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Am J Respir Crit Care Med Vol 157. pp 1294–1300, 1998 ..... Am. Rev. Respir. Dis. 134:1241–1245. 31. Hartz, R. S., J. G. Byrne, S. Levitski, J. Park, and S. Rich.
Lung Reperfusion Injury after Chronic or Acute Unilateral Pulmonary Artery Occlusion ELIE FADEL, GUY-MICHEL MAZMANIAN, ALAIN CHAPELIER, BRUNO BAUDET, HÉLÈNE DETRUIT, VINCENT de MONTPREVILLE, JEAN-MARIE LIBERT, MYRIAM WARTSKI, PHILIPPE HERVE, and PHILIPPE DARTEVELLE Laboratoire de Chirurgie Experimentale, Centre Chirurgical Marie Lannelongue, Université Paris Sud, Le Plessis Robinson, France

Because the lungs receive their blood supply from both the pulmonary and bronchial systems, chronic pulmonary artery obstruction does not necessarily result in severe ischemia. Ischemia-reperfusion (IR) lung injury may therefore be attenuated after long-term pulmonary artery obstruction. To test this hypothesis, isolated left lungs of pigs were reperfused two days (acute IR group) or 5 wk (chronic IR group) after left pulmonary artery ligation and compared to those of sham-operated animals. The severity of IR-lung injury after 60 min ex vivo reperfusion of the left lung was assessed based on lung histology and measurements of filtration coefficient (Kfc), pulmonary arterial resistance (Rpa), and lung myeloperoxidase (MPO) activity. Marked bronchial circulation hypertrophy was seen in the chronic IR group. Hemorrhagic alveolar edema was found in all acute IR lungs but not in sham or chronic IR lungs. Compared with the sham-operated controls, Kfc and Rpa increased twofold and threefold, and MPO 1.5-fold and twofold in the chronic and acute IR groups, respectively. In conclusion, IR-induced lung injury was markedly reduced when it occurred 5 wk after pulmonary artery ligation, probably because the systemic blood supply to the lung had time to develop, limiting ischemia. Fadel E, Mazmanian G-M, Chapelier A, Baudet B, Detruit H, de Montpreville V, Libert J-M, Wartski M, Herve P, Dartevelle P. Lung reperfusion injury after chronic or acute unilateral pulmonary artery occlusion. AM J RESPIR CRIT CARE MED 1998;157:1294–1300.

Ischemia-reperfusion (IR) lung injury is characterized by increased permeability of lung microvessels (1), pulmonary hypertension (2), and polymorphonuclear neutrophil (PMN) activation and sequestration in the lung (3, 4). Increasingly, ischemia and reperfusion are being recognized as two distinct events capable of inducing different lung lesions (5, 6). The term “IR injury” refers to the seemingly paradoxical worsening of tissue damage due to ischemia during acute reperfusion. Ischemia-reperfusion injury has been extensively studied after acute (7–12), but not after chronic, lung ischemia. Chronic lung ischemia occurs in chronic thromboembolic obstruction of the pulmonary arteries in humans and can be induced by chronic ligation of the pulmonary artery in experimental animals. Chronic obstruction of the pulmonary artery may increase the severity of IR injury because of more severe ischemic damage. However, because the lungs receive their blood supply from both the pulmonary and the bronchial circulations, and because chronic pulmonary artery obstruction is associated with marked bronchial circulation expansion (13–15), the possibility exists that chronic pulmonary artery obstruction may actually be associated with less severe ischemic injury than acute obstruction. Enlargement of the bronchial arteries

(Received in original form July 14, 1997 and in revised form September 24, 1997) Correspondence and requests for reprints should be addressed to Dr. Elie Fadel, Centre Chirugical Marie Lannelongue, 133 Avenue de la Résistance, 92250, Le Plessis Robinson, France. E-mail: [email protected] Am J Respir Crit Care Med Vol 157. pp 1294–1300, 1998

(16) and increased bronchial blood flow (17) have been reported to occur after 3 d of pulmonary artery ligation, reaching a maximum within 2–4 wk (16–18). We tested the hypothesis that IR-induced lung injury may be less rather than more severe after chronic pulmonary obstruction because development of bronchial circulation maintains the viability of the ischemic lung. We compared reperfusion-induced increases in lung microvascular permeability, pulmonary vascular resistance, and lung PMN sequestration 2 d and 5 wk after left pulmonary artery ligation in pigs.

METHODS Fifteen young pigs (large white, mean weight 6 SE 23 6 4.4 kg) were used. All animals received care in compliance with the “Principles of Laboratory Animal Care” developed by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” written by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication No. 86-23, revised in 1985). Pigs were randomly allocated to three groups (n 5 5 in each group). The studies were done 2 d after left pulmonary artery ligation in the acute IR group, 5 wk after left pulmonary artery ligation in the chronic IR group, and 5 wk after left pulmonary artery dissection without ligation in the control group. Ligation of the pulmonary artery. Anesthesia was induced with ketamine given intramuscularly (100 mg/kg) and maintained with pentobarbital given intravenously (10 mg/kg bolus, followed by a continuous infusion of 0.1 mg/kg/min). The animals were paralyzed with pancuronium (0.3 mg/kg). After endotracheal intubation, intermittent positive-pressure ventilation was provided (MMS RET 107 ventilator; MMS, Pau, France) at a tidal volume of 15 ml/kg, with a respiratory

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Fadel, Mazmanian, Chapelier, et al.: Reperfusion Injury after Pulmonary Artery Occlusion rate of 18 cycles/min and a fraction of inspired oxygen (FIO2) of 0.5. Body temperature was maintained at 378 C. A midline sternotomy was performed under sterile conditions, the pericardium was opened, and the intrapericardiac left pulmonary artery was dissected and ligated using a nonabsorbable loop. The chest was closed, and the animal was allowed to recover. Isolated perfused lung. The pigs were anesthetized as described above. A midline sternotomy was performed. In all the acute IR animals, nonadherent luminal thrombi were found in and removed from the proximal pulmonary arteries distal to the site of ligation. The chronic IR group animals had no thrombi but exhibited back-bleeding distal to the ligation, indicating the presence of bronchopulmonary anastomoses. After heparinization, the animals were killed by exsanguination and the left lung was rapidly removed from the chest. The left hilum was dissected and the left bronchus, left pulmonary artery, and left atrium were isolated and cannulated. The isolated left lungs were suspended by the left main bronchus to a force-displacement transducer in a thermostat-equipped humidified chamber to monitor weight changes. Ventilation with a humidified, warm gas mixture (20% O2, 75% N2, and 5% CO2) was supplied by an MMS 107 ventilator set at 20 breaths/min, a tidal volume of 200 ml, and a positive end-expiratory pressure of 2 cm H2O. A peristaltic pump (Ismatec; Bioblock, Strasbourg, France) was used for reperfusion with 300 ml heparinized autologous blood at a constant flow of 0.03 ml/g body weight for 60 min. Hematocrit values were similar in the three groups. Venous blood was collected from the left atrium cannula into a perfusion reservoir. To prevent loss of reservoir volume via retrograde perfusion of the bronchial circulation, the bronchial arteries were ligated. Pulmonary arterial pressure (Ppa) and pulmonary venous pressure (Ppv) were continuously monitored by pressure transducers (model P23 ID; Statham, Paris, France) connected to an amplifier (model M52; Telco, SaintCloud, France), and recorded on a polygraph recorder (ED 69; Alco, Paris, France). Zone 3 conditions (arterial . venous . alveolar pressures) were maintained throughout all experiments. Measurements of pulmonary vascular permeability. Pulmonary capillary pressure (Ppc) was estimated by using the double-occlusion method. When arterial and venous catheters are simultaneously occluded, Ppa and Ppv will equilibrate to the same pressure, well correlated with Ppc (19). The pulmonary arterial (Rpa) and venous resistances (Rpv) were calculated as follows, where Q is flow: Rpa 5 (Ppa – Ppc)/Q, Rpv 5 (Ppc – Ppv)/Q. The filtration coefficient (Kfc) was used as an index of endothelial permeability to fluid and measured using the isogravimetric method described by Drake (20). After an isogravimetric period of 30 min, Ppv was rapidly increased by 20 cm H2O for 20 min by raising the outflow end of the left atrium cannula. The resultant increase in lung weight was recorded. The characteristic rapid weight gain due to vascular filling was followed by a phase of slower weight gain reflecting filtration of fluid into the pulmonary interstitium. The rate of slow weight change (DW/Dt) was analyzed using linear regression of the log10-transformed weight changes per minute. The initial rate of weight gain was calculated by extrapolating DW/Dt to Time 0. Then Kfc was obtained by dividing DW/Dt at Time 0 by the change in Ppc that occurred after the venous outflow pressure increase, normalized for the baseline wet-lung weight, and expressed as ml/min/cm H2O/ 100 g lung tissue. Baseline wet-lung weight was estimated by measuring the weight of the left lung at the beginning of the experiment. At the end of the experiment the lungs were weighed for determination of the final wetlung weight. They were then dried in an oven at 608 C. Dry weights were obtained after the weights no longer changed on successive weighings (i.e., after about 30 d). The wet to dry-lung weight ratio was then determinated. Myeloperoxidase activity. Myeloperoxidase (MPO) lung activity was used as an indirect measure of tissue neutrophil infiltration (21). A tissue biopsy sample was taken after surgery from the right lung’s lower lobe (n 5 3 in control group, n 5 5 in acute IR group, and n 5 5 in chronic IR group). At the end of the reperfusion, a large tissue sample was taken from the lower left lobes in (n 5 3 in control group, n 5 5 in acute IR group, and n 5 5 in chronic IR group). These tissue samples were snap-frozen in liquid nitrogen. The method described by Mullane was used (21). Frozen lung tissue was pulverized and homogenized in 10% wt/vol of hexadecyltrimethyl ammonium bromide

Figure 1. Ischemia-reperfusion–induced microvascular injury as assessed by Kfc 2 d (IR acute) or 5 wk (IR chronic) after pulmonary artery ligation and in a sham-operated control group. †p 5 0.009, chronic IR group versus sham group; *p 5 0.03, chronic IR group versus acute IR group; and **p 5 0.001, acute IR group versus sham group. Results are expressed as means 6 SE.

(HTAB) buffer (0.5% HTAB in 50 mM phosphate buffer at pH 6.0), using a Polytron homogenizer. The homogenate was sonicated on ice for 15 s, frozen at –708 C and thawed three times, then centrifuged at 40,000 g for 15 min. Spectrophotometry was used to assay MPO in the supernatant. Twenty microliters of supernatant were combined with 12 ml of 25 mM H2O2, 30 ml of 40 mM o-dianisidine hydrochloride and 1.938 ml of mM phosphate buffer (pH 6.0). The change in absorbance was measured at 460 nm on a Beckman spectrometer (Model 25 Spectrometer; Beckman, Paris, France). One unit of MPO activity was defined as the activity degrading 1 mmol of peroxide per min at 258 C. White blood cell counts. White blood cell (WBC) counts were performed before and after the reperfusion period. Absolute and differential counts were determined using an Argos counter (ABX, Paris, France). Automated counts were routinely verified by manual counts. Counts were expressed as cells per microliter. The WBC counts were utilized to calculate percentage decrease of WBC as the ratio of difference in WBC counts before and after perfusion to the WBC count before perfusion. Morphology. Gross anatomic examination of the left lung was performed with special attention to the bronchial and systemic circulation supplying the left lung. At the end of the ex vivo reperfusion phase, large specimens were taken from the upper and lower lobes of the left lung and fixed by immersion in 10% neutral buffered formalin. After staining with hematoxylin and eosin, all biopsy specimens were examined in a blind fashion. Statistical analysis. All results are expressed as means 6 SE. Oneway analysis of variance followed by the Fisher test for multiple comparison was done using Statview II (Abacus Concept, Berkeley, CA). Probability values of less than 0.05 were considered significant. TABLE 1 HEMODYNAMIC RESULTS

Control Acute IR Chronic IR

Ppa

Rpa

Rpv

Kfc

11.8 6 2.0 23.4 6 3.9† 24.0 6 6.4*‡

9.6 6 7.1 32.4 6 3.8† 20.8 6 6.7*‡

12.4 6 2.2 14.4 6 4.6 27.2 6 12.9*‡

0.11 6 0.03 0.30 6 0.08† 0.21 6 0.04*‡

Definition of abbreviations: Ppa 5 pulmonary artery pressure; Rpa 5 pulmonary arterial resistance; Rpv 5 pulmonary venous resistance; Kfc 5 coefficient of filtration. Results are expressed as means 6 SE. Pressures are expressed as mm Hg, resistances as mm Hg/ml/min, and Kfc as ml/min/cm H2O/100 g lung. * Significant difference between chronic IR and control groups. † Significant difference between acute IR and control groups. ‡ Significant difference between acute IR and chronic IR groups. The respective p values are given in the text or figure legends.

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Figure 2. Ischemia-reperfusion–induced increase in pulmonary arterial resistance (Rpa) 2 d (IR acute) or 5 wk (IR chronic) after pulmonary artery ligation and in a sham-operated control group. † p 5 0.01, chronic IR group versus sham group; *p 5 0.01, chronic IR group versus acute IR group; and **p , 0.0001, acute IR group versus sham group. Results are expressed as means 6 SE.

RESULTS There were no differences in body weight, perfusate cell concentration, or hematocrit among the three groups. As in previous studies (11), leukocyte concentrations fell to similarly low levels in all three groups after reperfusion. The leukocyte percentage decreases from baseline values after reperfusion were 56% 6 6% in the control group, 37% 6 9% in the acute IR group, and 33% 6 9% in the chronic IR group. The Kfc values are shown in Figure 1 and Table 1. Those values were higher in the acute IR group (0.30 6 0.03 ml/cm H2O/min/100 g) than the chronic IR group (0.21 6 0.02 ml/cm H2O/min/100 g, p 5 0.03), or the sham group (0.10 6 0.01 ml/ cm H2O/min/100 g, p 5 0.0001). The Kfc values were significantly higher in the chronic IR group than in the control group (p 5 0.009). Wet to dry ratios were not significantly different among the three groups.

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Figure 4. Relationship of coefficient of filtration (Kfc) to lung MPO activity after reperfusion (r 5 0.76, p 5 0.0002).

Hemodynamic measurements are shown in Table 1. Both Ppa and Rpa values were higher in the acute and chronic IR groups than in the control group. The Rpa was higher in the acute IR group than in the chronic IR group (Figure 2). The Rpv was higher in the chronic IR group than in the acute IR and control groups. Measures of Ppv and Ppc were not significantly different among the three groups. Right-lung MPO activities were similar in the three groups. Left-lung MPO activity (Figure 3) was higher in the acute IR group (0.40 6 0.05 U/100 mg) than in the chronic IR group (0.29 6 0.04 U/100 mg; p 5 0.007) or the control group (0.18 6 0.05 U /100 mg, p 5 0.0001). Also, left-lung MPO activity was higher in the chronic IR group than in the control group (p 5 0.01). A significant positive correlation was found between left-lung Kfc (r 5 0.76, p 5 0.0002) and left-lung MPO activity (Figure 4). The gross appearance of the lung parenchyma was unremarkable in the control and chronic IR groups. In the acute IR lungs, atelectatic and hemorrhagic zones separated by morphologically normal zones were seen. In the chronic IR group, there was ample macroscopic evidence of expansion of the systemic supply to the left lung. The bronchial circulatory system was hypertrophied, and in all five pigs the visceral pleura was supplied by vessels that either continued bronchial arteries or stemmed from mediastinal arteries (Figure 5). Some of these pleural vessels traveled through the pulmonary ligament and coursed on the surface of the lower lobe of the lung. Histologic examination of the reperfused lungs from the acute IR group consistently showed hemorrhagic areas with extravasation of red cells into alveolar spaces, as well as areas of alveolar edema. The lungs from the chronic IR and control groups were histologically normal (Figure 6).

DISCUSSION

Figure 3. Ischemia-reperfusion–induced lung PMN sequestration as assessed by MPO lung activity 2 d (IR acute) or 5 wk (IR chronic) after pulmonary artery ligation and in a sham-operated control group. † p 5 0.0001, chronic IR group versus sham group; *p 5 0.007, chronic IR group versus acute IR group; and **p 5 0.0001, acute IR group versus sham group. Results are expressed as means 6 SE.

We found that lung reperfusion induced less severe injury when it occurred 5 wk, rather than 2 d, after pulmonary artery occlusion. This difference may have been related to supplementation of the deficient pulmonary arterial blood flow by expansion of the bronchial circulatory system. Lung reperfusion after a period of pulmonary artery occlusion is associated with pulmonary edema, fever, and leukopenia (22). Ischemia-reperfusion lung injury is characterized by increased microvascular permeability, pulmonary hyperten-

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Figure 5. Representative light photomicrographs of sections from ligated lungs after reperfusion for 1 h. Hematoxylin and eosin stain, original magnification: 3150. (A) sham-operated lung. (B) lung reperfused 5 wk after left pulmonary artery ligation. (C) lung reperfused 2 d after left pulmonary artery ligation. Panels A and B show normal parenchyma, whereas panel C shows foci of alveolar edema and intra-alveolar hemorrhage.

sion, and pulmonary PMN activation and sequestration (1–4). In our study, the lungs were reperfused ex vivo to normalize pulmonary blood flow and to ensure recruitment of the entire pulmonary vascular surface area. The measure Kfc was used to evaluate changes in lung microvascular permeability using the isogravimetric method (4, 11, 20). By this measure (20), weight gain essentially occurred only during the short period of determination of Kfc, which implies that Kfc is a more sensi-

tive index of vascular permeability than wet to dry weight ratio (2). Lung PMN sequestration was assessed by measuring lung MPO activity, which is a marker of tissue PMN infiltration (21, 23). Because infiltrating PMNs have been implicated as key mediators of IR-induced lung damage, our isolated pig lungs were perfused with autologous blood rather than a buffer solution. In the control group, Kfc values were similar to those previously reported in normal lungs of other species (10,

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Figure 5. Continued.

Figure 6. Surfaces of the left lungs of two representative animals. One was studied 5 wk after pulmonary artery dissection without ligation (A), and the other 5 wk after left pulmonary artery ligation (B). Large systemic arteries are visible on the lung surface under the visceral pleura on (B).

Fadel, Mazmanian, Chapelier, et al.: Reperfusion Injury after Pulmonary Artery Occlusion

24). As expected, reperfusion after pulmonary occlusion induced increases in Kfc, Rpa, and MPO; Kfc values were correlated with MPO (Figure 4), indicating that pulmonary PMN activation and sequestration were also central mechanisms in our model of reperfusion-induced microvascular lung injury. However, the reperfusion injury was markedly attenuated after chronic pulmonary artery obstruction. Compared to the control group, Kfc and Rpa increased threefold in the acute IR group, but only twofold in the chronic IR group; MPO activity increased twofold in the acute IR group, but only 1.5-fold in the chronic IR group. In keeping with these findings, histologic examination consistently showed diffuse alveolar hemorrhage after reperfusion in the acute IR group but not in the chronic IR group, which was not different histologically from the control group. These differences in the severity of IR lung injury support our working hypothesis that reperfusion is better tolerated after chronic than acute lung ischemia. Ischemia and reperfusion are increasingly being considered two separate events, each of which causes specific lung lesions (5). Bishop (5) and Barie (8, 25) and their colleagues demonstrated ischemic microvascular damage during short-term pulmonary artery occlusion. Hypoxia is an unlikely mechanism for these ischemic lesions because ventilation is not interrupted after pulmonary artery occlusion. Alternative mechanisms include a decrease in tissue CO2 level (17), an interruption of the supply of nutrients to endothelial cells (25), and diminished surfactant production in lung zones distal to the pulmonary occlusion (26). Before reperfusion, we found areas of hemorrhagic atelectasis in the acute IR group, whereas the lung parenchyma was macroscopically normal in the chronic IR group. We suspect that limitation of IR lung injury in the chronic group was related to development of the systemic bronchial vascular network. We consistently found marked expansion of the bronchial circulation in the animals studied 5 wk after pulmonary artery ligation, whereas the bronchial arteries were normal in the animals studied 2 d after ligation. Moreover, all the chronic IR animals exhibited back-bleeding distal to the site of pulmonary artery ligation, indicating the presence of bronchopulmonary anastomoses (27). These bronchopulmonary anastomoses could account for the increase in Rpa and Rpv in the chronic IR group, related to the development of a postobstructive vasculopathy (15). Studies of the effects of pulmonary artery ligation on the bronchial circulation have been carried out in dogs (14, 28), sheep (17), rats (16), rabbits (7), and pigs (29). In sheep (17), bronchial blood flow dropped during the first 24–48 h, then increased to a maximum value over the next 4 wk. Bronchial blood flow was increased by more than 100 ml/min 2 wk after pulmonary artery ligation in dogs (28) and sheep (17), which amounts to about a fivefold increase over the normal value. In pigs, bronchial circulation enlargement after pulmonary artery ligation may occur faster than in other species (29), and a study by Haworth and colleagues (29) showed rapid bronchial circulation hypertrophy during the first 2 wk, producing larger bronchial arteries than the accompanying pulmonary arteries after 4 wk. Although we did not measure bronchial blood flow, our macroscopic observations and data in the literature suggest that bronchial blood flow was markedly increased in our chronic IR group, and that our acute IR group was studied at a time when bronchial blood flow was normal or decreased. Reperfusion lung damage has not been evaluated after long-term pulmonary artery obstruction. Recent studies by Kowalski (7) and Pearse and their colleagues (9) indicated that the extent of reperfusion edema after acute pulmonary artery occlusion was negatively correlated with bronchial

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blood flow. Two mechanisms have been suggested to explain this finding: bronchial perfusion may attenuate ischemiainduced lung damage or direct absorption of fluid by the enlarged bronchial vessels may accelerate pulmonary edema clearance during reperfusion. Because the bronchial arteries were ligated and not perfused during reperfusion in our ex vivo lung preparation, we believe the first mechanism is the most likely explanation for the lesser severity of reperfusion injury in our chronic ischemic group. Our findings may have important clinical implications. Reperfusion edema is common after thromboendarterectomy in patients with chronic thromboembolic pulmonary artery obstructions (30), although it varies widely in severity, ranging from mild edema resulting in hypoxemia to acute, hemorrhagic edema with a fatal outcome (30, 31). The unique feature of this edema is that it is limited to lung areas from which thromboembolic obstructions have been removed (30). Angiography shows a marked increase in bronchial circulation in patients with chronic pulmonary thromboembolic obstructions (32). Moreover, vigorous bronchial back-bleeding has been observed during thromboendarterectomy, indicating the presence of significant bronchial-to-pulmonary anastomoses (33). Interestingly, patients with dilated bronchial arteries on preoperative computed tomography (34) or with back-bleeding during surgery (27, 35) had a significantly lower risk for postoperative death. Also, recent unpublished observations made by our group suggest that absence of bronchial blood supply to an obstructed lung area is associated with an increased risk of localized reperfusion edema after pulmonary thromboendarterectomy. These clinical observations are consistent with our experimental findings, and suggest that bronchial perfusion could attenuate reperfusion edema after thromboendarterectomy in patients with chronic thromboembolic obstruction of the pulmonary arteries. In conclusion, we provide the first compelling evidence that IR-induced lung injury is substantially attenuated after long-term pulmonary artery ligation, and we speculate that development of the bronchial circulation may prevent true ischemia from occurring in the chronically occluded lung. References 1. Khimenko, P. L., J. W. Barnard, T. M. Moore, P. S. Wilson, S. T. Ballard, and A. E. Taylor. 1994. Vascular permeability and epithelial transport effects on lung edema formation in ischemia and reperfusion. J. Appl. Physiol. 77:1116–1121. 2. Allison, R. C., J. Kyle, W. K. Adkins, V. R. Prasad, J. M. McCord, and A. E. Taylor. 1990. Effect of ischemia reperfusion or hypoxia reoxygenation on lung vascular permeability and resistance. J. Appl. Physiol. 69:597–603. 3. Horgan, M. J., M. Ge, J. Gu, R. Rothlein, and A. B. Malik. 1991. Role of ICAM-1 in neutrophil-mediated lung vascular injury after occlusion and reperfusion. Am. J. Physiol. 261:H1578–H1584. 4. Seiber, A. F., J. Haynes, and A. E. Taylor. 1993. Ischemia-reperfusion injury in the isolated rat lung. Am. Rev. Respir. Dis. 147:270–275. 5. Bishop, M. J., W. Lamm, S. M. Guidotti, and R. K. Albert. 1992. Pulmonary artery occlusion is sufficient to increase pulmonary vascular permeability in rabbits. J. Appl. Physiol. 73:272–275. 6. Johnson, R. L., S. S. Cassidy, M. Haynes, R. L. Reynolds, and W. Schulz. 1981. Microvascular injury distal to unilateral pulmonary artery occlusion. J. Appl. Physiol. 51:845–851. 7. Kowalski, T. F., S. Guidotti, M. Deffebach, P. Kubilis, and M. Bishop. 1990. Bronchial circulation in pulmonary artery occlusion and reperfusion. J. Appl. Physiol. 68:125–129. 8. Barie, P. S., T. S. Hakim, and A. B. Malik. 1981. Effect of pulmonary artery occlusion and reperfusion on extravascular fluid accumulation. J. Appl. Physiol. 50:102–106. 9. Pearse, D. B., and E. M. Wagner. 1994. Role of the bronchial circulation in ischemia-reperfusion lung injury. J. Appl. Physiol. 76:259–265. 10. Murakami, S., E. A. Bacha, P. Hervé, H. Détruit, A. R. Chapelier, P. G.

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