Pulmonary artery occlusion and lung collapse depletes rabbit lung adenosine triphosphate.

BACKGROUND: Although the bronchial circulation has traditionally been thought to provide adequate blood flow for the lung when the pulmonary artery is obstructed, recent studies have demonstrated that pulmonary artery occlusion results in lung injury. We hypothesized that after pulmonary artery occlusion, aerobic lung metabolic function is altered. We studied the changes in the concentration of adenine nucleotides as markers of injury in the intact rabbit lung after pulmonary artery occlusion in the presence and absence of pneumothorax. METHODS: A thoracotomy was performed on the rabbits, and on occlusive microvascular clamp was placed on the left pulmonary artery. The rabbit lungs were studied after 24 h of in vivo left pulmonary artery occlusion (n = 5), 24 h of left pulmonary artery occlusion with the lung collapsed by pneumothorax (n = 6), or 24 h of lung collapse alone (n = 5). RESULTS: Adenosine triphosphate concentrations of the occluded left lung decreased dramatically at 24 h in the group with pulmonary artery occlusion and collapse (adenosine triphosphate concentration 196 +/- 32 ng/g for the left lung and 1,479 +/- 197 ng/g for the right lung; P < 0.001). There were no differences between the lungs in the rabbits undergoing occlusion alone or collapse alone. CONCLUSIONS: After pulmonary artery occlusion or lung collapse, adenine nucleotides are preserved if ventilation is continued. The increased permeability of rabbit lungs after 24 h of left pulmonary artery occlusion alone cannot be explained on the basis of depletion of high-energy phosphates. In the absence of ventilation due to lung collapse, pulmonary artery occlusion results in decreased adenosine triphosphate concentrations, demonstrating that the residual circulations (bronchial and pulmonary venous flow) are inadequate to support normal lung aerobic metabolism.

Pulmonary artery occlusion is sufficient to increase pulmonary vascular permeability in rabbits.

Unilateral pulmonary artery obstruction (PAO) for 24-48 h, followed by reperfusion, results in pulmonary edema and lung inflammation. We hypothesized that lung injury actually occurred during the period of PAO but, because of low microvascular pressures during the period of occlusion, was not detected until perfusion was reestablished. To test this hypothesis, we studied 14 rabbits divided into three groups: group I rabbits underwent sham occlusion of the left pulmonary artery for 24 h; group II rabbits underwent PAO but were not reperfused; and group III rabbits were subjected to PAO and then reperfused for 4 h. The fluid filtration coefficient measured during a zone 3 no-flow hydrostatic stress (pulmonary arterial pressure = pulmonary venous pressure, both greater than alveolar pressure) in group I lungs was less than that of lungs in either group II or III [0.52 +/- 0.02 (SE) ml.min-1.cmH2O.100 g wet wt-1 vs. 0.94 +/- 0.11 and 0.86 +/- 0.13 for groups II and III, respectively, P less than 0.05]. The wet-to-dry weight ratio of the left lung measured after the zone 3 stress was applied for 20 min was 6.90 +/- 0.09 in group I rabbits and 9.21 +/- 0.75 and 11.75 +/- 0.44 in groups II and III, respectively (P less than 0.05). Radiolabeled microspheres demonstrated that flow to the left lung was diminished after the period of PAO (38 +/- 4, 9 +/- 5, and 2 +/- 1% of cardiac output in groups I, II, and III, respectively; P less than 0.05 for group I vs. groups II and III).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody against neutrophil adhesion improves reperfusion and limits alveolar infiltrate following unilateral pulmonary artery occlusion.

Relief of unilateral pulmonary arterial occlusion results in bilateral lung injury and results in only partial restoration of pulmonary blood flow distal to the site of occlusion. We hypothesized that the "no reflow" phenomenon was in part due to neutrophil adherence and aggregation in the pulmonary vasculature. The study was carried out in two phases. First, we studied the effect of neutrophil depletion on left lung blood flow following 24 hr of left pulmonary artery occlusion. Hydroxyurea was used to deplete circulating neutrophils to 77 +/- 18/mm3 (means +/- sem) (n = 6) as compared to 708 +/- 165/mm3 in control rabbits (n = 8). In both groups left lung blood flow immediately following reperfusion was markedly reduced at 6.4 +/- 2.2% of cardiac output in control rabbits and 7.3 +/- 2.3 in treated rabbits. However, at 4 hr, neutrophil-depleted animals had significantly greater flow (18.7 +/- 3.6 vs 8.4 +/- 2.3% for control rabbits, P less than 0.05). In both groups, flow remained substantially below the normal rabbit left lung blood flow of 39.8 +/- 2.2%. To test whether the improved reflow was due to decreased numbers of neutrophils limiting aggregation, or whether active neutrophil adherence played a role, we tested the effect of a monoclonal antibody that interferes with neutrophil adhesiveness (MoAb 60.3) on reflow and on neutrophil emigration into the alveoli. We found that MoAb 60.3 did not affect initial reflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement activation is a secondary rather than a causative factor in rabbit pulmonary artery ischemia/reperfusion injury.

We have previously demonstrated that reperfusion of a rabbit lung in vivo after 24 h of unilateral pulmonary artery occlusion results in edema, transient leukopenia, and intravascular leukocyte aggregation. We hypothesized that complement was activated by reperfusion and that this in turn contributed to lung injury. In the preliminary phase of the study, we found that ischemia followed by reperfusion resulted in a drop in C3 to 15 +/- 10% (mean +/- SEM) of the prereperfusion value as compared with no change in a group of control animals that had undergone an identical thoracotomy but without pulmonary artery occlusion and reperfusion (p less than 0.05). We then studied three groups of animals to determine if complement depletion with cobra venom factor (CVF) prior to ischemia and reperfusion would prevent the injury. Rabbits treated with CVF but without occlusion and reperfusion did not develop significant lung edema, with left and right lung wet/dry ratios of 5.32 +/- 0.11 and 5.26 +/- 0.12, respectively. For rabbits that were not treated with CVF but underwent ischemia and reperfusion, the comparable numbers were 6.15 +/- 0.36 and 5.19 +/- 0.32 (p less than 0.05 for right versus left). For CVF-treated rabbits that underwent ischemia and reperfusion, the right/left difference persisted (6.77 +/- 0.48 versus 5.35 +/- 0.14, p less than 0.01). Immunocytochemistry documented C3 deposition in non-CVF rabbits that underwent ischemia and reperfusion but not in CVF-treated rabbits. We conclude that ischemia/reperfusion of the lung results in complement activation, but it is not a complement-dependent injury.

Salicylic acid causes a diuresis and natriuresis in normal and common bile-duct-ligated cirrhotic miniature swine.

In patients with liver disease, or in normal subjects who are sodium-depleted, the administration of either a nonsteroidal anti-inflammatory drug or acetylsalicylate (aspirin) has a detrimental effect on the kidney; profound renal vasoconstriction and the retention of sodium and water may occur. We observed recently that salicylate (SA), in contrast to meclofenamate (MECLO) or aspirin, caused a diuresis and natriuresis in the sodium-depleted dog. To determine if SA would similarly affect the kidneys in a cirrhotic subject, the effects of SA (40 mg/kg) and subsequent MECLO treatment (2 mg/kg) were evaluated in five normal and six common bile-duct-ligated (CBDL) miniature swine. All six CBDL animals showed signs of biliary cirrhosis and four of the six were ascitic at the time of study. SA did not significantly alter renal blood flow or glomerular filtration rate in either the normal or CBDL animals. In both groups, SA caused a significant diuresis and natriuresis. MECLO, given after SA, caused a reduction in renal blood flow in the normal but not in the CBDL animals, but did not alter glomerular filtration rate in either group. In the CBDL animals, when MECLO was given alone a significant decrease in renal blood flow occurred. MECLO abolished the SA-induced diuresis and natriuresis in the normal swine but only affected the SA-mediated natriuresis in the CBDL animals. SA significantly reduced renal prostaglandin E2 excretion in both groups. With MECLO, prostaglandin E2 excretion was reduced further in the normals but not in the CBDL animals. These data demonstrate that SA does not produce detectable renal vasoconstriction in the cirrhotic pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal prostaglandin E2 and F2 alpha synthesis during exercise: effects of indomethacin and sulindac.

To assess the effects of acute exercise on renal prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) synthesis, urine collections were obtained from six women before and after 30 min of treadmill exercise at approximately 80% of their maximal oxygen consumption. After receiving a placebo for 3 days, with acute exercise, there was a significant increase only in recovery urine PGE2 concentration. Due to a decline in urine volume, PGF2 excretion was unchanged and PGF2 alpha excretion was significantly decreased by exercise. Subjects repeated the tests after 3 d of indomethacin treatment (150 mg X d-1), a known renal prostaglandin (PG) inhibitor, and 3 d of sulindac (300 mg X d-1), a non-steroidal anti-inflammatory drug which may not inhibit renal PG synthesis. Pre-exercise urine PGE2 concentrations were decreased by indomethacin but not by sulindac, whereas, PGF2 alpha concentrations were decreased by both drugs. When compared to the control test, indomethacin and sulindac had different effects on pre-exercise urine/plasma osmolality ratios and free water clearances. Neither indomethacin nor sulindac influenced the decreases in free water clearances, which were observed during the placebo tests. Exercise proteinuria was significantly increased by indomethacin but not by sulindac. In conclusion, these data demonstrate that acute exercise may stimulate renal PGE2 synthesis. During exercise, renal PG synthesis attenuates protein excretion. There also appear to be differences between indomethacin and sulindac with regard to the effects on renal PG synthesis and kidney function.