Perfusion distribution and lung thermal volume in canine hydrochloric acid aspiration

We investigated the effects of a brief period of positive end-expiratory pressure (PEEP) ventilation or nitroglycerin (NTG) infusion on the distribution of pulmonary blood flow and extravascular thermal volume (ETV) in anesthetized dogs with unilateral HCl lung injury. ETV was determined by the thermal dye technique by use of a monoexponential extrapolation to exclude recirculating indicator, and regional blood flow was determined by a particle distribution technique (radiolabeled plastic microspheres). The lungs were weighted after the animals were killed, and extravascular lung mass (ELM) was determined with the use of hemoglobin to correct for trapped lung blood. Measurements were obtained before instillation of HCl into the right lung and repeated 3 h later before, during, and after PEEP ventilation or NTG infusion. Fractional perfusion of the severely injured portion of the right lung (Qinj/QT) fell from 44.3 +/- 11.1% at base line to 27.8 +/- 15.4% after the onset of lung injury. PEEP produced an acute reversible increase in ETV (63 +/- 37% over average of pre- and post-PEEP values), and the changes in ETV were closely correlated with changes in Qinj/QT (r = 0.91). NTG infusion produced insignificant increases in ETV (14 +/- 10% over average of pre- and postinfusion values) and Qinj/QT (59 +/- 35%), but the changes in ETV and Qinj/QT were strongly correlated (r = 0.92). The fraction of extravascular lung mass detected by the thermodilution measurement averaged 0.44 (range 0.24-0.77).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary and bronchial circulatory responses to segmental lung injury.

In regional lung injury, pulmonary blood flow decreases to the injured regions, and anastomotic bronchial blood flow and total bronchial blood flow increase. However, the pattern of redistribution of the two blood flows to the injured and noninjured areas is not known. In six anesthetized sheep, pulmonary and bronchial blood flows were measured with 15-microm fluorescent microspheres by using the reference flow method. Blood flows were measured in the control state and 1 h after instilling 1 ml/kg of 0. 1 N hydrochloric acid into a dependent segment of the left lung. The lungs were then removed, dried, and cubed into approximately 2-cm cubes while spatial coordinates were noted. Blood flow to each piece was calculated. Mean pulmonary blood flow to the noninjured pieces went from 730 +/- 246 to 574 +/- 347 ml/min (P = 0.22), whereas in the injured pieces the pulmonary blood flow decreased from 246 +/- 143 to 56 +/- 46 ml/min (P < 0.01). In contrast, bronchial blood flow to the injured pieces increased from 0.51 +/- 0.1 to 1.43 +/- 0. 85 ml/min (P = 0.005). We measured the change in flow as it related to the distance from the center of the injured area. Pulmonary blood flow decreased most at the center of the injury, whereas bronchial blood flow doubled at the center of injury and decreased with the distance away from the injury. The absolute increase in bronchial blood flow was substantially less than the decrease in pulmonary blood flow in the injured pieces. We also partitioned the observed variation in pulmonary and bronchial blood flow into that attributable to structure and that due to lung injury and found that 48% of the variation in pulmonary blood flow could be attributed to structure, whereas in the bronchial circulation 70% was attributable to structure. The reasons for these differences are not known and may reflect the intrinsic properties of the systemic and pulmonary circulations.     

Increased leukotriene C4 in ethchlorvynol-induced acute lung injury in dogs

We investigated whether ethchlorvynol (ECV)-induced acute lung injury (ALI) is associated with an increase in leukotriene C4 (LTC4) production. In six pentobarbital sodium-anesthetized dogs, ECV (15 mg/kg iv) introduced into the pulmonary circulation resulted in a 164 +/- 31% increase in extravascular lung water 120 min after ECV administration. Concomitantly, the mean (+/- SE) concentration of LTC4 in arterial plasma measured by radioimmunoassay following 80% EtOH precipitation, XAD-7 extraction and high-pressure liquid chromatography purification was 5.0 +/- 1.3 pg/ml, unchanged from control (pre-ECV) values. In contrast, in pulmonary edema fluid 120 min post-ECV, the LTC4 concentration was 35.2 +/- 10.8 pg/ml, sevenfold greater than those values found in the arterial plasma (P less than 0.01). In six additional dogs, 120 min after unilateral ALI had been induced with ECV (9 mg/kg iv), LTC4 in the bronchoalveolar lavage (BAL) of the uninjured lung was 12.1 +/- 1.5 pg/ml, unchanged from pre-ECV values, whereas, LTC4 in the BAL of the injured lung increased from a control value of 10.2 +/- 1.6 to 24.2 +/- 3.5 pg/ml (P less than 0.01) 120 min after ECV administration. These results demonstrate that, in ECV-induced acute lung injury, LTC4 concentrations in pulmonary edema fluid are considerably greater than those found in arterial plasma in the case of bilateral acute lung injury and significantly greater in the BAL of the injured lung compared with the uninjured lung in the case of unilateral acute lung injury. The results are a necessary first step in support of the hypothesis that leukotrienes participate in the altered permeability of ECV-induced acute lung injury.     

Lung edema formation following inhalation injury: role of the bronchial blood flow

We investigated the contribution of the bronchial blood flow to the lung lymph flow (QL) and lung edema formation after inhalation injury in sheep (n = 18). The animals were equally divided into three groups and chronically prepared by implantation of cardiopulmonary catheters and a flow probe on the common bronchial artery. Groups 1 and 2 sheep were insufflated with 48 breaths of cotton smoke while group 3 received only room air. Just before injury, the bronchial artery of group 2 animals was occluded. The occlusion was maintained for the duration of the 24-h study period. At the end of the investigation, samples of lung were taken for determination of blood-free wet weight-to-dry weight ratio (W/D). Inhalation injury induced a sevenfold increase in QL in group 1 (7 +/- 1 to 50 +/- 9 ml/h; P less than 0.05) but only a threefold increase in group 2 (10 +/- 2 to 28 +/- 7 ml/h; P less than 0.05). The mean W/D value of group 1 animals was 23% higher than that of group 2 (5.1 +/- 0.4 vs. 3.9 +/- 0.2; P less than 0.05). Our data suggest that the bronchial circulation contributes to edema formation in the lung that is often seen after the acute lung injury with smoke inhalation.     

Effect of alveolar hypoxia on regional pulmonary perfusion

We examined the effects of varying levels of alveolar hypoxia on regional distribution of pulmonary blood flow (QL) in control-ventilated sheep. Regional distribution of QL was measured using 15-micron-diam labeled microspheres during the base-line period and at two levels of hypoxemia (arterial O2 partial pressure 44 and 20 Torr). During the base-line period, regional distribution of QL in the prone position was uniform [14 +/- 4% (SE) of QL/g bloodless dry lung wt in the upper lung and 16 +/- 2% of QL/g in the dependent lung]. During hypoxemia, however, the regional distribution of QL increased in the upper lung (20 +/- 3% of QL/g) while it decreased in the dependent lung (10 +/- 2% of QL/g). The degree of flow distribution was proportional to the severity of hypoxemia. The flow distribution was not associated with significant increases in pulmonary blood flow (2.0 +/- 0.4----2.4 +/- 0.5----2.6 +/- 0.1 l/min) but was associated with increases in mean pulmonary arterial pressure (17.8 +/- 1.3----21.7 +/- 1.1----29.0 +/- 3.8 Torr). Therefore alveolar hypoxia results in a relative increase in regional pulmonary perfusion to the upper lung, which depends on the level of pulmonary hypertension. The increased upper lung perfusion may be due to recruitment in the upper lung or to vasodilation in this region.     

Respiratory failure after endotoxin infusion in sheep: lung mechanics and lung fluid balance

Infusion of Escherichia coli endotoxin (0.12-1.5 micrograms/kg) into unanesthetized sheep causes transient pulmonary hypertension and several hours of increased lung vascular permeability, after which sheep recover. To produce enough lung injury to result in pulmonary edema with respiratory failure, we infused larger doses of E. coli endotoxin (2.0-5.0 micrograms/kg) into 11 chronically instrumented unanesthetized sheep and continuously measured pulmonary arterial, left atrial and aortic pressures, dynamic lung compliance, lung resistance, and lung lymph flow. We intermittently measured arterial blood gas tensions and pH, made interval chest radiographs, and calculated postmortem extravascular bloodless lung water-to-dry lung weight ratio (EVLW/DLW). Of 11 sheep 8 developed respiratory failure; 7 died spontaneously 6.3 +/- 1.1 h, and one was killed 10 h after endotoxin infusion. All sheep that had a premortem room air alveolar-arterial gradient in partial pressure of O2 (PAo2-Pao2) greater than 42 Torr (58 +/- 5 (SE) Torr) died. Of eight sheep that had radiographs made, six developed radiographically evident interstitial or interstitial and alveolar edema. Pulmonary artery pressure rose from base line 22 +/- 2 to 73 +/- 3 cmH2O and remained elevated above baseline levels until death. There was an initial fourfold decrease in dynamic compliance and sixfold increase in pulmonary resistance; both variables remained abnormal until death. EVLW/DLW increased with increasing survival time after endotoxin infusion, suggesting that pulmonary edema accumulated at the same rate in all fatally injured sheep, regardless of other variables. The best predictor of death was a high PAo2-Pao2. The marked increase in pulmonary resistance and decrease in dynamic compliance occurred too early after endotoxin infusion (15-30 min) to be due to pulmonary edema. The response to high-dose endotoxin in sheep closely resembles acute respiratory failure in humans following gram-negative septicemia. Respiratory failure and death in this model were not due to pulmonary edema alone.     

Effect of bronchial artery blood flow on cardiopulmonary bypass-induced lung injury

Cardiovascular surgery requiring cardiopulmonary bypass (CPB) is frequently complicated by postoperative lung injury. Bronchial artery (BA) blood flow has been hypothesized to attenuate this injury. The purpose of the present study was to determine the effect of BA blood flow on CPB-induced lung injury in anesthetized pigs. In eight pigs (BA ligated) the BA was ligated, whereas in six pigs (BA patent) the BA was identified but left intact. Warm (37 degrees C) CPB was then performed in all pigs with complete occlusion of the pulmonary artery and deflated lungs to maximize lung injury. BA ligation significantly exacerbated nearly all aspects of pulmonary function beginning at 5 min post-CPB. At 25 min, BA-ligated pigs had a lower arterial Po(2) at a fraction of inspired oxygen of 1.0 (52 +/- 5 vs. 312 +/- 58 mmHg) and greater peak tracheal pressure (39 +/- 6 vs. 15 +/- 4 mmHg), pulmonary vascular resistance (11 +/- 1 vs. 6 +/- 1 mmHg x l(-1) x min), plasma TNF-alpha (1.2 +/- 0.60 vs. 0.59 +/- 0.092 ng/ml), extravascular lung water (11.7 +/- 1.2 vs. 7.7 +/- 0.5 ml/g blood-free dry weight), and pulmonary vascular protein permeability, as assessed by a decreased reflection coefficient for albumin (sigma(alb); 0.53 +/- 0.1 vs. 0.82 +/- 0.05). There was a negative correlation (R = 0.95, P < 0.001) between sigma(alb) and the 25-min plasma TNF-alpha concentration. These results suggest that a severe decrease in BA blood flow during and after warm CPB causes increased pulmonary vascular permeability, edema formation, cytokine production, and severe arterial hypoxemia secondary to intrapulmonary shunt.     

Independent influence of blood flow rate and mixed venous PO2 on shunt fraction

We have tested the independent and combined effects of changes in mixed venous PO2 (PvO2) and blood flow (QT) on shunt fraction (Qs/QT) in isolated blood-perfused canine left lower lobes with edema. The lobes were ventilated with pure O2. Inflow (Pi) and outflow (Po) pressures always exceeded lobar alveolar pressure. PvO2 was varied by means of a clinical bubble oxygenator with appropriate mixtures of O2 and N2. QT was varied by changes in Pi and Po with care not to produce changes in lobar weight. Changes in QT did not influence Qs/QT. Increasing PvO2 from 40 +/- 6 to 88.4 +/- 40 Torr at constant QT significantly increased Qs/QT from 5.5 +/- 2.0 to 15.6 +/- 7.0%. Combined increases in QT and PvO2 from 66.4 +/- 2.7 to 135.6 +/- 21.5 ml/min and from 38.8 +/- 1.3 to 61.8 +/- 2.2 Torr, respectively, also produced a significant increase in Qs/QT from 7.33 +/- 2.27 to 15.43 +/- 4.45%. However, this combined change was explained exclusively by changes in PvO2. We therefore concluded that, under the conditions of our experiment, changes in PvO2 influence Qs/QT, and this may account for apparent dependence of Qs/QT on cardiac output in pulmonary edema.     

Endogenous and exogenous catalase in reoxygenation lung injury.

Reexpansion pulmonary edema parallels reperfusion (reoxygenation) injuries in other organs in that hypoxic and hypoperfused lung tissue develops increased vascular permeability and neutrophil infiltration after reexpansion. This study investigated endogenous lung catalase activity and H2O2 production during hypoxia (produced by lung collapse) and after reoxygenation (resulting from reexpansion), in addition to assessing the effects of exogenous catalase infusion on the development of unilateral pulmonary edema after reexpansion. Lung collapse resulted in a progressive increase in endogenous catalase activity after 3 (14%) and 7 days (23%), while activities in contralateral left lungs did not change (normal left lungs averaged 180 +/- 11 units/mg DNA). Tissue from control left lungs released H2O2 into the extracellular medium at a rate calculated to be 242 +/- 34 nmol.h-1.lung-1. No significant change in extracellular release of H2O2 occurred after 7 days of right lung collapse. However, after reexpansion of the previously collapsed right lungs for 2 h, H2O2 release from both reexpanded right and contralateral left lungs significantly increased (88 and 60%, respectively) compared with controls. Infusion of exogenous catalase significantly increased plasma and lung catalase activities. Exogenous catalase infusion prevented neither the increase in lung permeability nor the infiltration with neutrophils that typically occurs in reexpanded lungs. These data indicate that lung hypoxia/reoxygenation, induced by sequential collapse and reexpansion, has specific effects on endogenous lung catalase activity and H2O2 release. However, exogenous catalase does not prevent reexpansion pulmonary edema, eliminating extracellular (but not intracellular) H2O2 as an important mediator of unilateral lung injury in this model.     

Ibuprofen reduces ethchlorvynol lung injury: possible role of blood flow distribution.

The role of cyclooxygenase products in acute lung injury was determined by pretreatment of dogs with ibuprofen before injury with intravenous ethchlovynol (ECV). In animals given ECV only, lung injury resulted in extravascular lung water of 18.9 ml/kg after 2 h, which was significantly higher than the 14.8 ml/kg in the group pretreated with ibuprofen. The comparison of gravimetric and indicator-dilution measurements of edema fluid indicates that edema fluid could not be reliably detected after treatment with ibuprofen because of diversion of flow from injured areas. Venous admixture increased from 6% at baseline to 32% 120 min after ECV in the vehicle-pretreated group compared with an increase from 4% at baseline to 7% in the ibuprofen-pretreated group. The regression analysis of the relationship between venous admixture and extravascular lung water indicated that, at any level of edema, venous admixture was significantly less in the group treated with ibuprofen than in the untreated group. Measurement of plasma and bronchoalveolar lavage fluid indicated that ibuprofen inhibited cyclooxygenase activity without affecting lipoxygenase activity. These results suggest that in intact dogs ibuprofen has a protective effect on both pulmonary gas transfer and pulmonary edema formation in ECV-injured lungs, which is consistent with limiting blood flow to injured segments of the lung.     

Effect of outflow pressure on lung lymph flow in unanesthetized sheep

Studies in anesthetized animals have shown that the flow rate from lung lymphatics (QL) depends on the pressure at the outflow end of the vessels (Po). We tested this in unanesthetized sheep prepared with chronic lung lymph cannula. We measured QL with the lymph cannula held at various heights above the olecranon and calculated Po as the height + QL X cannula resistance. QL decreased with increases in Po (delta QL/delta Po = -8.2 +/- 6.4 microliter X min-1 X cmH2O-1, mean +/- SD). We increased QL by raising left atrial pressure or infusing Ringer solution or Escherichia coli endotoxin and found that QL was even more sensitive to Po (delta QL/delta Po = -32 +/- 22). Cannula resistance caused a 9-70% reduction in QL. Changes in QL caused by increasing Po were not associated with changes in lymph protein concentration for up to 330 min. This indicates that increases in Po shunt lymph away from cannulated vessels but do not substantially effect microvascular filtration rate. The shunted lymph may flow into other vessels or collect in the lung. We conclude that QL does not accurately represent microvascular filtration rate because it depends on the cannula resistance and position at which the investigator chooses to place the cannula.     

Hypoxic pulmonary vasoconstriction does not affect hydrostatic pulmonary edema formation

We studied the effects of regional hypoxic pulmonary vasoconstriction (HPV) on lobar flow diversion in the presence of hydrostatic pulmonary edema. Ten anesthetized dogs with the left lower lobe (LLL) suspended in a net for continuous weighing were ventilated with a bronchial divider so the LLL could be ventilated with either 100% O2 or a hypoxic gas mixture (90% N2-5% CO2-5% O2). A balloon was inflated in the left atrium until hydrostatic pulmonary edema occurred, as evidenced by a continuous increase in LLL weight. Left lower lobe flow (QLLL) was measured by electromagnetic flow meter and cardiac output (QT) by thermal dilution. At a left atrial pressure of 30 +/- 5 mmHg, ventilation of the LLL with the hypoxic gas mixture caused QLLL/QT to decrease from 17 +/- 4 to 11 +/- 3% (P less than 0.05), pulmonary arterial pressure to increase from 35 +/- 5 to 37 +/- 6 mmHg (P less than 0.05), and no significant change in rate of LLL weight gain. Gravimetric confirmation of our results was provided by experiments in four animals where the LLL was ventilated with an hypoxic gas mixture for 2 h while the right lung was ventilated with 100% O2. In these animals there was no difference in bloodless lung water between the LLL and right lower lobe. We conclude that in the presence of left atrial pressures high enough to cause hydrostatic pulmonary edema, HPV causes significant flow diversion from an hypoxic lobe but the decrease in flow does not affect edema formation.     

Effects of coronary ischemia on lung fluid balance in conscious sheep

It has been suggested that coronary ischemia increases extravascular lung water. To determine whether pulmonary microvascular permeability is increased by coronary ischemia, we measured pulmonary hemodynamics, lung lymph flow (QL), and lymph-to-plasma protein concentration ratio (L/P) in 12 sheep with chronic lung lymph fistulas. Studies were done in 3 groups: in group 1 (n = 7) a marginal branch of the left circumflex artery (Lcx) was occluded, in group 2 (n = 5) left atrial pressure (Pla) was mechanically raised by 10 mmHg, and in group 3 (n = 5) Lcx was occluded and Pla was raised by 10 mmHg. In group 1, coronary occlusion increased QL (4.6 +/- 0.4 to 8.3 +/- 2.6 ml/h) without changes in L/P. In group 2, elevated Pla increased QL (5.1 +/- 1.2 to 10.1 +/- 3.0 ml/h) with decreases in L/P (0.71 +/- 0.02 to 0.61 +/- 0.02). In group 3, coronary occlusion with elevated Pla caused a further increase in QL (5.0 +/- 1.5 to 16.9 +/- 4.6 ml/h) without significant decreases in L/P (0.71 +/- 0.01 to 0.65 +/- 0.06). Lung lymph concentrations of 6-keto-prostaglandin F1 alpha (a degradation product of prostacyclin) increased transiently after coronary occlusion. These results indicate that coronary occlusion can increase transcapillary protein transport in lungs of conscious sheep and simultaneously increase prostacyclin production in the lung.     

Whole-body hypoxic preconditioning protects mice against acute hypoxia by improving lung function.

Survival in severe hypoxia such as occurs in high altitude requires previous acclimatization, which is acquired over a period of days to weeks. It was unknown whether intrinsic mechanisms existed that could be rapidly induced and could exert immediate protection on unacclimatized individuals against acute hypoxia. We found that mice pretreated with whole-body hypoxic preconditioning (WHPC, 6 cycles of 10-min hypoxia-10-min normoxia) survived significantly longer than control animals when exposed to lethal hypoxia (5% O2, survival time of 33.2 +/- 6.1 min vs. controls at 13.8 +/- 1.2 min, n = 10, P < 0.005). This protective mechanism became operative shortly after WHPC and remained effective for at least 8 h. Accordingly, mice subjected to WHPC demonstrated improved gas exchange when exposed to sublethal hypoxia (7% O2, arterial blood Po2 of 49.9 +/- 4.2 vs. controls at 39.7 +/- 3.6 Torr, n = 6, P < 0.05), reduced formation of pulmonary edema (increase in lung water of 0.491 +/- 0.111 vs. controls at 0.894 +/- 0.113 mg/mg dry tissue, n = 10, P < 0.02), and decreased pulmonary vascular permeability (lung lavage albumin of 7.63 +/- 0.63 vs. controls at 18.24 +/- 3.39 mg/dl, n = 6-10, P < 0.025). In addition, the severity of cerebral edema caused by exposure to sublethal hypoxia was also reduced after WHPC (increase in brain water of 0.254 +/- 0.052 vs. controls at 0.491 +/- 0.034 mg/mg dry tissue, n = 10, P < 0.01). Thus WHPC protects unacclimatized mice against acute and otherwise lethal hypoxia, and this protection involves preservation of vital organ functions.     

Effect of interstitial edema on lung lymph flow in goats in the absence of filtration.

We tested the effect of interstitial edema on lung lymph flow when no filtration occurred. In 16 anesthetized open-thorax ventilated supine goats, we set pulmonary arterial and left atrial pressures to nearly zero and measured lymph flow for 3 h from six lungs without edema and ten with edema. Lymph flow decreased exponentially in all experiments as soon as filtration ceased. In the normal lungs the mean half time of the lymph flow decrease was 12.7 +/- 4.8 (SD) min, which was significantly shorter (P less than 0.05) than the 29.1 +/- 14.8 min half time in the edematous lungs. When ventilation was stopped, lymph flow in the edematous lungs decreased as rapidly as in the normal lungs. The total quantity of lymph after filtration ceased was 2.7 +/- 0.8 ml in normal lungs and 9.5 +/- 6.3 ml in edematous lungs, even though extravascular lung water was doubled in the latter (8.4 +/- 2.4 vs. 3.3 +/- 0.4 g/g dry lung, P less than 0.01). Thus the maximum possible clearance of the interstitial edema liquid by the lymphatics was 6.3 +/- 4.8%. When we restarted pulmonary blood flow after 1-2 h in four additional goats, lymph flow recovered within 30 min to the baseline level. These findings support the hypothesis that lung lymph flow originates mainly from alveolar wall perimicrovascular interstitial liquid and that the contribution of the lung lymphatic system to the clearance of interstitial edema (bronchovascular cuffs, interlobular septa) is small.     

Control of shunt pathway perfusion in diffuse granulomatous lung disease

To assess the roles of cyclooxygenase inhibition and alveolar hypoxia in controlling the distribution of pulmonary perfusion in granulomatous lung injury, we studied 15 dogs (anesthetized and ventilated) 4 wk after intravenous injection of complete Freund's adjuvant (0.5-0.75 ml/kg). Base-line hemodynamic and blood gas observations were obtained at fractional O2 concentration (FIO2) 0.21 and 0.10. Observations at each FIO2 were repeated 30 min after infusion of meclofenemate (2 mg/kg; n = 10) or saline (n = 5). Resistance to pulmonary blood flow was assessed using the difference between pulmonary arterial diastolic and left atrial pressures (PDG). Distribution of blood flow between normal and diseased regions of the lung was evaluated with measurement of inert gas shunt flow. Before infusion, there were no significant differences between the two groups at either FIO2. At FIO2 0.10 PDG rose from 3 +/- 1 to 7 +/- 3 mmHg in the saline group and from 3 +/- 1 to 8 +/- 3 mmHg in the meclofenemate group, although the shunt flow increased from 8.7 +/- 7.7 to 12.2 +/- 9.2% and from 10.7 +/- 11.0 to 17.6 +/- 18.3 in the two groups, respectively. Saline induced no significant changes at either FIO2. After meclofenemate, PDG at FIO2 0.21 rose to 7 +/- 4 mmHg (P less than 0.015) while shunt flow fell to 5.2 +/- 6.2% (P less than 0.0125), whereas at FIO2 0.10 PDG rose to 15 +/- 5 mmHg (P less than 0.001) while shunt flow rose only to 14.3 +/- 16.4% (P = NS). We propose that perivascular inflammation enhanced perfusion of abnormal lung by elaborating vasodilator prostanoids. By inhibiting prostanoid biosynthesis, meclofenemate selectively increased resistance in diseased lung at FIO2 0.21 and lowered shunt flow. The persistent rise in shunt during hypoxia after meclofenemate suggests that factors other than prostanoids may account for the apparent attenuation of hypoxic vasoconstriction in diseased lung.     

Effect of cyclooxygenase inhibition on ethchlorvynol-induced acute lung injury in dogs

In anesthetized dogs ethchlorvynol (ECV, 9 mg/kg) was selectively administered into the right pulmonary circulation to produce unilateral acute lung injury (ALI) characterized by nonhydrostatic pulmonary edema and systemic hypoxemia. To investigate the hypothesis that products of cyclooxygenase activity are mediators of the arterial hypoxemia, but not the edema formation in this injury, animals were pretreated with one of two chemically dissimilar cyclooxygenase inhibitors, indomethacin (5 mg/kg), or ibuprofen (12.5 mg/kg), or vehicle (0.1 M sodium carbonate) prior to the administration of ECV. Pretreatment with either inhibitor prevented the ECV-induced systemic hypoxemia observed in animals pretreated with vehicle (P less than 0.01). Despite this protection of systemic oxygenation, there was no redistribution of blood flow to the uninjured lung following unilateral ECV administration. Cyclooxygenase inhibition prior to ALI did not attenuate the accumulation of lung water. In the ibuprofen group, left atrial pressure increased significantly following ECV administration. We conclude that a product(s) of cyclooxygenase-mediated arachidonic acid metabolism is responsible for the altered vascular reactivity and consequent systemic hypoxemia in this model, but that the edema formation following ECV is not related to cyclooxygenase activity. In addition, ibuprofen, administered prior to the induction of ALI, exhibits properties not shared by indomethacin but is not different in its capacity to attenuate hypoxemia or in its failure to limit edema formation.     

Relationship between regional pulmonary edema and blood flow

We studied the effect of edema on the regional distribution of pulmonary blood flow in 12 anesthetized dogs. Two were controls, six had low-pressure pulmonary edema, and four had high-pressure pulmonary edema. All were ventilated with 100% O2. The physiological shunt fraction (Qs/QT), as an indicator of the degree of venous admixture, was determined by measuring the arterial and venous blood gases and the hemoglobin at different times during the experiment. Cardiac output (QT) was modestly increased by opening the femoral arteriovenous shunts. The initial regional blood flow (Qi) and final regional blood flow (Qf) were marked before and after the shunts were opened, using two differently labeled macroaggregates. The dogs were then killed, and the lungs were removed and sampled completely so that Qi and Qf and the amount of regional extravascular lung water (Wdl) in each regional sample could be measured (sample size: wet wt = 5.9 +/- 2.9 g, n = 833; Wdl ranged from 5.15 +/- 1.18 to 14.42 +/- 2.34 g). The data show that QS/QT increased as QT increased in the three conditions studied. However, there was no correlation between Wdl and Qi, Qf, or the relative change in regional blood flow. The data also show that gravity affects regional blood flow more than it affects regional edema. We conclude that the increased Qs/QT seen with increased pulmonary blood flow cannot be explained by a preferential increase of blood flow to the more edematous regions.     

A positron emission tomographic comparison of diffuse and lobar oleic acid lung injury

We tested whether severity of injury measured from the pulmonary transcapillary escape rate for transferrin (PTCER), lung water accumulation, and changes in regional pulmonary blood flow (PBF) would be similar after oleic acid (OA) injection into either all lung lobes or directly into the pulmonary artery feeding the left caudal lobe (LCL) only. Measurements were made with positron emission tomography. After 0.015 ml/kg OA was injected into the LCL (Lobar, n = 5), lung water increased in the left dorsal region from 37 +/- 5 to 50 +/- 8 ml/100 ml lung (P less than 0.05), PTCER was 533 +/- 59 10(-4)/min, and regional PBF decreased 62%. No significant change occurred in the uninjured right dorsal lung where PTCER was 85 +/- 32. In the left ventral region PTCER was 357 +/- 60, PBF decreased only 31%, and the increase in lung water was less (25 +/- 3 to 30 +/- 6). In contrast after 0.08 ml/kg OA was injected via the right atrium (Diffuse, n = 6), PTCER (283 +/- 94) was lower in the left dorsal region of this group than in the corresponding region of the Lobar group (P less than 0.05). The increase in lung water, however, was the same, but no change occurred in PBF distribution. These results indicate important differences between the two methods of causing lung injury with OA. After injury lung water accumulates primarily in dependent portions of lung and is not always accompanied by a decrease in regional PBF. These decreases, when they occur, may instead indicate severe vascular injury.     

Acute increases in anastomotic bronchial systemic to pulmonary blood flow due to generalized lung injury

Since pulmonary blood flow to regions involved in adult respiratory disease syndrome (ARDS) is reduced by hypoxic vasoconstriction, compression by cuffs of edema, and local thromboses, we postulated that the bronchial circulation must enlarge to provide for the inflammatory response. We measured anastomotic bronchial systemic to pulmonary blood flow [QBr(s-p)] serially in a lung lobe in 31 open-chest dogs following a generalized lobar injury simulating ARDS. The pulmonary circulation of the weighed left lower lobe (LLL) was isolated and perfused (zone 2) with autologous blood in anesthetized dogs. QBr(s-p) was measured from the amount of blood which overflowed from this closed vascular circuit corrected by any changes in the lobe weight. The LLL was ventilated with 5% CO2 in air. The systemic blood pressure (volume infusion), gases, and acid-base status (right lung ventilation) were kept constant. We injured the LLL via the airway by instilling either 0.1 N HCl or a mixture of glucose and glucose oxidase or via the pulmonary vessels by injecting either alpha-naphthylthiourea or oleic acid into the LLL pulmonary artery. In both types of injury, there was a prompt rise in QBr(s-p) (mean rise = 247% compared with control), which was sustained for the 2 h of observation. The cause of this increase in flow was studied. Control instillation of normal saline into the airways or into the pulmonary vessels did not change QBr(s-p) nor did a similar increase in lobar fluid (weight) due to hydrostatic edema. Neither cardiac output nor systemic blood pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)