Loss Of Hypoxic Pulmonary Vasoconstriction Research Articles

Effects of rescue inhaled nitric oxide on right ventricle and pulmonary circulation in severe COVID-related acute respiratory distress syndrome.

PurposesTo assess the effects of inhaled Nitric Oxide (iNO) on right ventricle dimension and function and systolic pulmonary arterial pressures in severe Acute Respiratory Distress (ARDS) due to Sars-Cov2 (COVID) infection.Materials and methodsWe assessed the effects of iNO on right ventricle dimension and function and systolic pulmonary arterial pressures in 12 consecutive COVID-related ARDS patients by means of serial echocardiographic exams (baseline, 12 and 24 h since iNO start).ResultsInhaled NO administration did not influence systolic pulmonary arterial pressures nor RV dimension and function. No changes were detectable in ventilatory data with iNO administration. Considering the negligible effect on oxygenation, iNO use was discontinued in all cases.ConclusionsIn COVID-related severe ARDS iNO administrated as rescue therapy is not able to ameliorate oxygenation nor pulmonary hypertension, as assessed by serial echocardiograms. This finding may be explained by the diffuse loss of hypoxic pulmonary vasoconstriction with increased perfusion around alveolar consolidations which characterizes COVID-related severe ARDS.

Dihydropyridine Calcium Channel Blockers and the Risk of Severe COVID-19

V˙/Q˙ mismatch and the loss of hypoxic pulmonary vasoconstriction play a pivotal role in the pathophysiology of COVID-19 respiratory distress.1,2 Dihydropyridine calcium channel blockers (CCBs), frequently prescribed first-line antihypertensive agents, have the potential to disrupt hypoxic pulmonary vasoconstriction3 and worsen V̇/Q̇ mismatch that leads to profound hypoxemia in patients with pulmonary disease.4 We hypothesized that CCBs would be associated with worse respiratory failure in patients with COVID-19.

Differentiating COVID-19 Pneumonia From Acute Respiratory Distress Syndrome and High Altitude Pulmonary Edema: Therapeutic Implications.

Differentiating COVID-19 Pneumonia From Acute Respiratory Distress Syndrome and High Altitude Pulmonary Edema: Therapeutic Implications.

Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice.

BackgroundInhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it’s biochemical mechanisms and effects on inflammatory reactions.MethodsMice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured.ResultsHPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3rd and 6th hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines.ConclusionLow-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression.

Hypoxic pulmonary vasoconstriction, carotid body function and erythropoietin production in adult rats perinatally exposed to hyperoxia.

Adult animals that have been perinatally exposed to oxygen-rich atmospheres (hyperoxia), recalling those used for oxygen therapy in infants, exhibit a loss of hypoxic pulmonary vasoconstriction, whereas vasoconstriction elicited by depolarizing agents is maintained. Loss of pulmonary hypoxic vasoconstriction is not linked to alterations in oxygen-sensitive K(+) currents in pulmonary artery smooth muscle cells. Loss of hypoxic vasoconstriction is associated with early postnatal oxidative damage and corrected by an antioxidant diet. Perinatal hyperoxia damages carotid body chemoreceptor cell function and the antioxidant diet does not reverse it. The hypoxia-elicited increase in erythropoietin plasma levels is not affected by perinatal hyperoxia. The potential clinical significance of the findings in clinical situations such as pneumonia, chronic obstructive pulmonary disease or general anaesthesia is considered. Adult mammalians possess three cell systems that are activated by acute bodily hypoxia: pulmonary artery smooth muscle cells (PASMC), carotid body chemoreceptor cells (CBCC) and erythropoietin (EPO)-producing cells. In rats, chronic perinatal hyperoxia causes permanent carotid body (CB) atrophy and functional alterations of surviving CBCC. There are no studies on PASMC or EPO-producing cells. Our aim is to define possible long-lasting functional changes in PASMC or EPO-producing cells (measured as EPO plasma levels) and, further, to analyse CBCC functional alterations. We used 3- to 4-month-old rats born and reared in a normal atmosphere or exposed to perinatal hyperoxia (55-60% O2 for the last 5-6days of pregnancy and 4weeks after birth). Perinatal hyperoxia causes an almost complete loss of hypoxic pulmonary vasoconstriction (HPV), which was correlated with lung oxidative status in early postnatal life and prevented by antioxidant supplementation in the diet. O2 -sensitivity of K(+) currents in the PASMC of hyperoxic animals is normal, indicating that their inhibition is not sufficient to trigger HPV. Perinatal hyperoxia also abrogated responses elicited by hypoxia on catecholamine and cAMP metabolism in the CB. An increase in EPO plasma levels elicited by hypoxia was identical in hyperoxic and control animals, implying a normal functioning of EPO-producing cells. The loss of HPV observed in adult rats and caused by perinatal hyperoxia, comparable to oxygen therapy in premature infants, might represent a previously unrecognized complication of such a medical intervention capable of aggravating medical conditions such as regional pneumonias, atelectases or general anaesthesia in adult life.

Pathophysiologie des akuten Lungenversagens bei Schwerbrandverletzten mit Inhalationstrauma

This review article describes the pathophysiological aspects of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), induced by combined burn and smoke inhalation and examines various therapeutic approaches. The injury results in a fall in arterial oxygenation as a result of airway obstruction, increased pulmonary transvascular fluid flux and loss of hypoxic pulmonary vasoconstriction. The changes in cardiopulmonary function are mediated by reactive oxygen and nitrogen species. Nitric oxide (NO) is generated by both inducible and constitutive isoforms of nitric oxide synthase (NOS). Recently, neuronal NOS emerged as a major component within the pathogenesis of ARDS. NO rapidly combines with the oxygen radical superoxide to form reactive and highly toxic nitrogen species such as peroxynitrite. The control of NO formation involves poly(ADP-ribose) polymerase and its ability to up-regulate the activity of nuclear transcription factors through ribosylation. In addition, present data support a major role of the bronchial circulation in the injury, as blockage of bronchial blood flow will also minimize the pulmonary injury. Current data suggest that cytotoxins and activated cells are formed in the airway and carried to the parenchyma.

Neuronal nitric oxide synthase inhibition attenuates cardiopulmonary dysfunctions after combined burn and smoke inhalation injury in sheep

We hypothesized that nitric oxide derived from the neuronal nitric oxide synthase (NOS) is responsible for much of the injury resulting from skin burn and smoke inhalation. Therefore, we aimed to examine the effects of selective neuronal NOS inhibition on cardiopulmonary functions and cellular injury in sheep with acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury. Prospective, randomized, controlled laboratory experiment. Investigational intensive care unit. A total of 22 chronically instrumented adult ewes. Sheep were randomly assigned to either healthy controls (sham), injured controls (40% third-degree flame burn; 48 breaths of cotton smoke), or an injury group treated with the specific neuronal NOS inhibitor 7-nitroindazole (1 mg x kg(-1) x hr(-1)) from 1 hr postinjury to the end of the 48-hr study period. Hypoxic pulmonary vasoconstriction was assessed as decrease in left pulmonary blood flow in response to single-lung hypoxic challenges (100% nitrogen) at baseline, 24 hrs, and 48 hrs. The combination injury contributed to a approximately 90% loss of hypoxic pulmonary vasoconstriction and was associated with significant pulmonary shunting and death of one animal. The increase in nitrate/nitrite plasma levels in injured controls (12 hrs: 17 +/- 2 vs. 6 +/- 1 microM in sham animals; p < .001) was linked to increases in inducible NOS messenger RNA and 3-nitrotyrosine formation in lung tissue (48 hrs: 22 +/- 1 vs. 0.8 +/- 0.3 nM in sham animals; p < .001). 7-Nitroindazole treatment prevented the injury-associated changes in inducible NOS messenger RNA, nitrate/nitrite, and 3-nitrotyrosine, thereby attenuating the loss of hypoxic pulmonary vasoconstriction and improving gas exchange. In addition, 7-nitroindazole decreased lung tissue concentrations of hemoxygenase-1 and ameliorated myocardial depression, airway obstruction, pulmonary edema, ventilatory pressures, and histopathologic changes seen in injured controls. The present study provides evidence that neuronal NOS-derived nitric oxide plays a pivotal role in the pathogenesis of acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

The role of the bronchial circulation in the acute lung injury resulting from burn and smoke inhalation

Smoke inhalation in burn patients is a serious medical problem around the world. Inhalation injury increases mortality in addition to increasing infections, ventilator-days, and hospital stays. There are also large numbers of patients subjected to smoke inhalation without burns from cooking fires, burning crops and forest fires. The injury results in a fall in arterial oxygenation as a result of airway blockade, increased pulmonary transvascular fluid flux and loss of hypoxic pulmonary vasoconstriction. The changes in cardiopulmonary function are mediated at least in part by reactive oxygen and nitrogen species. Nitric oxide (NO) is generated by both inducible and constitutive isoforms of nitric oxide synthase (NOS). NO combines with superoxide to form reactive nitrogen species such as peroxynitrite. These reactive nitrogen species can be detected by measuring their reaction products such as 3-nitrotyrosine. The latter is elevated in the airway following smoke/burn injury. The control of NO formation involves poly (ADP ribose) polymerase (PARP) and its ability to up-regulate the activity of nuclear transcription factors through ribosylation. Present data also support a major role for the bronchial circulation in the injury since blockade of bronchial blood flow will also minimize the pulmonary injury. The data suggest that cytotoxins or activated cells are formed in the airway and carried to the parenchyma. These materials cause the formation of oedema and a reduction of PaO 2.

Combined burn and smoke inhalation injury impairs ovine hypoxic pulmonary vasoconstriction*

To examine the effects of combined burn and smoke inhalation injury on hypoxic pulmonary vasoconstriction, 3-nitrotyrosine formation, and respiratory function in adult sheep. Prospective, placebo-controlled, randomized, single-blinded trial. University research laboratory. Twelve chronically instrumented ewes. Following a baseline measurement, sheep were randomly allocated to either healthy controls (sham) or the injury group, subjected to a 40%, third-degree body surface area burn and 48 breaths of cotton smoke according to an established protocol (n = 6 each). Hypoxic pulmonary vasoconstriction was assessed as changes in pulmonary arterial blood flow (corrected for changes in cardiac index) in response to left lung hypoxic challenges performed at baseline and at 24 and 48 hrs postinjury. Combined burn and smoke inhalation was associated with increased expression of inducible nitric oxide (NO) synthase, elevated NO2/NO3 (NOx) plasma levels (12 hrs, sham, 6.2 +/- 0.6; injury, 16 +/- 1.6 micromol.L; p < .01) and increased peroxynitrite formation, as indicated by augmented lung tissue 3-nitrotyrosine content (30 +/- 3 vs. 216 +/- 8 nM; p < .001). These biochemical changes occurred in parallel with pulmonary shunting, progressive decreases in Pao2/Fio2 ratio, and a loss of hypoxic pulmonary vasoconstriction (48 hrs, -90.5% vs. baseline; p < .001). Histopathology revealed pulmonary edema and airway obstruction as the morphologic correlates of the deterioration in gas exchange and the increases in airway pressures. This study provides evidence for a severe impairment of hypoxic pulmonary vasoconstriction following combined burn and smoke inhalation injury. In addition to airway obstruction, the loss of hypoxic pulmonary vasoconstriction may help to explain why blood gases are within physiologic ranges for a certain time postinjury and then suddenly deteriorate.

Effects of a Selective Nitric Oxide Synthase Inhibitor on Endotoxin-Induced Alteration in Hypoxic Pulmonary Vasoconstriction in Sheep

It has been suggested that overproduction of nitric oxide (NO) by nitric oxide synthase (NOS) contributes to blunted hypoxic pulmonary vasoconstriction (HPV) during endotoxemia. We investigated the effect of a selective inducible NOS (iNOS) inhibitor, ONO-1714, on the loss of HPV during endotoxemia in awake sheep to clarify the role of iNOS. We prepared 11 intubated, awake sheep with hemodynamic monitoring. Hypoxic challenges (FiO2; 12%) were performed before, and 5, 24, 48, 72 hours after endotoxin (1 microg/kg) infusion for 15 minutes. Pulmonary artery (Ppa) and left atrial pressure (Pla) were continuously measured and cardiac output (CO) was measured by the thermodilution method. Pulmonary vascular resistance (PVR) was calculated by (Ppa - Pla)/CO. The percent change in PVR (%PVR) before (pre-PVR) and after (post-PVR) hypoxia was calculated as (post-PVR - pre-PVR)/pre-HPV x 100. ONO-1714 (0.1 mg/kg, n=5, Exp 1) or normal saline (n=6, Exp 2) was administered 5 hours before hypoxic challenge every day. ONO-1714 did not affect the baseline pulmonary hemodynamics before endotoxin administration. % PVR before and after hypoxic exposure was significantly decreased 5 hours after endotoxin administration and gradually improved to baseline at 72 hours. Treatment with iNOS inhibition significantly restored % HPV (24.7+/-5.5% in Exp1 versus -3.1+/-3.6% in Exp 2, 5 hours, 25.3+/-2.5% in Exp 1 versus 7.7+/-2.2% in Exp 2, 24 hours). It is suggested that inducible nitric oxide is related to pulmonary vascular hyporesponsiveness to hypoxia during endotoxemia in sheep.

Alterations in a redox oxygen sensing mechanism in chronic hypoxia.

The mechanism of acute hypoxic pulmonary vasoconstriction (HPV) may involve the inhibition of several voltage-gated K+ channels in pulmonary artery smooth muscle cells. Changes in PO2 can either be sensed directly by the channel(s) or be transmitted to the channel via a redox-based effector mechanism. In control lungs, hypoxia and rotenone acutely decrease production of activated oxygen species, inhibit K+ channels, and cause constriction. Two-day and 3-wk chronic hypoxia (CH) resulted in a decrease in basal activated oxygen species levels, an increase in reduced glutathione, and loss of HPV and rotenone-induced constriction. In contrast, 4-aminopyridine- and KCl-mediated constrictions were preserved. After 3-wk CH, pulmonary arterial smooth muscle cell membrane potential was depolarized, K+ channel density was reduced, and acute hypoxic inhibition of whole cell K+ current was lost. In addition, Kv1.5 and Kv2.1 channel protein was decreased. These data suggest that chronic reduction of the cytosol occurs before changes in K+ channel expression. HPV may be attenuated in CH because of an impaired redox sensor.

The effect of inducible nitric oxide synthase (iNOS) inhibition on smoke inhalation injury in sheep.

Recent studies on smoke inhalation injury have been focused on nitric oxide (NO) as an essential factor of progressive lung injury. We studied the effects of inducible nitric oxide synthase (iNOS) inhibition on inhalation injury in sheep. Sheep (n = 14) were prepared surgically for chronic study. After recovery period, the sheep received 48 breaths of cotton smoke. The animals were then randomised into two groups: MEG group [30 mg/kg mercaptoethylguanidine (MEG), selective inhibitor of iNOS and peroxynitrite scavenger, was given 1 h after injury and then 8 h for 41 h, n = 7] and control group (0.9% NaCl, n = 7). All animals were ventilated mechanically, and airway blood flow was measured using colored microspheres. In the control group, following significant increase in airway blood flow, deterioration in the PaO2/FiO2 ratio was observed. Whereas in the MEG group, it was not observed. In addition, the MEG group did not show significant increase in pulmonary vascular resistance and intrapulmonary shunt fraction. Lung wet/dry ratios, a marker of pulmonary edema, were significantly lower in the MEG group. At 48 h after injury, lung tissue-conjugated dienes, an index of lung oxidative tissue injury, were significantly lower in the MEG group than in the control group. Our data suggest that 1) iNOS-NO produced in the airway circulation plays a major role on the significant increase in airway blood flow, which may contribute to the spread of injury from injured airway to the lung parenchyma; 2) iNOS-NO induced in the pulmonary circulation contributes to the loss of hypoxic pulmonary vasoconstriction; and 3) iNOS-NO plays an important role on the lung oxidative tissue injury.

Nitric oxide synthase inhibition restores hypoxic pulmonary vasoconstriction in sepsis.

Hypoxic pulmonary vasoconstriction (HPV) is inhibited by inhaled nitric oxide (NO) in healthy animals and is blunted in endotoxemia. We investigated whether the loss of HPV during sepsis could be reversed by NO synthase (NOS) inhibition. Hypoxic challenges were induced in intubated, awake sheep breathing 100% nitrogen to the left lung and 100% oxygen to the right lung. HPV was assessed as the decrease in left pulmonary blood flow during hypoxia, measured with an ultrasonic flow probe around the left pulmonary artery. Group I (n = 5) received carrier solutions and Groups II (n = 6) and III (n = 8) received an infusion containing Pseudomonas aeruginosa. After 24 h, Group III also received an infusion of 6.6 mg.kg.h-1 N omega-monomethyl-L-arginine (L-NMMA). After 24 h of sepsis, HPV decreased from 60 +/- 9% in Group II and 56 +/- 4% in Group III to 27 +/- 2% and 26 +/- 4%, respectively. Group I showed no change in HPV. During infusion of L-NMMA, HPV increased to 38 +/- 4%. Pulmonary shunt during hypoxia increased in Group III to 161 +/- 10% of its baseline value, and decreased to 121 +/- 11% during infusion of L-NMMA. We conclude that L-NMMA improves but does not restore HPV, indicating that other vasodilatory mediators besides NO also influence HPV in sepsis.

Augmentation of hypoxic pulmonary vasoconstriction by N G-L-methyl-arginine in a rabbit model of thermal injury

We tested deeply anesthetized rabbits to determine if a burn acutely diminished the strength of hypoxic pulmonary vasoconstriction (HPV) and if this could be augmented by L-NMMA, a nitric oxide synthase inhibitor. We induced a burn using water heated to 75°C and assessed the strength of HPV as the difference in pulmonary vascular resistance during 100% and 13% O 2 ventilation. The rabbits then were randomized to receive 10 mg/kg L-NMMA (n = 8) or a placebo (n = 8). The strength of HPV decreased from 0.42 ± 0.11 mm Hg/mL/min preburn to 0.22 ± 0.11 mm Hg/mL/min postburn ( P < .05). L-NMMA administration augmented HPV to a postburn value of 0.48 ± 0.014 mm Hg/mL/min ( P < .05). We speculate that the loss of HPV following a burn could worsen ventilation to perfusion mismatch and thereby aggravate the hypoxia associated with burns. Augmentation of HPV might be a short-term goal during the acute stabilization of hypoxic burn patients.

Loss of hypoxic pulmonary vasoconstriction in chronic pneumonia is not mediated by nitric oxide

In pulmonary inflammatory processes such as pneumonia there is diminished hypoxic pulmonary vasoconstriction (HPV). We investigated whether the attenuated HPV in pneumonia is a due to excess nitric oxide (NO) release. Sprague-Dawley rats were anesthetized, and a slurry (0.06 ml) of infected agar beads (containing 6 x 10(5) Pseudomonas aeruginosa organisms) or control (sterile) beads was then injected into a distal bronchus through a tracheotomy. After the establishment of a chronic P. aeruginosa pneumonia (7-10 days later) animals were instrumented for hemodynamic monitoring, and the response to exposure to hypoxic gas (fraction of inspired O2 = 0.08) was recorded before and after the administration of NG-monomethyl-L-arginine (L-NMMA; 50 mg/kg), an inhibitor of NO synthesis. The hypoxic pressor response, as assessed by the absolute increase in pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR), was reduced in infected animals compared with control animals. The change in PAP and TPR was 8.5 +/- 0.7 and 0.053 +/- 0.007, respectively, in control animals compared with 5.9 +/- 0.5 and 0.041 +/- 0.011 in infected animals. After L-NMMA the increase in PAP and TPR during hypoxia was greater in both control and infected animals. However, treatment with L-NMMA did not affect the difference between control and infected animals. We conclude that excess release of NO does not account for the attenuated hypoxic pressor response in pneumonia.

NG-monomethyl-L-arginine does not restore loss of hypoxic pulmonary vasoconstriction induced by TNF-alpha

Tumor necrosis factor-alpha (TNF-alpha) causes systemic hypotension, pulmonary vasodilation, and loss of hypoxic pulmonary vasoconstriction. NG-monomethyl-L-arginine (L-NMMA) inhibits nitric oxide (NO) production and prevents some systemic manifestations of TNF-alpha. We tested using an isolated perfused canine lobe whether NO also mediates the pulmonary vascular effects of TNF-alpha. Total resistance (RT) was measured during control and hypoxic ventilation over a 90-min period in six control lobes, five lobes treated with TNF-alpha (250 micrograms), six lobes treated with L-NMMA (200 mg), and five lobes treated with L-NMMA (200 mg) + TNF-alpha (250 micrograms). In the control lobes RT increased (P < 0.02) from 0.0474 +/- 0.0105 to 0.0677 +/- 0.0133 cmH2O.ml-1 x min during normoxic and hypoxic ventilation, respectively. RT decreased (P < 0.05) from a baseline of 0.0593 +/- 0.0133 to 0.0449 +/- 0.0176 cmH2O.ml-1 x min 30 min after TNF-alpha administration and did not further change during hypoxic ventilation (0.0475 +/- 0.0107 cmH2O.ml-1 x min). L-NMMA pretreatment did not prevent the TNF-alpha-induced loss of hypoxic pulmonary vasoconstriction, with values of RT unchanged from normoxic (0.0541 +/- 0.0067 cmH2O.ml-1 x min) to hypoxic (0.0545 +/- 0.0078 cmH2O.ml-1.min) ventilation (P > 0.10) in the L-NMMA + TNF-alpha group after TNF-alpha administration. We conclude that NO is not the mediator responsible for the acute pulmonary vascular effects of TNF-alpha.

Pulmonary vascular reactivity and ischaemia-reperfusion injury in the rat.

1. The endothelium has been shown to modulate the pulmonary vascular response to hypoxia in the rat. Acute lung injury is associated with loss of hypoxic pulmonary vasoconstriction and increased pulmonary vascular permeability. Similar loss of the vascular response to hypoxia is seen after ischaemia-reperfusion injury of the myocardium. 2. The effects of reperfusion injury on pulmonary endothelial integrity, as shown by the albumin escape index and hypoxic pulmonary vasoconstriction, were investigated in isolated, blood-perfused rat lungs. 3. Ischaemia for 0.5 h, which itself caused no increase in the albumin escape index, was followed by reperfusion for 0.25 h, 0.5 h and 1 h. Controls were subjected to 2 h of perfusion only (n = 5 in all groups). The pulmonary pressor response to hypoxia (fractional inspired oxygen concentration, 3%) was measured before and after ischaemia-reperfusion, and the dilator response to acetylcholine was measured after ischaemia-reperfusion in all cases. 4. Ischaemia-reperfusion significantly increased the albumin escape index after 0.5 h (mean +/- SEM, 1.40 +/- 0.27) and 1 h (2.0 +/- 0.30) compared with controls (0.54 +/- 0.30, P < 0.05 in both cases). The pulmonary pressor response to hypoxia was augmented significantly after reperfusion when compared with baseline hypoxic pulmonary vasoconstriction (change from baseline: 13.2 +/- 4.63 and 22.2 +/- 7.1% after 0.5 and 1.0 h of reperfusion, respectively, P < 0.05). Vasorelaxation of sustained hypoxic vasoconstriction using acetylcholine was similar in both control lungs and those subjected to ischaemia-reperfusion. 5. These results suggest tht the pressor response to hypoxia is augmented after damage to the pulmonary vascular endothelium induced by ischaemic-reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased pulmonary vascular permeability in rats with biliary cirrhosis: role of thromboxane A2.

Rats with liver cirrhosis exhibit arterial hypoxemia and loss of hypoxic pulmonary vasoconstriction similar to some patients with end-stage liver disease. We hypothesized that the pulmonary circulatory dysfunction in cirrhosis results from vascular endothelial cell injury and interstitial lung edema. To investigate this hypothesis, we compared the extravascular lung albumin leak, lung ultrastructural changes, and tissue eicosanoid levels in control and cirrhotic rats. In comparison to sham-operated controls, rats with biliary cirrhosis, 6 wk after ligation of the common bile duct, had increased lung albumin leak index (1.46 +/- 0.12 vs. 0.80 +/- 0.04, P < 0.001) and bloodless lung wet-to-dry weight ratio (4.94 +/- 0.05 vs. 4.78 +/- 0.03, P < 0.05). Electron-microscopic sections of lungs from cirrhotic rats demonstrated infiltration with intravascular macrophage-like cells, endothelial cell injury, and interstitial edema. In addition, lung tissue thromboxane B2 was significantly increased in cirrhotic rats, and pretreatment with a thromboxane synthase inhibitor, dazoxiben, reduced lung thromboxane B2 level and attenuated extravascular lung albumin leak (control 1.03 +/- 0.07, cirrhotic 2.29 +/- 0.06, cirrhotic plus dazoxiben, 1.57 +/- 0.17). In contrast, WEB 2086, a platelet-activating factor antagonist, had no effect on lung albumin leak. We conclude that pulmonary vascular permeability is increased in rats with biliary cirrhosis and that thromboxane A2 contributes to the pulmonary circulatory abnormalities in cirrhosis.

Effect of endotoxin on hypoxic pulmonary vasoconstriction--the role of prostaglandins and leukotrienes.

In this study, we observed the effect of endotoxemia on hypoxic pulmonary vasoconstriction (HPV) in dogs and explored roles played by prostaglandins and leukotrienes in this process. 5 micrograms/kg BW of E. coli endotoxin induced transient rise in pulmonary arterial pressure and pulmonary vascular resistance (PVR). 30 min after injection of endotoxin when PVR tended to decline, pulmonary vasoconstriction response to alveolar hypoxia was lost, and the ratio of TXB2 to 6-keto-PGF1 alpha decreased significantly. HPV was enhanced at 60-100 min and then returned to the control level at 2 h after injection of endotoxin. At these periods the ratio of TXB2 to 6-keto-PGF1 alpha was the same as before use of endotoxin, whereas plasma concentration of leukotrienes was markedly increased. Indomethacin could prevent the early loss of HPV, but no effect on the late increment of HPV was found. Diethylcarbamazine, which blocked the production of leukotrienes after use of endotoxin, could inhibit late increment of HPV. We concluded that the early loss of HPV was related to the vasodilator prostacyclin, and the late increment of HPV was mainly brought about by leukotrienes.

Simultaneous Exposure of Sheep to Endotoxin and 100% Oxygen

The purpose of this study was to determine the effect of endotoxin on the development of vascular and airway dysfunction during O2 toxicity. Sheep were prepared for chronic measurement of vascular pressures, cardiac output, gas exchange, and collection of lung lymph. Tracheostomies were made for accurate delivery of gas mixtures. Sheep were placed in one of three experimental groups: those receiving endotoxin (n = 9), those breathing 100% O2 and receiving endotoxin (n = 7), and those exposed to 100% O2 alone (n = 6). Sheep had daily measurements of hypoxic vasoconstriction (FIO2 = 0.12), gas exchange, circulating white blood cell counts, lymph flow, and lymph and plasma protein concentrations. Lung neutrophils were counted, and copper-zinc superoxide dismutase and manganous superoxide dismutase were measured in lung samples from some sheep biopsies taken at baseline surgery and postmortem. Endotoxin markedly prolonged survival time and partially protected against the increased lung vascular permeability in sheep breathing 100% oxygen, but impairment of gas exchange, loss of hypoxic pulmonary vasoconstriction, and ultimate progression of respiratory failure were not prevented. Induction of MnSOD occurred in sheep breathing 100% O2, in sheep receiving endotoxin alone, and in those exposed to 100% O2 plus endotoxin. We conclude that endotoxin markedly increases tolerance to O2 toxicity but that some of the pathophysiology of O2 toxicity is unaltered. The role of superoxide dismutase in the observed protection is unclear.