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A comparison of the effects of aspirin and histamine on fluid balance in the recruited lung
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A COEPARISON OF THE EFFECTS OF ASPiR!I{ AND H!STAHIUE OF FLUID F~LA~CE IN THE RECRUITED LONG ~. Jeffrey Weidner and Diane E. McClure D e p a r t m e n t of Animal Physiology, U n i v e r s i t y of California, Davis, California 95616 USA Abstract Salicylate administration has been reported to increase the flow of protein-rich lymph from the lungs of animals, however, the mechanism of this response is unclear. In the present study we m e a s u r e d pulmonary hemodynamics and l u n g f l u i d and p r o t e i n f l u x in a n e s t h e t i z e d sheep, surgically prepared for the collection of lung lymph, in order to examine tile possible effect of aspirin (ASP) on lung v a s c u l a r permeability. ASP was given during r e c r u i t m e n t of pulmonary microvascular surface area induced by sustained elevation of left atrial pressure (Pla) (Group I) or continuous infusion of adenosine triphosphate (ATP) (Group 2). We compared the results of ASP administration to those found in similarly prepared animals given h i s t a m i n e (H) during like periods of increased Pla (Group 3) or ATP infusion (group 4). ASP a d m i n i s t r a t i o n resulted in increased lymphatic protein clearance (Cp) in both Groups I and 2. In Group I, f o l l o w i n g the c h a r a c t e r i s t i c increase in lung lymph flow (QI) and fall in the ratio of lung lymph to plasma protein concentration (L/P) produced by Pla elevation, ASP administration resulted in a further increase in QI and a significant increase in L/P. The results found in ASP animals are qualitatively similar to those observed in Groups 3 and 4 after H. While we cannot specifically rule out a hemodynamic effect of the drug, our results suggest tile increased protein flux observed following ASP administration was mediated at least in part through an increase in lung microvascular permeability. Introduction A d m i n i s t r a t i o n of cycloexygenase inhibitors, such as aspirin (ASP) and i n d o m e t h a c i n (IND0), to sheep surgically prepared for the collection of lung l y m p h has been reported to increase the protein c o n c e n t r a t i o n and flow rate of that lymph. The m e c h a n i s m of the response is, however, unclear. Bowers et al., in a 1979 study, suggested that the increase in lung fluid and protein flux caused by ASP resulted from an increase in pulmonary microvascular permeability (I). In a 1982 report, Ogletree suggested that INDO increased lung fluid and protein transport through a mechanism involving primarily a pressure dependent increase in pulmonary microvascular surface area (PMSA) rather than increased vascular p e r m e a b i l i t y (2). Maron has recently reported that v a s o c o n s t r i c t i o n rather than increased vascular p e r m e a b i l i t y might explain the alterations in lung fluid balance which follow the administration of cyclooxygenase inhibitors (3). The following study was undertaken to examine the effect of ASP
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on l u n g f l u i d b a l a n c e in s h e e p u n d e r c o n d i t i o n s of v a s c u l a r r e c r u i t m e n t with e l e v a t e d left a t r i a l p r e s s u r e or a d e n o s i n e triphosphate (ATP) a d m i n i s t r a t i o n in order to m i n i m i z e changes in PMSA. Results of ASP administration during recruitment are compared to s i m i l a r studies in which h i s t a m i n e (H), a substance reported to increase lung vascular permeability, was given during recruitment. Methods We initially induced anesthesia in 22 fasted adult sheep (40.7 + 5.6 kg) with 15 mg/kg thiamyl sodium given intravenously. After tracheal intubation, anesthesia was m a i n t a i n e d at a surgical plane with 1.O1.5% halothane in 50% oxygen delivered by a positive pressure ventilator. End expiratory pressure was maintained at approximately 4 Tort for the duration of the study. Blood gas values were measured p e r i o d i c a l l y throughout the experiments. Arterial oxygen tension remained above 200 Torr in all animals. S y s t e m i c a r t e r i a l b l o o d p r e s s u r e (Psa) w a s r e c o r d e d f r o m a polyethylene catheter (2.4 mm O.D.) placed in the descending aorta via a femoral artery. A femoral vein was cannulated for collection of blood samples and administration of drugs or fluid as needed. A 7-F Swan-Canz thermodilution catheter was placed in the pulmonary artery to measure p u l m o n a r y arterial blood pressure (Ppa). Cardiac output (CO) was determined by thermodilution with a cardiac output computer (Edwards Laboratories, model 9520). Left atrial pressure (Pla) was measured with a catheter placed via a left fifth rib thoracotomy. A 22-F (30 ml balloon) Foley catheter was placed in the left atrium. The left atrium was used as the zero-pressure reference with pressure transducers placed 10 cm above the level of the sternum. Each animal received a p p r o x i m a t e l y 850 ml of saline during the course of the experiment, as a result of routine catheter flushing and cardiac output determinations. We collected lung l y m p h using a technique described by Staub et al. (4). An efferent duct of the caudal mediastinal lymph node (CMN~ was cannulated with a Silastic catheter (Dow C o m i n g ) . The tail of the node was resected and visible diaphragmatic lymphatics were ligated. Lymph samples were collected over 15 min in graduated centrifuge tubes for the d e t e r m i n a t i o n of the rate of lung lymph flow (QI). Blood samples were drawn at 30 minute intervals. Lymph (L) and plasma (P) total protein concentrations were m e a s u r e d with a calibrated r e f r a c t o m e t e r (American Optical, model 10400) and c o n f i r m e d with a biuret technique. Lung lymph to plasma protein concentration ratios (L/P) were calculated from these. All hemodynamic and lymphatic flux parameters were tabulated during each 15 minute collection period. Each animal was studied in sternal recumbancy. Inspired halothane concentration was lowered following surgery and 3-6 mg of metocurine iodide was given intravenously and supplemented every two hours for
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the duration of the experiment. Inspired halothane concentration was m a i n t a i n e d in the range 0.7-1.O, a level that does not block adrenergic responses (5). All animals were studied during a baseline period of at least I hour p r i o r to i n t e r v e n t i o n . H e m o d y n a m i c and l y m p h a t i c flux p a r a m e t e r s were evaluated during steady state periods of at least one hour after intervention when possible. A steady state was defined as at least 4 c o n s e c u t i v e e x p e r i m e n t a l p e r i o d s during which these parameters did not change s i g n i f i c a n t l y . The p a i r e d t-test was used to e x a m i n e c h a n g e s in p a r a m e t e r s across animals. We a c c e p t e d P
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c o m p a r e d to baseline as a result of a 54.9% increase in QI (from 7.1 + 2.2 m l / h r to 11.0 + 3.1 ml/hr) while L/P did not change (0.83 + ~.02 vs. 0.85 + 0.01 d~ring baseline). A representative e x p e r i m e n t is illustrate~in Figure 2. Group 3 (Pla + H). Elevation of Pla in this group also produced a characteristic increase in QI (from a baseline level of 6.4 + 2.30 m l / h r to 10.1 ~ 2.3 ml/hr) and fall in L/P (from O.71 + 0~02 to 0.60 + 0.04). Histamine (H) administration during hydrostatic recruitment resulted in a further, albeit slight, increase in QI to 11.1 + 0.6 ml for the group as a whole which occurred despite a significant fall in both Ppa and Pla. W h i l e L/P f e l l to 0.54 ~ 0.04 f o l l o w i n g H administration, this value was not significantly different from that obtained during elevated Pla alone. Figure 3 illustrates a representative experiment. Group 4 (ATP + H). In this group H a d m i n i s t r a t i o n during the e x p e r i m e n t a l period resulted in a doubling of lymphatic protein clearance, which occurred largely due to an increase in QI from a baseline level of 10.6 + 1.90 ml/hr to 21.3 + 5-5 ml/hr, while L/P r e m a i n e d unchanged. (0~79 + 0.02 vs 0.80 + 0[O2). A representative experiment is illustrated in Figure 4. Discussion The p a t h o p h y s i o l o g y of s a l i c y l a t e p u l m o n a r y edema has been extensively studied and has b e e n w e l l r e v i e w e d (1,6). That salicylate overdose causes p u l m o n a r y edema in h u m a n s is well established. However, due to differences in e x p e r i m e n t a l species, dosage and model, the mechanism of edemogenesis is not clear. Bowers et al. observed an increased flow of protein-rich lung lymph in sheep f o l l o w i n g ASP a d m i n i s t r a t i o n and suggested increased p u l m o n a r y microvascular permeability to proteins as the mechanism responsible (I). However, M a r o n has recently reported that ASP a d m i n i s t r a t i o n does not increase extravascular water content in isolated canine lung lobes, but does increase lobar arterial and venous tone (3). Be has suggested that v e n o c o n s t r i c t i o n and the associated increase in p u l m o n a r y capillary pressure, rather than increased microvascular permeability might explain the alterations in lung fluid balance that follow aspirin administration. But, he further suggested that perfused surface area must have decreased enough to offset the increase in microvascular filtration. Group I animals in the present study were subjected to increased Pla of approximately 14 Torr prior to ASP administration, a procedure intended to minimize changes in PMSA and, by forcing high lung lymph flow, minimize nodal alteration of lymph c o m p o s i t i o n prior to collection (7,8,9). We a d m i n i s t e r e d ASP in a dosage sufficient to raise plasma salicylate concentration to an average of a p p r o x i m a t e l y 23 mg/dl, a level reported to be in the high therapeutic range in humans (10). Our dosage is comparable
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to that used by Bowers et al., but is l o w e r than the average c o n c e n t r a t i o n of 97.8 mg/dl a d m i n i s t e r e d in Maron's study. ASP administration in Group I animals resulted in an increase in QI to a level s i g n i f i c a n t l y higher than was produced by recruitment alone and, despite continued elevation of Pla, group L/P rose significantly from 0.59 to 0.66 (Table I). These responses occured with little change in either Ppa or Pla and with an increase in CO for the group as c o m p a r e d to the period of elevated Pla alone. Under these h e m o d y n a m i c conditions it is unlikely that d e r e c r u i t m e n t occured. The data suggest that the increased protein flux observed following ASP a d m i n i s t r a t i o n in this group occured at least in part due to an increase in lung m i c r o v a s c u l a r p e r m e a b i l i t y to p l a s m a proteins. Results from Group 3 in w h i c h h i s t a m i n e (H) was given during recruitment are qualitatively similar to Group I. Histamine has been found to increase fluid and protein transport in the sheep lung through a mechanism t h o u g h t to i n v o l v e i n c r e a s e d v a s c u l a r permeability (11, 12, 13), although the effect may be transient (14), and confined to the bronchial circulation (13). While steady state data were difficult to obtain in this group, due to the hypotensive effects produced by H infusion during the period of elevated Pla, L/P showed a steadily increasing trend f o l l o w i n g H after the marked dilution produced by increased Pla (Figure 3). This response is consistent with increased lung microvascular permeability, although alterations outside the lung can not be ruled out (15). As has been discussed in a recent review (16), the e x p e r i m e n t a l manuever of elevating Pla to minimize changes in PMSA is not without disadvantages. One c o m p l i c a t i o n of this technique is the dramatic f a l l in s y s t e m i c a r t e r i a l p r e s s u r e (and CO) that s o m e t i m e s a c c o m p a n i e s this procedure, which, p a r t i c u l a r l y in the acutely prepared, anesthetized animal, can be fatal. R e c r u i t m e n t of P M S A with ATP infusion has several advantages when compared to the use of a Foley balloon catheter to elevate Pla. ATP is an endogenous compound which is rapidly metabolized in the pulmonary circulation (17) and does not alter lung microvascular permeability (18). With ATP infusion, surgical intervention to i m p l e m e n t recruitment is minimized and sysytemic h e m o d y n a m i c s are well maintained. In the present study, ATP infusion was employed to recruit PMSA in Groups 2 and 4. In Group 2 ASP a d m i n i s t r a t i o n during r e c r u i t m e n t resulted in a sigificant increase in lymphatic protein clearance (Table I). This response occured with little or no change in CO, Ppa or Pla, L/P was u n c h a n g e d a l t h o u g h QI increased by 54.9%. Results from this group are qualitatively similar to those found after H infusion in Group 4, although the proportionately greater increase in QI in these animals may reflect a hemodynamic effect of H which is masked by hydrostatic recruitment (3). ATP infusion does not in itself provide the means for forcing the lung to the degree of r e c r u i t m e n t seen when high pulmonary vascular pressures are used. Thus, an effect of ASP (or H) on P M S A can not be specifically ruled out by these experiments,
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however, the results are consistent with an effect on microvascular permeability and, when considered with results from Group I, suggest that ASP can increase m i c r o v a s c u l a r p e r m e a b i l i t y in the recruited lung. As has been suggested from the data from other investigations on the effects of cyclosxygenase inhibitors on pulmonary hemodynamics (3, 20, 21), the response may be m e d i a t e d by the inhibition of a vasodilator prostaglandin, such as prostacyclin. It is also possible that ASP may have shifted arachidonate metabolism to the lipooxygenase p a t h w a y with the consequent p r o d u c t i o n of leukotrienes, substances which may increase pulmonary microvascular permeability (21). In summary, we have found that ASP increases the flow of protein-rich lymph from the lungs of sheep during recruitment of PMSA either with ATP or elevated Pla. The response is similar to that produced by H. While the response may be mediated in part by alterations in the surface area of exchange vessels, the fact that it was not prevented by hydrostatic recruitment of PMSA suggests that lung microvascular permeability was increased. Acknowledgments This study was supported in part by grants from the A m e r i c a n Heart Association: California Affiliate Nos. 82-136, 84-157 and 85-149A.
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REFERENCES I.
2. 3. 4.
5.
6. 7.
8.
9. 10. 11. 12.
13.
14.
15. 16.
17.
18.
442
Bowers, R.E., K.L. Brigham, and P.J. Owen. Salicylate Pulmonary Edema: The M e c h a n i s m in Sheep and Review of the Clinical Literature. Am. Rev. Respir. Dis. 115:261. 1977. Ogletree, M.L. Pharmacology of the Prostaglandins in the Pulmonary Circulation. Ann. NY Acad. Sci. 384:191. 1982. Maron, M.B. Effect of High Doses of Aspirin on P u l m o n a r y Hemodynamics and Lung Water. Am. J. Physiol. 248:H225. 1985. Stauh, N.C., R.D. Bland, K.L. Brigham, R. Demling, A.J. Erdmann III and W. Woolverton. Preparation of Chronic Lung Lymph Fistulas in Sheep. J. Surg. Res. 19:315. 1975. Roizen, M.R., W. Horrigan, and B.M. Frazer. Anesthetic doses blocking adrenergic (stress) and cardiovascular responses to incision - MACBAR. Anesthesiology. 54:390. 1981. Heffner, J.E., and S.A. Sahn. Salicylate-induced P u l m o n a r y Edema. Clinical Features and Prognosis. Ann. Intern. Med. 95:405. 1981. Jones, T.A., M.I. T o w n s l e y , and W.J. W e i d n e r . E f f e c t s of Intracranial and Left Atrial Hypertension on Lung Fluid Balance in Sheep. J. Appl. Physiol. 52:1324. 1982. Townsley, M.I., D.E. McClure, and W.J. Weidner. Assessment of Pulmonary Microvascular Permeability in Acutely Prepared Sheep. J. Appl. Physiol. 56:857. 1984. Adair, T . H . Studies of Lymph M o d i f i c a t i o n by Lymph Nodes. Microcirc. Endothel. and Lymph. 2:251. 1985. Trinder, P. Determination of Serum Salicylate Levels. Biochem. J. 57:301. 1954. Brigham, K.L., and P.J. 0wen. Increased Sheep Lung Vascular Permeability Caused by Histamine. Circ. Res. 73:647. 1975. Nakahara, K.K., K. 0hkuda, and N.C. Staub. Effect of Infusing Histamine into P u l m o n a r y or Bronchial Artery on Sheep P u l m o n a r y Fluid Balance. Am. Rev. Resp. Dis. 120:$75. 1979. Pietra, C.C., M. Magno, L. Johns, and A.P. Fishman. In: P u l m o n a r y Edema. (A. P. F i s h m a n and E. !4. Renkin, eds.) American Physiological Society, Bethesda, 1979. p. 199. Bernard, C.R., J.R. Snapper, A.A. Hutchinson, and K.L. Brigham. Effects of Left Atrial Pressure Elevation and Histamine Infusion on Lung Lymph in Awake Sheep. J. Appl. Physiol. 56:1083. 1984. Maron, M.B. Modification of lymph during passage through the Lymph Node: Effect of Histamine. Am. J. Physiol. 245:H553. 1983. Taylor, A., M.I. Townsley, and R.J. Korthius. Macromolecule Transport Across the Pulmonary Microvessel Walls. E x p . Lung Res. 8:97. 1985. Ryan, J.W., R.S. Niemeyer, and D.W. Coedwin. Metabolic Fates of Bradykinin, Angiotensin I, Adenine Nucleotides and Prostaglandins El and F1alpha in the P u l m o n a r y Circulation. Advan. Exp. Med. Biol. 21:259. 1972. Townsley, M.I. and W.J. W e i d n e r . I n f l u e n c e of A d e n o s i n e Triphosphate on Lung Fluid Balance in Sheep. Physiologist. 24:17. 1981.
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19.
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21 .
K a d o w i t z , P.J., B.M. C h a p n i c k , P.D. J o i n e r , and A.L. H y m a n . Influence of Inhibitors of P r o s t a g l a n d i n Synthesis on the canine Pulmonary Vascular Bed. Am. J. Physiol. 229:941. 1975. Leffler, C.W., and J.C. Passmore. Contribution of P r o s t a g l a n d i n s to the Regulation of P u l m o n a r y V a s c u l a r Resistance in Adult Cats and Dogs. Prostaglandins Med. 3:343. 1979. Noonan, T.C., D.F. K e r n , and A.B. M a l i k . Pulmonary Microcirculatory Responses to Leukotrienes B4, C4, and D4 in Sheep. Pros taglandins. 30:419. 1985.
Editor:
J.R. Fletcher
Received:
MARCH 1987 VOL. 33 NO. 3
10-8-86
Accepted:
12-9-86
443
A COEPARISON OF THE EFFECTS OF ASPiR!I{ AND H!STAHIUE OF FLUID F~LA~CE IN THE RECRUITED LONG ~. Jeffrey Weidner and Diane E. McClure D e p a r t m e n t of Animal Physiology, U n i v e r s i t y of California, Davis, California 95616 USA Abstract Salicylate administration has been reported to increase the flow of protein-rich lymph from the lungs of animals, however, the mechanism of this response is unclear. In the present study we m e a s u r e d pulmonary hemodynamics and l u n g f l u i d and p r o t e i n f l u x in a n e s t h e t i z e d sheep, surgically prepared for the collection of lung lymph, in order to examine tile possible effect of aspirin (ASP) on lung v a s c u l a r permeability. ASP was given during r e c r u i t m e n t of pulmonary microvascular surface area induced by sustained elevation of left atrial pressure (Pla) (Group I) or continuous infusion of adenosine triphosphate (ATP) (Group 2). We compared the results of ASP administration to those found in similarly prepared animals given h i s t a m i n e (H) during like periods of increased Pla (Group 3) or ATP infusion (group 4). ASP a d m i n i s t r a t i o n resulted in increased lymphatic protein clearance (Cp) in both Groups I and 2. In Group I, f o l l o w i n g the c h a r a c t e r i s t i c increase in lung lymph flow (QI) and fall in the ratio of lung lymph to plasma protein concentration (L/P) produced by Pla elevation, ASP administration resulted in a further increase in QI and a significant increase in L/P. The results found in ASP animals are qualitatively similar to those observed in Groups 3 and 4 after H. While we cannot specifically rule out a hemodynamic effect of the drug, our results suggest tile increased protein flux observed following ASP administration was mediated at least in part through an increase in lung microvascular permeability. Introduction A d m i n i s t r a t i o n of cycloexygenase inhibitors, such as aspirin (ASP) and i n d o m e t h a c i n (IND0), to sheep surgically prepared for the collection of lung l y m p h has been reported to increase the protein c o n c e n t r a t i o n and flow rate of that lymph. The m e c h a n i s m of the response is, however, unclear. Bowers et al., in a 1979 study, suggested that the increase in lung fluid and protein flux caused by ASP resulted from an increase in pulmonary microvascular permeability (I). In a 1982 report, Ogletree suggested that INDO increased lung fluid and protein transport through a mechanism involving primarily a pressure dependent increase in pulmonary microvascular surface area (PMSA) rather than increased vascular p e r m e a b i l i t y (2). Maron has recently reported that v a s o c o n s t r i c t i o n rather than increased vascular p e r m e a b i l i t y might explain the alterations in lung fluid balance which follow the administration of cyclooxygenase inhibitors (3). The following study was undertaken to examine the effect of ASP
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on l u n g f l u i d b a l a n c e in s h e e p u n d e r c o n d i t i o n s of v a s c u l a r r e c r u i t m e n t with e l e v a t e d left a t r i a l p r e s s u r e or a d e n o s i n e triphosphate (ATP) a d m i n i s t r a t i o n in order to m i n i m i z e changes in PMSA. Results of ASP administration during recruitment are compared to s i m i l a r studies in which h i s t a m i n e (H), a substance reported to increase lung vascular permeability, was given during recruitment. Methods We initially induced anesthesia in 22 fasted adult sheep (40.7 + 5.6 kg) with 15 mg/kg thiamyl sodium given intravenously. After tracheal intubation, anesthesia was m a i n t a i n e d at a surgical plane with 1.O1.5% halothane in 50% oxygen delivered by a positive pressure ventilator. End expiratory pressure was maintained at approximately 4 Tort for the duration of the study. Blood gas values were measured p e r i o d i c a l l y throughout the experiments. Arterial oxygen tension remained above 200 Torr in all animals. S y s t e m i c a r t e r i a l b l o o d p r e s s u r e (Psa) w a s r e c o r d e d f r o m a polyethylene catheter (2.4 mm O.D.) placed in the descending aorta via a femoral artery. A femoral vein was cannulated for collection of blood samples and administration of drugs or fluid as needed. A 7-F Swan-Canz thermodilution catheter was placed in the pulmonary artery to measure p u l m o n a r y arterial blood pressure (Ppa). Cardiac output (CO) was determined by thermodilution with a cardiac output computer (Edwards Laboratories, model 9520). Left atrial pressure (Pla) was measured with a catheter placed via a left fifth rib thoracotomy. A 22-F (30 ml balloon) Foley catheter was placed in the left atrium. The left atrium was used as the zero-pressure reference with pressure transducers placed 10 cm above the level of the sternum. Each animal received a p p r o x i m a t e l y 850 ml of saline during the course of the experiment, as a result of routine catheter flushing and cardiac output determinations. We collected lung l y m p h using a technique described by Staub et al. (4). An efferent duct of the caudal mediastinal lymph node (CMN~ was cannulated with a Silastic catheter (Dow C o m i n g ) . The tail of the node was resected and visible diaphragmatic lymphatics were ligated. Lymph samples were collected over 15 min in graduated centrifuge tubes for the d e t e r m i n a t i o n of the rate of lung lymph flow (QI). Blood samples were drawn at 30 minute intervals. Lymph (L) and plasma (P) total protein concentrations were m e a s u r e d with a calibrated r e f r a c t o m e t e r (American Optical, model 10400) and c o n f i r m e d with a biuret technique. Lung lymph to plasma protein concentration ratios (L/P) were calculated from these. All hemodynamic and lymphatic flux parameters were tabulated during each 15 minute collection period. Each animal was studied in sternal recumbancy. Inspired halothane concentration was lowered following surgery and 3-6 mg of metocurine iodide was given intravenously and supplemented every two hours for
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the duration of the experiment. Inspired halothane concentration was m a i n t a i n e d in the range 0.7-1.O, a level that does not block adrenergic responses (5). All animals were studied during a baseline period of at least I hour p r i o r to i n t e r v e n t i o n . H e m o d y n a m i c and l y m p h a t i c flux p a r a m e t e r s were evaluated during steady state periods of at least one hour after intervention when possible. A steady state was defined as at least 4 c o n s e c u t i v e e x p e r i m e n t a l p e r i o d s during which these parameters did not change s i g n i f i c a n t l y . The p a i r e d t-test was used to e x a m i n e c h a n g e s in p a r a m e t e r s across animals. We a c c e p t e d P
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c o m p a r e d to baseline as a result of a 54.9% increase in QI (from 7.1 + 2.2 m l / h r to 11.0 + 3.1 ml/hr) while L/P did not change (0.83 + ~.02 vs. 0.85 + 0.01 d~ring baseline). A representative e x p e r i m e n t is illustrate~in Figure 2. Group 3 (Pla + H). Elevation of Pla in this group also produced a characteristic increase in QI (from a baseline level of 6.4 + 2.30 m l / h r to 10.1 ~ 2.3 ml/hr) and fall in L/P (from O.71 + 0~02 to 0.60 + 0.04). Histamine (H) administration during hydrostatic recruitment resulted in a further, albeit slight, increase in QI to 11.1 + 0.6 ml for the group as a whole which occurred despite a significant fall in both Ppa and Pla. W h i l e L/P f e l l to 0.54 ~ 0.04 f o l l o w i n g H administration, this value was not significantly different from that obtained during elevated Pla alone. Figure 3 illustrates a representative experiment. Group 4 (ATP + H). In this group H a d m i n i s t r a t i o n during the e x p e r i m e n t a l period resulted in a doubling of lymphatic protein clearance, which occurred largely due to an increase in QI from a baseline level of 10.6 + 1.90 ml/hr to 21.3 + 5-5 ml/hr, while L/P r e m a i n e d unchanged. (0~79 + 0.02 vs 0.80 + 0[O2). A representative experiment is illustrated in Figure 4. Discussion The p a t h o p h y s i o l o g y of s a l i c y l a t e p u l m o n a r y edema has been extensively studied and has b e e n w e l l r e v i e w e d (1,6). That salicylate overdose causes p u l m o n a r y edema in h u m a n s is well established. However, due to differences in e x p e r i m e n t a l species, dosage and model, the mechanism of edemogenesis is not clear. Bowers et al. observed an increased flow of protein-rich lung lymph in sheep f o l l o w i n g ASP a d m i n i s t r a t i o n and suggested increased p u l m o n a r y microvascular permeability to proteins as the mechanism responsible (I). However, M a r o n has recently reported that ASP a d m i n i s t r a t i o n does not increase extravascular water content in isolated canine lung lobes, but does increase lobar arterial and venous tone (3). Be has suggested that v e n o c o n s t r i c t i o n and the associated increase in p u l m o n a r y capillary pressure, rather than increased microvascular permeability might explain the alterations in lung fluid balance that follow aspirin administration. But, he further suggested that perfused surface area must have decreased enough to offset the increase in microvascular filtration. Group I animals in the present study were subjected to increased Pla of approximately 14 Torr prior to ASP administration, a procedure intended to minimize changes in PMSA and, by forcing high lung lymph flow, minimize nodal alteration of lymph c o m p o s i t i o n prior to collection (7,8,9). We a d m i n i s t e r e d ASP in a dosage sufficient to raise plasma salicylate concentration to an average of a p p r o x i m a t e l y 23 mg/dl, a level reported to be in the high therapeutic range in humans (10). Our dosage is comparable
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to that used by Bowers et al., but is l o w e r than the average c o n c e n t r a t i o n of 97.8 mg/dl a d m i n i s t e r e d in Maron's study. ASP administration in Group I animals resulted in an increase in QI to a level s i g n i f i c a n t l y higher than was produced by recruitment alone and, despite continued elevation of Pla, group L/P rose significantly from 0.59 to 0.66 (Table I). These responses occured with little change in either Ppa or Pla and with an increase in CO for the group as c o m p a r e d to the period of elevated Pla alone. Under these h e m o d y n a m i c conditions it is unlikely that d e r e c r u i t m e n t occured. The data suggest that the increased protein flux observed following ASP a d m i n i s t r a t i o n in this group occured at least in part due to an increase in lung m i c r o v a s c u l a r p e r m e a b i l i t y to p l a s m a proteins. Results from Group 3 in w h i c h h i s t a m i n e (H) was given during recruitment are qualitatively similar to Group I. Histamine has been found to increase fluid and protein transport in the sheep lung through a mechanism t h o u g h t to i n v o l v e i n c r e a s e d v a s c u l a r permeability (11, 12, 13), although the effect may be transient (14), and confined to the bronchial circulation (13). While steady state data were difficult to obtain in this group, due to the hypotensive effects produced by H infusion during the period of elevated Pla, L/P showed a steadily increasing trend f o l l o w i n g H after the marked dilution produced by increased Pla (Figure 3). This response is consistent with increased lung microvascular permeability, although alterations outside the lung can not be ruled out (15). As has been discussed in a recent review (16), the e x p e r i m e n t a l manuever of elevating Pla to minimize changes in PMSA is not without disadvantages. One c o m p l i c a t i o n of this technique is the dramatic f a l l in s y s t e m i c a r t e r i a l p r e s s u r e (and CO) that s o m e t i m e s a c c o m p a n i e s this procedure, which, p a r t i c u l a r l y in the acutely prepared, anesthetized animal, can be fatal. R e c r u i t m e n t of P M S A with ATP infusion has several advantages when compared to the use of a Foley balloon catheter to elevate Pla. ATP is an endogenous compound which is rapidly metabolized in the pulmonary circulation (17) and does not alter lung microvascular permeability (18). With ATP infusion, surgical intervention to i m p l e m e n t recruitment is minimized and sysytemic h e m o d y n a m i c s are well maintained. In the present study, ATP infusion was employed to recruit PMSA in Groups 2 and 4. In Group 2 ASP a d m i n i s t r a t i o n during r e c r u i t m e n t resulted in a sigificant increase in lymphatic protein clearance (Table I). This response occured with little or no change in CO, Ppa or Pla, L/P was u n c h a n g e d a l t h o u g h QI increased by 54.9%. Results from this group are qualitatively similar to those found after H infusion in Group 4, although the proportionately greater increase in QI in these animals may reflect a hemodynamic effect of H which is masked by hydrostatic recruitment (3). ATP infusion does not in itself provide the means for forcing the lung to the degree of r e c r u i t m e n t seen when high pulmonary vascular pressures are used. Thus, an effect of ASP (or H) on P M S A can not be specifically ruled out by these experiments,
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MARCH 1987 VOL. 33 NO. 3
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however, the results are consistent with an effect on microvascular permeability and, when considered with results from Group I, suggest that ASP can increase m i c r o v a s c u l a r p e r m e a b i l i t y in the recruited lung. As has been suggested from the data from other investigations on the effects of cyclosxygenase inhibitors on pulmonary hemodynamics (3, 20, 21), the response may be m e d i a t e d by the inhibition of a vasodilator prostaglandin, such as prostacyclin. It is also possible that ASP may have shifted arachidonate metabolism to the lipooxygenase p a t h w a y with the consequent p r o d u c t i o n of leukotrienes, substances which may increase pulmonary microvascular permeability (21). In summary, we have found that ASP increases the flow of protein-rich lymph from the lungs of sheep during recruitment of PMSA either with ATP or elevated Pla. The response is similar to that produced by H. While the response may be mediated in part by alterations in the surface area of exchange vessels, the fact that it was not prevented by hydrostatic recruitment of PMSA suggests that lung microvascular permeability was increased. Acknowledgments This study was supported in part by grants from the A m e r i c a n Heart Association: California Affiliate Nos. 82-136, 84-157 and 85-149A.
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REFERENCES I.
2. 3. 4.
5.
6. 7.
8.
9. 10. 11. 12.
13.
14.
15. 16.
17.
18.
442
Bowers, R.E., K.L. Brigham, and P.J. Owen. Salicylate Pulmonary Edema: The M e c h a n i s m in Sheep and Review of the Clinical Literature. Am. Rev. Respir. Dis. 115:261. 1977. Ogletree, M.L. Pharmacology of the Prostaglandins in the Pulmonary Circulation. Ann. NY Acad. Sci. 384:191. 1982. Maron, M.B. Effect of High Doses of Aspirin on P u l m o n a r y Hemodynamics and Lung Water. Am. J. Physiol. 248:H225. 1985. Stauh, N.C., R.D. Bland, K.L. Brigham, R. Demling, A.J. Erdmann III and W. Woolverton. Preparation of Chronic Lung Lymph Fistulas in Sheep. J. Surg. Res. 19:315. 1975. Roizen, M.R., W. Horrigan, and B.M. Frazer. Anesthetic doses blocking adrenergic (stress) and cardiovascular responses to incision - MACBAR. Anesthesiology. 54:390. 1981. Heffner, J.E., and S.A. Sahn. Salicylate-induced P u l m o n a r y Edema. Clinical Features and Prognosis. Ann. Intern. Med. 95:405. 1981. Jones, T.A., M.I. T o w n s l e y , and W.J. W e i d n e r . E f f e c t s of Intracranial and Left Atrial Hypertension on Lung Fluid Balance in Sheep. J. Appl. Physiol. 52:1324. 1982. Townsley, M.I., D.E. McClure, and W.J. Weidner. Assessment of Pulmonary Microvascular Permeability in Acutely Prepared Sheep. J. Appl. Physiol. 56:857. 1984. Adair, T . H . Studies of Lymph M o d i f i c a t i o n by Lymph Nodes. Microcirc. Endothel. and Lymph. 2:251. 1985. Trinder, P. Determination of Serum Salicylate Levels. Biochem. J. 57:301. 1954. Brigham, K.L., and P.J. 0wen. Increased Sheep Lung Vascular Permeability Caused by Histamine. Circ. Res. 73:647. 1975. Nakahara, K.K., K. 0hkuda, and N.C. Staub. Effect of Infusing Histamine into P u l m o n a r y or Bronchial Artery on Sheep P u l m o n a r y Fluid Balance. Am. Rev. Resp. Dis. 120:$75. 1979. Pietra, C.C., M. Magno, L. Johns, and A.P. Fishman. In: P u l m o n a r y Edema. (A. P. F i s h m a n and E. !4. Renkin, eds.) American Physiological Society, Bethesda, 1979. p. 199. Bernard, C.R., J.R. Snapper, A.A. Hutchinson, and K.L. Brigham. Effects of Left Atrial Pressure Elevation and Histamine Infusion on Lung Lymph in Awake Sheep. J. Appl. Physiol. 56:1083. 1984. Maron, M.B. Modification of lymph during passage through the Lymph Node: Effect of Histamine. Am. J. Physiol. 245:H553. 1983. Taylor, A., M.I. Townsley, and R.J. Korthius. Macromolecule Transport Across the Pulmonary Microvessel Walls. E x p . Lung Res. 8:97. 1985. Ryan, J.W., R.S. Niemeyer, and D.W. Coedwin. Metabolic Fates of Bradykinin, Angiotensin I, Adenine Nucleotides and Prostaglandins El and F1alpha in the P u l m o n a r y Circulation. Advan. Exp. Med. Biol. 21:259. 1972. Townsley, M.I. and W.J. W e i d n e r . I n f l u e n c e of A d e n o s i n e Triphosphate on Lung Fluid Balance in Sheep. Physiologist. 24:17. 1981.
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19.
20.
21 .
K a d o w i t z , P.J., B.M. C h a p n i c k , P.D. J o i n e r , and A.L. H y m a n . Influence of Inhibitors of P r o s t a g l a n d i n Synthesis on the canine Pulmonary Vascular Bed. Am. J. Physiol. 229:941. 1975. Leffler, C.W., and J.C. Passmore. Contribution of P r o s t a g l a n d i n s to the Regulation of P u l m o n a r y V a s c u l a r Resistance in Adult Cats and Dogs. Prostaglandins Med. 3:343. 1979. Noonan, T.C., D.F. K e r n , and A.B. M a l i k . Pulmonary Microcirculatory Responses to Leukotrienes B4, C4, and D4 in Sheep. Pros taglandins. 30:419. 1985.
Editor:
J.R. Fletcher
Received:
MARCH 1987 VOL. 33 NO. 3
10-8-86
Accepted:
12-9-86
443