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Unlabelled: We previously reported bronchial circulation contributes to pulmonary edema and increases shunt fraction following smoke inhalation, and bronchial blood flow significantly increases in inhalation injury. We hypothesized reduction of bronchial blood flow reduces exudation to the airway and ameliorates lung injury from combined burn and smoke insults (B&S injury)., Method: Merino ewes (n=28) randomly divided into three groups: (1) bronchial artery ligated and injured (injury+ligation group); (2) bronchial artery left intact and injured (injury+no ligation group); (3) bronchial artery ligated but not injured (no injury+ligation group) were subjected to a flame burn and inhalation injury under halothane anesthesia. Parameters were analyzed using Scheffe's post hoc test (P<0.05). All Groups were resuscitated with Ringer lactate solution and placed on a ventilator for 48h., Results: Pulmonary gas exchange (PaO(2)/FiO(2)) improved in injury+ligation group. Further, obstruction score, an index of airway cast formation, significantly changed between injury+no ligation group compared to both ligation groups., Conclusion: Bronchial circulation plays a significant role in lung injury after B&S injury, and reduction of bronchial blood flow by bronchial artery ligation reduces bronchial exudates, resulting in improved gas exchange., (Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.)

The authors devised a novel bronchial artery catheterization technique to deliver agents directly into bronchial circulation with preserved blood flow in an awake ovine model. A polyurethane catheter was inserted into bronchial artery via an incision into the 4th intercostal space. Regional blood flow of the airway was measured by fluorescent microspheres before cannulation, after cannulation, and 7 days after the operative procedure. The blood flows were also measured in a sham group (no cannulation, no ligation, n = 6), cannulation group (bronchial artery cannulation, n = 5), and ligation group (bronchial artery ligation, n = 5) at baseline and 6 hours after burn and smoke inhalation injury. The regional blood flows decreased slightly after cannulation in proximal bronchi, but recovered after 7 days. The regional blood flow increased 10-fold after inhalation injury in bronchi of the sham group. Bronchial artery ligation significantly attenuated the increase of blood flow. However, cannulation preserved regional blood flow and did not prevent the blood flow increases after burn and smoke inhalation injury, thus constituting a novel bronchial artery catheterization technique.

Purpose: To evaluate the effects of a monoclonal antibody against interleukin-8 (K2.2) on the microvascular fluid flux after combined injury by burn and smoke inhalation., Methods: Fourteen sheep were prepared surgically by placing a lung lymph catheter and a flank lymph catheter to examine the microvascular fluid flux. After a recovery period, they were subjected to a combined injury of 40% third-degree burns on the flank and smoke inhalation., Results: This combined injury induced a rapid increase in burned tissue lymph flow (b-Q(L)) and a delayed-onset increase in lung lymph flow (l-Q(L)). The initial increase in b-Q(L) was associated with an elevation of the lymph-to-plasma oncotic pressure ratio, which led to a predominant increase in the burned tissue permeability index (b-PI). Pretreatment with K2.2 had no effect on the permeability change seen in the burned tissue; however, the lung permeability changes were attenuated by pretreatment with K2.2., Conclusion: These findings indicate that the pathogenesis of the increase in microvascular fluid flux seen after the combined injury differs in burned tissue and the lung.

The bronchial circulation plays a significant role in the pathogenesis of smoke inhalation. We investigated the physiological manifestations in both the systemic and the pulmonary circulation after smoke inhalation injury, and determined whether ablation of the bronchial circulation had any effect on these changes. We used a chronically instrumented ovine model with lung and prefemoral lymph fistulae to determine the changes in pulmonary and systemic microvascular permeability. Fourteen animals were divided into two groups. The injection group had bronchial circulation ablation with an ethanol injection into the bronchial artery, whereas it was left intact in the sham group. The sham group showed a four-fold increase in lung lymph flow (l-Q(L)) and a two-fold increase in prefemoral lymph flow (s-Q(L)) 24 h after injury. The increase in s-Q(L) was associated with a decrease in lymph oncotic pressure. Therefore, systemic colloid clearance (s-CC), an indicator of systemic microvascular permeability to protein, was unchanged. The ablated bronchial circulation reversed the pulmonary but not the systemic manifestations after smoke inhalation. In conclusion, the pathophysiological events occurring after smoke inhalation were confined to the lung with increased bronchial blood flow delivering inflammatory mediators directly to the lung parenchyma.

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).

Smoke inhalation increases mortality and morbidity in burn patients. We have reported that smoke inhalation increases lung lymph flow, an index of pulmonary transvascular fluid flux and decreases reflection coefficient, an index of microvascular permeability to protein. Nitric oxide has been reported to decrease microvascular permeability to protein. We hypothesize that inhaled nitric oxide decreases pulmonary microvascular hyperpermeability following smoke inhalation. Sheep were prepared for study with a chronic lung lymph fistula, Swan-Ganz, left atrial, and femoral arterial catheters. Occluders were placed on pulmonary veins to measure reflection coefficient. All animals were insufflated with 4 x 12 breaths of cotton smoke. Sheep were randomly divided into two groups: NO (injured, treated with nitric oxide (40 ppm) inhalation, n=6) and control (injured, not treated, n=6). Nitric oxide inhalation was started 22 h after the insult. Control animals showed an increase in lung lymph flow, and lung water content. These changes were associated with marked increase in pulmonary microvascular resistance, pulmonary artery pressure, and decrease in reflection coefficient. Nitric oxide inhalation ameliorated the above-mentioned pathological changes. The results suggest that nitric oxide inhalation has potential for beneficial effect in the treatment of patients suffering from smoke inhalation.

Hyperdynamic shock can be modeled in pigs by chronic administration of a continuous, low-dose infusion of endotoxin. Lipopolysaccharide (LPS, E. coli 0111:B4, 80 ng/kg/min i.v.) initially resulted in a hypodynamic shock state with significant decreases in mean arterial pressure (112+/-3 mmHg at baseline to 94+/-4 mmHg at 8 h) and cardiac index (5.35+/-0.32 L/min/m2 at baseline to 4.07+/-0.32 L/min/m2 at 4 h). Eight hours after the initiation of the LPS infusion, cardiac index rose to above baseline values (5.82+/-0.4 L/min/m2 at 8 h) and remained elevated for the duration of the 48-h study (6.54+/-0.39 L/min/m2 at 48 h). Similarly, systemic vascular resistance fell significantly by 8 h (1640+/-100 dyne sec cm(-5) at baseline to 1239+/-80 dyne sec cm(-5) at 8 h) and remained decreased for the duration of the study. Blood flow in major abdominal vessels, including the left renal artery, the cranial mesenteric artery, and the portal vein, paralleled changes in the cardiac index. Serum concentrations of tumor necrosis factor were increased after 2 h of LPS infusion, but did not remain elevated above baseline concentrations for more than about 4 h despite continuous LPS challenge. Concentrations of tumor necrosis factor did not differ between arterial and portal venous samples. This model of hyperdynamic shock should be useful to assess potential therapies for septic shock.

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.

The effects of a monoclonal antibody against L-selectin [leukocyte adhesion molecule (LAM)1-3] on microvascular fluid flux were determined in conscious sheep subjected to a combined injury of 40% third-degree burn and smoke inhalation. This combined injury induced a rapid increase in systemic prefemoral lymph flow (sQlymph) from the burned area and a delayed-onset increase in lung lymph flow. The initial increase in sQlymph was associated with an elevation of the lymph-to-plasma oncotic pressure ratio; consequently, it leads to a predominant increase in the systemic soft tissue permeability index (sPI). In an untreated control group, the increased sPI was sustained beyond 24 h after injury. Pretreatment with LAM1-3 resulted in earlier recovery from the increased sPI, although the initial responses in sQlymph and sPI were identical to those in the nontreatment group. The delayed-onset lung permeability changes were significantly attenuated by pretreatment with LAM1-3. These findings indicate that both leukocyte-dependent and -independent mechanisms are involved in the pathogenesis that occurs after combined injury with burn and smoke inhalation.

Nitric oxide (NO) influences microvascular integrity. NO synthase inhibitors are regarded as therapeutic options, but their impact on the pulmonary microvasculature is not well defined. We studied the microvascular effects of the nonselective NO synthase inhibitor N(omega)-nitro L-arginine methylester (L-NAME) in healthy sheep and during systemic inflammation. Permeability analysis was performed in 30 adult ewes with chronic lung lymph fistulas and pulmonary venous occluders. Experiment 1: 20 sheep received Escherichia coli endotoxin (lipopolysaccharide, 10 ng/kg/min) for 32 h. After 24 h of endotoxemia, 10 sheep were given L-NAME (25 mg/kg), and 10 sheep received NaCl 0.9%. Experiment 2: six sheep were treated with L-NAME (25 mg/kg), and four animals received NaCl 0.9%. Endotoxin induced a phasic pulmonary microvascular response with early transiently increased endothelial permeability at 4 h and late normalization of microvascular integrity to large molecules after 24 h. At that time systemic vasodilation had occurred. L-NAME raised pulmonary artery pressure and pulmonary vascular resistance index without signs of increased permeability in either experiment. NO is involved in vascular tone in healthy sheep and during systemic inflammation, but it does not seem to play a role in the integrity of the pulmonary microvascular barrier function to large molecules.

Positive pressure ventilation with PEEP has been reported to reduce hypoxic pulmonary vasoconstriction (HPV) and thus increase venous admixture. This effect was investigated in six chronically instrumented unanesthetized healthy sheep. The change in left pulmonary arterial blood flow (Qlpa, ultrasonic transit time) in response to unilateral lung hypoxia (10 min of N2 alternately to the left (LLH) and right lung (RLH) was evaluated during mechanical ventilation with and without PEEP of 10 cm H2O in comparison to spontaneous breathing. In the spontaneously breathing animal and during mechanical ventilation without PEEP, Qlpa decreased during LLH from 30% to 16% of cardiac index, during RLH it increased to 51%. With 10 cm H2O of PEEP, Qlpa showed an identical reaction to hypoxia both in the left and right lung. It is concluded that mechanical ventilation and PEEP up to 10 cm H2O does not interfere with pulmonary blood flow regulation to hypoxia.

The lymphatic drainage of the lung has been used as a quantitation of pulmonary microvascular fluid flux in normal animals and after various forms of injury. This review supports the importance of the bronchial microvasculature in the formation of lung lymph. Proof that the lymph drainage of the lung comes from the pulmonary circuit has been based on the finding of an elevation of lymph flow when the pulmonary venous pressure is elevated. This proof is wanting since recent work demonstrates that the venous drainage of the intrapulmonary bronchi flows into the pulmonary vascular system at the precapillary level. The administration of endotoxin induces an elevation of lung lymph. The bronchial circuit may play a role in this response since it is likewise exposed to the high pulmonary pressures induced by endotoxin, and there is evidence that ischemia/reperfusion injury to the airway occurs with endotoxin administration. After acute lung injury from smoke inhalation, lung lymph flow is markedly elevated. The lymph drainage from the airway may play an important role in this response. Bronchial blood flow is markedly increased after inhalation injury and there is airway edema. The increases in lung lymph flow and extravascular lung water are markedly reduced by occlusion of the bronchial artery. These data support the need for additional study of the role of the bronchial circulation in the formation of lung lymph.

Discrepancies exist between experimental measurements of the systemic blood flow to sheep lung by use of microsphere techniques and flow probes on the bronchial artery. In these studies, we simultaneously measured the blood flow through the bronchial artery, using a transit time flow probe, and the systemic blood flow to left lung, using radioactive microspheres. All measurements were made on conscious sheep previously prepared with chronic catheterizations of the left atrium, aorta, and vena cava and a flow probe around the bronchial artery. Inflatable occluder cuffs were placed around the pulmonary and bronchoesophageal arteries. Bronchial artery blood flow in six sheep was 25.3 +/- 5.2 ml/min or 0.4% of the cardiac output. Systemic blood flow to left lung, measured with microspheres, was 54.1 +/- 14.2 ml/min. Calculated systemic blood flow to that portion of sheep lung perfused by the bronchial artery was 127.6 +/- 35.3 ml/min or 1.9% of cardiac output. Occlusion of the bronchoesophageal artery reduced bronchial artery flow to near zero, whereas total systemic blood to the lung was reduced by only 55%. Blood flow to the intraparenchymal cartilaginous airways was reduced 60-90% after occlusion of the bronchoesophageal artery. Sheep, like most mammals, have multiple and complex systemic arterial inputs to the lungs. We conclude that multiple branches of the bronchoesophageal artery provide most but not all of the systemic blood flow to the intraparenchymal cartilaginous airways but that over one-half of the total systemic blood flow to sheep lung comes from sources other than the common bronchial artery.

The direct pulmonary vasoconstrictive effects of inhaled carbon monoxide were evaluated in chronically instrumented and anesthetized sheep (1.7% halothane in air) (n = 8). The response to carbon monoxide (2%), which was applied for 8 minutes through a double-lumen tube alternately to the left or right lung of each animal, was compared with baseline values. The induced carboxyhemoglobin level (65%) led to increases in cardiac output, pulmonary arterial pressure, stroke volume index, and heart rate. Systemic vascular resistance decreased, and pulmonary vascular resistance and mean arterial pressure were unchanged. The changes in pressure and flow were equivalent no matter which lung was exposed to carbon monoxide. No diversion of blood from one lung to the other was observed during the test period. We conclude that carbon monoxide does not have a direct pulmonary vasoconstrictive effect. The increase in pulmonary arterial pressure is a result of the decrease in mixed venous oxygen content (stimulus for hypoxic pulmonary vasoconstriction) and the increase in cardiac output.

Hypoxic pulmonary vasoconstriction and reduced blood flow occur as a result of smoke inhalation. The aim of this study was to investigate how the amelioration of blood flow reduction by the vasodilator dopamine affects histopathologic outcome. We exposed the left lungs of chronically instrumented sheep (n = 12) to smoke, awakened them, and studied them for 24 hours. Six hours after inhalation injury, the sheep received randomized infusions of dopamine (9 micrograms/kg/min) or equal volumes of 0.9% saline solution. Pulmonary resistance in the left lungs of animals in the group that received saline solution rose continuously throughout the study period (624 +/- 48 dyne.sec.cm-5/m2 to 1747 +/- 140 dyne.sec.cm-5/m2, baseline to 24 hours after injury). Dopamine treatment caused a significantly lower vascular resistance in the injured lung than did saline solution between 8 and 24 hours after injury. The histologic evaluation of the injured lungs showed epithelial necrosis and cast formation in both groups in addition to an increased wet/dry ratio. No difference in lung injury between the groups could be distinguished. We conclude that the amelioration of blood flow reduction by treatment with dopamine in the lungs that were exposed to smoke did not affect pulmonary damage after inhalation injury.

The degree of pulmonary perfusion may have an important role in the pathogenesis of inhalation injury. We studied this in sheep that had only one lung exposed to smoke. The right lung and upper airway of 12 chronically instrumented sheep were insufflated with cotton smoke. In six animals, the left pulmonary artery was occluded between 4 and 10 h after smoke insufflation. All animals were studied for 24 h and then killed, and lung tissue was harvested. The smoked as well as the air-insufflated lung of all animals showed an increase in wet-to-dry weight ratio and tissue conjugated dienes (products of lipid peroxidation). Neither the intermittent blood flow increase to the smoked lung nor the simultaneous blood flow reduction with a concomitant polymorphonuclear neutrophil entrapment in the air-insufflated lung significantly affected the histopathological outcome of the respective lung. We conclude that tissue damage after inhalation injury cannot be diminished by increasing the flow to smoked areas. Ischemia-reperfusion injury does not have a major role in the lung damage seen with inhalation injury.

The relative roles of hematogenous mediators and direct bacterial toxicity due to phagocytosis by pulmonary intravascular macrophages were determined by selective bacterial infusion into the left pulmonary artery and comparison of right and left lungs at 24 h. Chronically instrumented sheep received 15-min pulmonary arterial infusions of live Pseudomonas aeruginosa (0.35-2.9 x 10(9), n = 6) or saline (n = 5). The saline group demonstrated stable cardiopulmonary function over time. Left lung blood flow, measured by Doppler flow probe, decreased 15 min into the bacterial infusion, with a concomitant sevenfold increase in left lung pulmonary vascular resistance index. The right lung pulmonary vascular resistance index doubled at 1 h, in association with increased plasma thromboxane B2 levels. An increase in cardiac index and decrease in systemic vascular resistance occurred at 12 h. The wet-to-dry weight ratio of the Pseudomonas-infused left lung was increased compared with that of the sham-infused lung. The tissue count of neutrophils in the lungs was doubled in both sides, but neutrophils on the left were more degranulated. The left lung tissue damage was caused by direct bacterial toxicity, including activation of phagocytic cells. Hematogenous mediators induced pulmonary and systemic hemodynamic changes and right lung neutrophil sequestration, but they did not damage the noninfused lung.

We estimated the reflection (sigma) and filtration coefficients (Kf) in a chronic sheep lung lymphatic preparation after smoke inhalation. Group I (n = 7) sheep were insufflated with cotton smoke and group II animals (n = 5) with room air. After inhalation injury, the lung lymph flow increased nearly four times the baseline value by 24 h after injury. There was a concomitant reduction of sigma (0.81 +/- 0.02 to 0.64 +/- 0.02) and elevation of Kf (0.020 +/- 0.002 to 0.042 +/- 0.009 ml.min-1.mmHg-1); pulmonary capillary pressure was also elevated (13 +/- 1 to 17 +/- 1 mmHg). By 48 h postinjury, sigma and Kf returned toward baseline but pulmonary capillary pressure was still elevated. We determined that 34% of the increase in capillary filtration was attributable to increased capillary pressure and 66% to increased permeability 24 h after inhalation, but 48 h after injury, 75% of the increase in capillary filtration was attributable to increased capillary pressure and 25% to increased permeability. We conclude that the lung edema formation following smoke inhalation is the result of marked increases in both capillary pressure and permeability.

Endotoxin [lipopolysaccharide (LPS)] has been reported to reduce hypoxic pulmonary vasoconstriction and thus increases venous admixture. The time course of this failure of pulmonary blood flow regulation was investigated in six chronically instrumented unanesthetized sheep after infusion of Escherichia coli LPS (1 microgram/kg). The change in left pulmonary arterial blood flow (LPBF, ultrasonic transit time) in response to unilateral lung hypoxia (10 min of N2 alternately to the left and right lungs) was compared before and at various time intervals after the administration of LPS. During baseline conditions, LPBF was 33% of total cardiac output and decreased to 15% when the left lung was ventilated with a hypoxic gas mixture. One hour after endotoxin infusion, LPBF remained at 33% of total cardiac output yet only decreased to 28% during the hypoxic challenge. The response to one-lung hypoxia was still significantly depressed 10 h post-LPS administration. It is concluded that hypoxic pulmonary vasoconstriction is almost completely abolished for a prolonged time period after a small dose of LPS.

Controversies exist over the influence of inhalation anaesthesia on blood flow regulation in response to local alveolar hypoxia. This study investigates the blood flow diversion from a hypoxic to an oxygenated lung in anaesthetized and ventilated animals in comparison to unanaesthetized animals. Chronically instrumented adult ewes (n = 14, 32-45 kg) were intubated one week after surgery with a modified Carlen's tube, allowing separate ventilation of the left and right lung. In the awake state (n = 7) or after one hour of constant anaesthetic conditions (n = 7, halothane 1.6% and 2.4%), cardiac output (thermodilution) and left pulmonary blood flow (ultrasonic transit time) were evaluated. Then, under identical ventilatory conditions, the left or right lung, alternately, was rendered hypoxic for 10 min by ventilation with nitrogen. The contralateral lung was ventilated with oxygen. After 10 min, haemodynamics were again recorded. The changes in left pulmonary blood flow under unilateral lung hypoxia were similar either in the awake or the anaesthetized state. Thus, we conclude that, under these experimental conditions, halothane anaesthesia and mechanical ventilation have no influence on blood flow regulation under unilateral lung hypoxia.

The lung is a critical organ in victims of thermal injury or multiple trauma since the blood that drains injured organs circulates through the pulmonary circulation before passing through any other organ. The lung therefore will receive the first volley of cytotoxins released postinjury. In addition to being a target of injury, the lung may also contribute to the injury of systemic organs. This injury may be the result of a reduced delivery of oxygenated blood or the direct release of cytotoxins into the systemic circulation. The injury to the lung may be to the pulmonary microvasculature or the airway. The bronchial circulation responds to injury by a marked elevation in its blood flow and microvascular permeability. These latter effects may be important in mediating the changes which occur in the lung parenchyma.

We devised a technique that permitted elevation of pulmonary pressures in unanesthetized sheep by occluding their pulmonary veins. Using this technique, we raised pulmonary capillary pressure from a baseline of 13.2 +/- 2.2 to 35.3 +/- 5.1 mmHg. This increased lung lymph flow (from 8.8 +/- 2.7 to 53.1 +/- 13.9 ml/h). We estimated the pulmonary microvascular oncotic reflection coefficient and found it to be 0.82 +/- 0.05 (SD). The filtration coefficient was 0.019 +/- 0.005 ml.mmHg-1.min-1. During the period of increased pressure, the animals had stable arterial pressures and cardiac outputs. None of the animals developed blood coagulation problems. These data illustrate the usefulness of pulmonary venous occlusion to elevate pulmonary microvascular pressure to obtain plasma-to-lymph protein concentration ratios independent of flow, allowing for the calculation of the oncotic reflection coefficient.

The systemic blood flow to the airways of the left lung was determined by the radioactive microsphere technique before and 17 h after smoke inhalation in six conscious sheep (smoke group) and six sheep insufflated with air alone (sham group). Smoke inhalation caused a sixfold increase in systemic blood flow to the lower trachea (baseline 10.6 +/- 1.7 vs. injury 60.9 +/- 16.1 ml.min-1.100 g-1) and an 11- to 14-fold increase to the intrapulmonary central airways (baseline range 9.5 +/- 1.9 to 13.5 +/- 3.7 ml.min-1.100 g-1 vs. injury 104.6 +/- 32.2 to 187.3 +/- 83.6 ml.min-1.100 g-1). There was a trend for this hyperemic response to be greater as airway diameter decreased from the trachea to 2-mm-diam central airways. In airways smaller than 2 mm, the hyperemic response appeared to diminish. The total systemic blood flow to whole lung is predominantly to small peripheral airways and showed no significant increase from its baseline level of 17.5 +/- 3.7 ml.min-1.100 g-1 in the lung homogenate. Occlusion of the bronchoesophageal artery decreased central airway blood flow 60-80% and peripheral airway blood flow 40-60% in both the sham and the smoke groups.

Smoke inhalation increases bronchial blood flow (Qbr) and produces edema of the airway system. This study investigates whether the increased Qbr seen 24 h after inhalation injury can be affected by mechanical ventilation with PEEP (5, 10, 15 cm H2O). Sheep (n = 8) previously prepared with cardiopulmonary catheters and ultrasonic transit time flow probes mounted around their bronchial arteries were insufflated with four sets of 12 breaths each of cotton smoke. Different levels of PEEP were added to the mechanical ventilation 24 h after injury; each PEEP level was applied for 45 min. There were significant increases in Qbr and lung lymph flow (QL) associated with a marked decrease in bronchial vascular resistance (BVR) 24 h after injury. However, no change was observed in mean arterial pressure (MAP) or cardiac index (CI). There was a substantial reduction in PaO2/FIO2 (P/F), which indicated a deterioration in arterial oxygenation. The application of varying levels of PEEP decreased Qbr (p less than .05) while BVR increased (p less than .05), but QL and P/F did not. CI and MAP were recorded. After removal of PEEP, none of the cardiopulmonary variables were significantly different from their postsmoke control values. These findings suggest that mechanical ventilation with PEEP markedly decreases the smoke-induced hyperemia edema frequently seen after inhalation injury without any significant alterations in MAP or CI.

The involvement of endorphins in the ovine cardiopulmonary response to endotoxin was evaluated by measuring blood levels of opiate receptor binding substances and administering the opiate receptor blocking agent naloxone prior to and after the administration of lipopolysaccharide. The animals were prepared for chronic study by placement of cardiovascular catheters and cannulation of the lung lymphatic at least 1 wk prior to study. The sheep were given endotoxin (0.75 micrograms/kg) and studied for 6 h. This was accomplished twice in the same animal. Naloxone (2 mg/kg bolus + 2 mg X kg-1 X h-1) was given with one of the two doses of the lipopolysaccharide. The response to endotoxin could be divided into two phases. In phase 1, there was an increase in protein-poor lung lymph and a marked increase in pulmonary artery pressure. In phase 2, the pulmonary lymph flow was elevated but the lymph protein level was higher than in phase 1. The pulmonary artery pressure, however, was near normal. During both phases leukocytes and cardiac output were reduced and the hematocrit was elevated. There was an increase in opiatelike materials in the plasma of these animals, and the response to endotoxin was partially blocked by naloxone. This suggested that endorphin-like materials were involved in the response to endotoxin.

The administration of endotoxin produces an early increase in hydrostatic pressure and pulmonary lymph flow, which is associated with elevated levels of thromboxane A2 in the lymph and can be blocked by the cyclooxygenase inhibitor ibuprofen. Two hours after the administration of endotoxin a secondary response is seen. The pulmonary lymph flow is elevated in association with a change in microvascular permeability to protein, this phase of the response can be reduced by the administration of the proteolytic enzyme inhibitor gabexate mesilate. In the present study we administered both compounds to eight sheep prepared for chronic cardiopulmonary and lung lymph studies to reduce both phases with the drug combination. The phase I response was reduced but the changes in lung lymph flow, associated with the phase II response, were unaffected by treatment. It is concluded that the effect of gabexate mesilate on the secondary response to endotoxin must in some way be related to the release of prostanoids.

Hyperdynamic sepsis (increased cardiac output and reduced peripheral vascular resistance) was created in sheep with chronic lung lymph fistulae (n = 8) by giving them a 30-min infusion of 1.5 micrograms/kg of endotoxin (LPS) iv. Four hours after LPS the cardiac output (CO) was reduced (6.56 +/- 0.43 to 4.96 +/- 0.33 liters/min) and lymph flow was increased (5.4 +/- 1.0 to 18.6 +/- 3.1 ml/h). Nine hours after LPS the CO output was increased (8.42 +/- 0.60 liters/min). Early cardiopulmonary changes were associated with a fall in neutrophils (PMNs) (2,667 +/- 748 to 450 +/- 90 cells/microliter) and an elevation of their chemiluminescence (CL), an indication of increased O2 free-radical formation in the blood (1,250 +/- 160 to 3,340 +/- 744 units/1,000 leukocytes). The granulocytic enzyme, aryl sulfatase, was increased in the lymph (0.19 +/- 0.03 to 0.37 +/- 0.05 microgram/h/mg protein) indicating degranulation (activation) of PMNs. When CO was increased (9 h after LPS), blood CL rose even higher (5,330 +/- 173 units/1,000 leukocytes) and CL in the lung lymph decreased (1,160 +/- 220 units/1,000 leukocytes). At this time, lymphatic aryl sulfatase had returned to baseline levels (0.25 +/- 0.02 microgram/h/mg protein). These data suggest that pulmonary microcirculatory injury produced by LPS may be the result of margination of PMNs in the lung and their release of permeability-inducing mediators. Later, as the CO increases, the PMNs or their lesion-producing mediators may be washed from the lung and the lung injury thus may be made less severe.

The cardiopulmonary effects of intravenously administered Escherichia coli endotoxin were studied in unanesthetized sheep. One group of animals was depleted of circulating T-lymphocytes while a non-depleted group served as control. T-lymphocyte depletion was accomplished by chronic thoracic duct drainage of lymph, removal of lymphocytes by continuous flow centrifugation and return of the cell free lymph intravenously. The T-lymphocyte depleted sheep demonstrated markedly obtunded increases in pulmonary arterial pressure and pulmonary vascular resistance following endotoxin when compared to the effects of the lipopolysaccharide in control animals. additionally, the lymphocyte depleted group showed a significant augmentation of myocardial contractility which occurred at the same time as marked systemic hypotension. This period of extreme hypotension following endotoxin is presumed to be accompanied by a reflex increase in the activity of the sympathetic nervous system. The control sheep, although equally hypotensive at this time, did not demonstrate a significant increase in myocardial contractility from the preendotoxin value. The results of these experiments indicate that T-lymphocytes may mediate some of the pathophysiological effects of bacterial endotoxin on the cardiovascular system.

An ovine anti-neutrophil antibody has been produced by immunizing rabbits with purified sheep neutrophils. Serial intraarterial infusions of anti-neutrophil antibody in awake instrumented sheep produced selective and profound neutropenia. Intravascular infusion of endotoxin (Escherichia coli, 1.5 micrograms/kg/30 min) resulted in significant and equivalent increases in pulmonary artery pressure, peripheral vascular resistance, and protein-rich pulmonary lymph flow in an endotoxin group (n = 9) and a depletion + endotoxin group (n = 4). Changes in cardiopulmonary parameters were most pronounced 2 to 8 hr after endotoxin administration in both groups. Cardiac index (CI) showed a precipitous and transient fall in both experimental groups at 0.5 to 1 hr after endotoxin infusion; however, by 8 hr CI rose significantly in the endotoxin group, while it remained unchanged in the depletion + endotoxin group. A significant rise in the peripheral neutrophil count was associated with the increase in CI in the endotoxin group. Plasma and pulmonary lymph levels of thromboxane-B2 were unchanged during the depletion period with a significant increase 1 hr after endotoxin infusion. In this study questions arise regarding the exclusive role of circulating neutrophils in the microvascular permeability changes seen in sepsis-mediated adult respiratory distress syndrome.