◽  
Rapid Binding

A literature review on nitric oxide would identify thousands of citations on the biological implications of this molecule. From the perspective of respiratory care, the effect inhaled nitric oxide has on pulmonary vasculature is the most intriguing. Over the past five years inhaled nitric oxide has been shown to be useful in the management of oxygenation during acute respiratory distress syndrome, alternation of pulmonary vascular tone in persistent pulmonary hypertension in the newborn, and in the management of chronic pulmonary hypertension in both heart and lung transplant candidates, as well as other potential clinical uses. The key physioligical response is vasodilation of pulmonary vessels in communication with well ventilated lung units and the absence of systemic vascular effects by rapid binding to hemoglobin. Nitric oxide therapy is considered experimental. A delivery system is not commercially available. This has resulted in the development of makeshift delivery systems, many of which may have the potential for adverse effects.

scholarly journals Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs

2016 ◽  
Vol 311 (4) ◽  
pp. L743-L753 ◽  
Author(s):  
Anna Dikalova ◽  
Judy L. Aschner ◽  
Mark R. Kaplowitz ◽  
Marshall Summar ◽  
Candice D. Fike
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Disease Onset ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Hypoxic Exposure ◽  
No Production ◽  
Major Purpose ◽  
Newborn Piglets ◽  
Enos Uncoupling

We previously showed that newborn piglets who develop pulmonary hypertension during exposure to chronic hypoxia have diminished pulmonary vascular nitric oxide (NO) production and evidence of endothelial NO synthase (eNOS) uncoupling (Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Am J Respir Cell Mol Biol 53: 255–264, 2015). Tetrahydrobiopterin (BH4) is a cofactor that promotes eNOS coupling. Current clinical strategies typically invoke initiating treatment after the diagnosis of pulmonary hypertension, rather than prophylactically. The major purpose of this study was to determine whether starting treatment with an oral BH4 compound, sapropterin dihydrochloride (sapropterin), after the onset of pulmonary hypertension would recouple eNOS in the pulmonary vasculature and ameliorate disease progression in chronically hypoxic piglets. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received oral sapropterin starting on day 3 of hypoxia and continued throughout an additional 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios (a measure of eNOS coupling), NO production, and superoxide (O2·−) generation. Although higher than in normoxic controls, pulmonary vascular resistance was lower in sapropterin-treated hypoxic piglets than in untreated hypoxic piglets. Consistent with eNOS recoupling, eNOS dimer-to-monomer ratios and NO production were greater and O2·− generation was less in pulmonary arteries from sapropterin-treated than untreated hypoxic animals. When started after disease onset, oral sapropterin treatment inhibits chronic hypoxia-induced pulmonary hypertension at least in part by recoupling eNOS in the pulmonary vasculature of newborn piglets. Rescue treatment with sapropterin may be an effective strategy to inhibit further development of pulmonary hypertension in newborn infants suffering from chronic cardiopulmonary conditions associated with episodes of prolonged hypoxia.

scholarly journals Vascular Remodeling Protects against Ventilator-induced Lung Injury in the In Vivo  Rat

2008 ◽  
Vol 108 (6) ◽  
pp. 1047-1054 ◽  
Author(s):  
Alik Kornecki ◽  
Doreen Engelberts ◽  
Patrick McNamara ◽  
Robert P. Jankov ◽  
Conán McCaul ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Vascular Remodeling ◽  
Kinase Inhibitor ◽  
Lung Mechanics ◽  
Pulmonary Vasculature ◽  
Ventilator Induced Lung Injury ◽  
Chronic Pulmonary Hypertension

Background The role of the pulmonary vasculature in the pathogenesis of ventilator-induced lung injury is not well established. In this study, the authors investigated the effect of vascular remodeling due to chronic pulmonary hypertension on susceptibility to ventilator-induced lung injury. The authors hypothesized that the enhanced vascular tensile strength associated with pulmonary vascular remodeling would protect against ventilator-induced lung injury. Methods Chronic pulmonary arterial hypertension was induced in rats by exposure to hypoxia for 28 days and was confirmed by demonstration of right ventricular hypertrophy. Normotensive and hypertensive groups of rats (as well as a group in which pulmonary hypertension was acutely reversed with a Rho-kinase inhibitor, Y-27632) were exposed to injurious ventilation (respiratory rate 30 min, 30/0 cm H2O) for 90 min. Lung injury was assessed by change in lung mechanics, oxygenation, edema development, and cytokine levels. Electron microscopy was used to examine vascular structure in additional animals. Results Injurious ventilation caused significant lung injury (lung compliance, oxygenation, pulmonary edema) in the normotensive controls, but not in the presence of pulmonary hypertension; acute reversal of pulmonary hypertension did not alter the lessened susceptibility to ventilator-induced lung injury. Electron microscopy demonstrated capillary endothelial and epithelial breaks in injuriously ventilated normotensive controls that were not seen with pulmonary hypertension, whether or not the pulmonary hypertension was acutely reversed. Conclusions Vascular remodeling induced by chronic pulmonary hypertension confers protection against the effects of injurious mechanical ventilation in vivo by a mechanism that may involve structural alterations rather than increased pulmonary artery pressure.

scholarly journals Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries

2021 ◽  
Author(s):  
Eric Leslie ◽  
Vanessa Lopez ◽  
Nana A.O. Anti ◽  
Rafael Alvarez ◽  
Isaac Kafeero ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Metabolic Reprogramming ◽  
Persistent Pulmonary Hypertension ◽  
Wall Thickening ◽  
Omega 3 ◽  
Alpha Linolenic Acid ◽  
Fetal Sheep ◽  
Functional Changes

Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g. eicosapentanoic acid, docosahexaenoic acid, alpha-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxydocosapentaenoic acid), and higher levels of some omega-6 metabolites (p<0.02) including 15-Keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.

scholarly journals Pulmonary hypertension: reasonable selection of specific therapy

2018 ◽  
Vol 15 (1) ◽  
pp. 45-50
Author(s):  
N A Karoli ◽  
S I Sazhnova ◽  
A P Rebrov
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial

Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.

Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats

2002 ◽  
Vol 282 (4) ◽  
pp. L703-L712 ◽  
Author(s):  
D. Dunbar Ivy ◽  
Masashi Yanagisawa ◽  
Cheryl E. Gariepy ◽  
Sarah A. Gebb ◽  
Kelley L. Colvin ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Pressure ◽  
Protective Role ◽  
Pulmonary Vasculature ◽  
Pulmonary Resistance ◽  
Hypoxic Pulmonary Hypertension ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Endothelin B ◽  
Nitric Oxide Metabolites

Mechanisms by which endothelin (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ETA) receptor causes vasoconstriction, stimulation of ET type B (ETB) receptors can elicit vasodilation or vasoconstriction. We hypothesized that the ETB receptor attenuates the development of hypoxic pulmonary hypertension and studied a genetic rat model of ETB receptor deficiency (transgenic sl/sl). After 3 wk of severe hypoxia, the transgenic sl/sl pulmonary vasculature lacked expression of mRNA for the ETB receptor and developed exaggerated pulmonary hypertension that was characterized by elevated pulmonary arterial pressure, diminished cardiac output, and increased total pulmonary resistance. Plasma ET-1 was fivefold higher in transgenic sl/sl rats than in transgenic controls. Although mRNA for prepro-ET-1 was not different, mRNA for ET-converting enzyme-1 was higher in transgenic sl/sl than in transgenic control lungs. Hypertensive lungs of sl/sl rats also produced less nitric oxide metabolites and 6-ketoprostaglandin F1α, a metabolite of prostacyclin, than transgenic controls. These findings suggest that the ETB receptor plays a protective role in the pulmonary hypertensive response to chronic hypoxia.

Selective Pulmonary Vasodilation Induced by Aerosolized Zaprinast 

1998 ◽  
Vol 88 (2) ◽  
pp. 410-416 ◽  
Author(s):  
Fumito Ichinose ◽  
Christophe Adrie ◽  
William E. Hurford ◽  
Kenneth D. Bloch ◽  
Warren M. Zapol
Keyword(s):  
Pulmonary Hypertension ◽  
Muscle Relaxation ◽  
Recovery Period ◽  
Phosphodiesterase Inhibitor ◽  
Smooth Muscle Relaxation ◽  
Pulmonary Vasculature ◽  
Pulmonary Vasodilation ◽  
Chronic Pulmonary Hypertension ◽  
Selective Pulmonary Vasodilation ◽  
Inhaled No

Background Zaprinast, an inhibitor of guanosine-3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase, augments smooth muscle relaxation induced by endothelium-dependent vasodilators (including inhaled nitric oxide [NO]). The present study was designed to examine the effects of inhaled nebulized zaprinast, alone, and combined with inhaled NO. Methods Eight awake lambs with U46619-induced pulmonary hypertension sequentially breathed two concentrations of NO (5 and 20 ppm), followed by inhalation of aerosols generated from solutions containing four concentrations of zaprinast (10, 20, 30, and 50 mg/ml). The delivered doses of nebulized zaprinast at each concentration (mean +/- SD) were 0.23 +/- 0.06, 0.49 +/- 0.14, 0.71 +/- 0.24, and 1.20 +/- 0.98 mg x kg(-1) x min(-1), respectively. Each lamb also breathed NO (5 and 20 ppm) and zaprinast (0.23 +/- 0.06 mg x kg[-1] x min[-1]) in combination after a 2-h recovery period. Results Inhaled NO selectively dilated the pulmonary vasculature. Inhaled zaprinast selectively dilated the pulmonary circulation and potentiated and prolonged the pulmonary vasodilating effects of inhaled NO. The net transpulmonary release of cGMP was increased by inhalation of NO, zaprinast, or both. The duration of the vasodilation induced by zaprinast inhalation was greater than that induced by NO inhalation. Conclusions Aerosolization of a cGMP-selective phosphodiesterase inhibitor alone or combined with NO may be a useful noninvasive therapeutic method to treat acute or chronic pulmonary hypertension.

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