Pulmonary Microembolism Research Articles

Comparative studies of antiplatelet activity of nonsteroidal antiinflammatory drugs and new pyrazine CH- and nh-acids

Nine known nonsteroidal antiinflammatory drugs (NSAID) and three new pyrazine derivatives possessing an active methylene moiety (pyrazine CH/NH-acids) were tested with regards to their in vitro and in vivo antiplatelet activity. Concentrations of the agents were determined which caused 25% and 50% inhibition of aggregation of human blood platelets induced by fixed concentrations of ADP, collagen and epinephrine. The in vivo test consisted in determination of percent protection of mice from pulmonary microembolism caused by injection of a mixture of collagen and epinephrine. The in vitro antiaggregatory activity of the agents studied was rather low, excepting the inhibition of the collagen-induced aggregation by ketoprofen. Several NSAID and two new pyrazine CH/NH-acids appeared highly potent antithrombotic agents in vivo. Activity of NSAID expressed as percent protection against lung thromboembolism in the mouse was demonstrated to depend quantitatively on acid properties of the agents. The new chemical class of pharmacologically active agents, pyrazine CH/NH-acids, offers an original pharmacophore which is distinctive from the carboxylic or enolic functionalities typical for the established NSAID, and as such, may be devoid of some disadvantages of known antiplatelet drugs.

Changes in cardiopulmonary variables and platelet count during anesthesia for total hip replacement in dogs.

Changes in cardiopulmonary function and platelet count were determined in 22 dogs of various breeds that underwent total hip replacement with cemented femoral prostheses. In 11 dogs (group I) polymethylmethacrylate (PMMA) was inserted without venting the reamed and lavaged femoral canal. In a second group of 11 dogs (group II) a urethral catheter (ID: approximately 2.7 mm) was placed into the medullary cavity before the insertion of PMMA. The application of PMMA resulted in a decrease in end-tidal carbon dioxide tension (PETCO2) until 5 minutes after insertion of bone cement. Increases in arterial to end-tidal pCO2 gradient [P(a-ET)CO2] and physiological dead space (VD/VT) were recorded between 2 minutes before and 5 minutes after insertion of PMMA in 12 dogs. A significant decrease in platelet count occurred in both groups of dogs. Decreases in arterial pO2 (PaO2), arterial/alveolar oxygen tension ratio (PaO2/PAO2), and percent O2 saturation of hemoglobin in arterial blood (SaO2) were not statistically significant. No significant differences could be detected between data obtained from both groups of dogs. An increase in femoral intramedullary pressure caused by the insertion of PMMA and subsequent pulmonary microembolism by medullary contents has been considered the most likely cause for changes in pulmonary function. The lack of statistically significant differences in cardiopulmonary variables and platelet count between the two groups of dogs could have been related to inefficient pressure reduction by the method used.

Effect of high-frequency ventilation of the lungs on the pulmonary and systemic circulation in pulmonary artery microembolism

Effect of high-frequency ventilation of the lungs on the pulmonary and systemic circulation in pulmonary artery microembolism

Tourniquet-related Hypotension in Venous Stasis Ulcer Excision

Extremity tourniquets are widely used to achieve bloodless dissection in the surgical field. Excision of venous stasis ulcers (VSU) is aided by tourniquet use because of large dilated veins associated with venous stasis disease. We present 3 patients with hypotensive shock occurring 10 to 15 minutes after tourniquet release after excision of venous stasis ulcers. All patients had long histories of venous stasis changes and two-thirds had prior histories of deep vein thromboses and pulmonary embolism. Mean tourniquet inflation time was 34 minutes and there were electrocardiographic changes in two-third of the patients. All patients responded rapidly to standard resuscitation measures and in all 3 postoperative testing for pulmonary embolus and myocardial infarction was negative. Wound cultures revealed no organisms in 1 patient, mixed Gram-positive cocci in another, and greater than 10(5) Serratia marcescens in the third patient. Although small decreases in blood pressure and blood pH, and increases in blood lactate, PcO2, and creatinine phosphokinase, are normally associated with the use of extremity tourniquets, hypotensive shock has not been reported. The combined effect of tourniquet ischemia and venous stasis changes may cause hypotensive shock by (1) an endotoxic bolus upon tourniquet release, (2) pulmonary microembolization of platelet, fibrin, and leukocyte aggregates causing vasoactive substance release, and (3) synergistic effects of platelet-activating factor, a known mediator of endotoxic shock. The untoward events noted in these patients may be prevented by (1) proximal to distal dissection of the ulcer with initial ligation of large veins, (2) pretreatment with steroids and/or platelet-activating factor antagonists, and/or (3) slow release of the tourniquet.

Effect of a single air dive on pulmonary diffusing capacity in professional divers

The aim of this study was to determine whether venous gas embolism after a single air dive, evaluated using precordial Doppler monitoring, was associated with alterations in spirometry, lung volumes, arterial blood gases, or pulmonary diffusing capacity for carbon monoxide (DLCO). Postdive time course monitoring of pulmonary function was undertaken in 10 professional divers exposed to absolute air pressure of 5.5 bar for 25 min in a dry walk-in chamber. The US Navy decompression table was followed. Venous bubbles were detected by precordial Doppler monitoring. Two types of decompression were used: air and 100% O2 applied for 21 min during decompression stops. Spirometry, flow-volume, and body plethysmography parameters were unchanged after the dive with air decompression (AD) as well as with O2 decompression (OD). A significant reduction in arterial PO2, on average 20 Torr, was found after the dive with AD. DLCO was decreased in all divers 20, 40, 60, and 80 min after diving with AD (P < 0.001), whereas it was not significantly decreased after diving with OD. Maximal DLCO decrease of approximately 15% occurred 20 min postdive. In AD diving, maximum bubble grade for each individual vs. maximum DLCO reduction correlated significantly (r = 0.85, P = 0.002), as well as DLCO vs. arterial PO2 (r = 0.64, P = 0.017). In conclusion, a reduction in pulmonary diffusing capacity is observed in parallel with the appearance of venous bubbles detected by precordial Doppler. We suggest that bubbles cause pulmonary microembolization, triggering a complex sequence of events that remains to be resolved. Measuring DLCO complements Doppler bubble detection in postdiving assessment of pulmonary function.

Time course of pulmonary vascular response to an acutely repetitive pulmonary microembolism in dogs--an analysis using pulmonary vascular impedance.

To understand the mechanism leading to progressive pulmonary hypertension, we investigated the time course of vascular response to an acutely repetitive pulmonary microembolism in dogs by using pulmonary vascular impedance. In a normal state, the mean pulmonary arterial pressure (mPAP) was transiently increased by emboli, and the impedance moduli of 0 Hz (= Rin), 1.5 Hz and 3 Hz were slightly increased. A four-element electrical vascular model showed the transient increase in peripheral pulmonary vascular resistance (R2) and inertia, and reduction in compliance (C). In contrast, in a state of a slight pulmonary hypertension, mPAP was continuously increased by the same amount of emboli, and the impedance moduli of both 0 Hz and 3 Hz were significantly increased. By a four-element model, a severe increase in R2 and reduction in C were observed, and these changes continued. Therefore, although the vascular response to pulmonary microembolism basically depends on the degree of mechanical obstruction, this response is thought to be modulated by the responsiveness of pulmonary vessels at that time, which is involved in the alteration in the local characteristics of pulmonary vessels, and/or the recruitment of a new blood flow.

Effects of platelet activating factor on rat platelets in vivo

Platelet activating factor (PAF) is not able to aggregate rat platelets in vitro. Due to the agonist effects of PAF on multiple cells, a possible role of PAF in the activation of rat platelets in vivo where different cells may influence each other was investigated. The pulmonary microembolization of 51Cr-labelles activated platelets was used as in vivo model. This model allowed us to monitor platelet behaviour by means of non-invasive methods. In contrast to results obtained in vitro, PAF activated rat platelets in vivo. The pulmonary microembolization of the platelets was dose-dependent and rapidly reversible. About 0.5 μg/kg PAF caused a half-maximal rise of platelet-bound radioactivity in the thorax. Activation of the platelets by PAF was followed by extreme desensitization, so that a second injection of PAF did not provoke a significant response of the platelets. Platelet function was, however, not completely impaired because they still accumulated in the thorax after the application of ADP (50 μg/kg). That pulmonary entrapment had taken place was shown by a 3-fold increase in lung specific radioactivity. This was accompanied by a short-lasting thrombocytopenia. The PAF antagonist, WEB 2170 (30 μg/kg), significantly inhibited the microembolization of the platelets induced by PAF. Under in vitro conditions leukocytes purified from rat blood and activated by PAF were able to induce platelet aggregation. These results demonstrate that a PAF-specific activation of rat platelets is achievable in vivo which is probably mediated by other cells.

Technique and feasibility of radical para-aortic and pelvic lymphadenectomy for gynecologic malignancies: a prospective study

Of 284 patients evaluated for entry into the study between January 1986 and June 1990, systematic para-aortic and pelvic lymphadenectomy was performed in 208 cases (108 cervical cancer, 43 and 57 ovarian and endometrial cancer, respectively). The median number of nodes removed was 58, 49 and 54 for cervical, ovarian and endometrial cancer, respectively. The operating data are divided into 2 groups according to the consecutive number of the cases. The median operating time and the median estimated blood loss of lymphadenectomy was 230 minutes (range 120–270) and 390 ml (range 200–3300) in the first 95 cases. These operating data decreased to 150 minutes (range 100–240) and 250 ml (range 100–2800) in the second 113 cases. No surgery-related deaths occurred. Severe hemor-rages (blood loss exceeding 1000 ml) occurred in 6 patients. The obturator nerve was dissected in 1 patient and in 1 case the left ureter was cut. Formation of lymphoceles occurred in 20.4% of patients. Eighteen patients (8.8%) developed deep venous thrombosis. Nine of these patients experienced pulmonary microembolism. In 3 patients a retroperitoneal abscess was diagnosed. One patient developed a fistula of the most proximal part of the right ureter during the third postoperative week. The resection or coagulation of branches of the genito-femoral and obturator nerves determined mild paresthesis localized at the supero-anterior and internal side of thigh in 11 cases (5.4%). No statistically significant differences were found between the clinical (age, weight and previous chemotherapy) and pathological (type of cancer and lymph node status) parameters considered on one hand and postoperative complications on the other.

Local and Global Function of the Right Ventricle in a Canine Model of Pulmonary Microembolism and Oleic Acid Edema

Right ventricular (RV) dysfunction may occur due to increased RV afterload and, hence, might also contribute to the decrease in cardiac output following institution of PEEP in patients with adult respiratory distress syndrome (ARDS). To test this hypothesis, the authors examined the influence of PEEP on local and global RV function in 12 anesthetized dogs with experimental ARDS (eARDS) induced by pulmonary microembolization with glass beads and oleic acid. Local RV function was analyzed in the RV inflow tract (RVIT) and RV outflow tract (RVOT) by assessing both diastolic segment length, systolic segment shortening, and segment work (sonomicrometry). Global RV contractility was quantified by measuring maximum rate of pressure rise (dRVP/dtmax) and maximum velocity of contractile element shortening (Vmax). In eARDS, despite a fivefold increase in pulmonary vascular resistance, there was no change in cardiac index (CI), global RV contractility, RVIT and RVOT work, and RVIT shortening, whereas RVOT shortening decreased from 12.4 to 7.4% (P less than 0.01). Diastolic segment length increased in RVIT (P less than 0.05) but not in RVOT. PEEP of 10 cmH2O did not alter global RV contractility, RVIT and RVOT shortening, and RVIT work but reduced RVOT work (-35%; P less than 0.01) and CI (-11%; P less than 0.001). Cardiac index further decreased during PEEP of 20 cmH2O (-38%; P less than 0.001), while global RV contractility remained intact despite decreased RVIT and RVOT shortening (-32% and -69%; P less than 0.05) and work (-26% and -59%; P less than 0.01) in the presence of reduced fiber preload in both regions. From these findings, it was concluded that 1) the decreased CI during mechanical ventilation with PEEP at constant right ventricular end-diastolic pressure (RVEDP) is not caused by depressed global RV contractility in dogs with eARDS and a normal myocardium prior to insult. Decreased diastolic segment length and segment shortening during PEEP suggest that 2) PEEP reduces stroke volume by the Starling mechanism rather than by ischemia of the RV free wall. Finally, regionally incongruent changes of fiber preload indicate that 3) local differences in RV wall compliance are likely to occur subsequent to eARDS and PEEP.

Acute pulmonary microembolism induces different regional changes in preload and contraction pattern in canine right ventricle

The aim of the study was to investigate the influence of acute pulmonary embolism on local myocardial preload and contraction pattern in right ventricle. Measurements of preload and contraction pattern were made in inflow and outflow tracts of canine right ventricular free wall by sonomicrometry. Local right ventricular preload was assessed from end diastolic segment length. Contraction pattern was assessed from pressure-length loops and quantified by calculating maximal, systolic, and postsystolic shortening, and protosystolic segment elongation. Data were obtained before and after microembolization with 100 microns glass beads in combination with oleic acid. 13 foxhounds of either sex were used, weight 20.4 +/- 4.0 kg. Pulmonary microembolization resulted in a rise in systolic, mean, and end diastolic right ventricular pressure and pulmonary vascular resistance. At the same time, the pressure-length loops, originally triangular or oval, became rectangular in both inflow and outflow tract. Normalised end diastolic segment length increased in the inflow tract from 10.0 to 10.3 mm (p less than 0.01), but simultaneously decreased in the outflow tract, from 10.0 to 9.6 mm (p less than 0.05). Segment shortening in the inflow tract was not affected but deteriorated in the outflow tract from 11.6 to 2.7% (p less than 0.01). Increase in afterload due to pulmonary microembolization caused regionally different changes in local preload and segment shortening in right ventricular free wall. Clinically available measures of global right ventricular preload do not assess these local differences in preload and therefore may fail to reflect the functional state of the right ventricle accurately.

Mechanisms of lung vascular injury and edema induced by pulmonary microembolism

Pulmonary vascular injury in adult respiratory distress syndrome is a multifactorial process. Activation of the clotting cascade during sepsis or tissue injury deposits fibrin microthrombi in pulmonary vessels. The fibrin clots act as a ‘sink’ for the residual α-thrombin and other clotting factors. Fibrin-induced plasminogen activation activates the complement system, resulting in the formation of neutrophil-activating peptides (C5a), which contribute to neutrophil sequestration in pulmonary microvessels. In addition, α-thrombin promotes neutrophil-endothelial adherence by effects on the endothelial cell. Macrophages may enhance increased vascular permeability by the secretion of monokines (TNF and IL-1) and lead to the recruitment and activation of neutrophils. The sequestration of neutrophils in the lung and the generation of toxic oxygen radicals and proteases in close proximity to the endothelial cell are the ultimate mediators of endothelial cell injury and increased vascular permeability.

Reticuloendothelial function and plasma fibronectin in a murine model of intra-abdominal sepsis

The lung is the target organ most frequently involved in the early phase of multiple organ failure. Microembolisation of the pulmonary vasculature by bacterial and non-bacterial particles and debris with failure of the clearance mechanism of the reticuloendothelial system (RES) and depletion of plasma fibronectin have been implicated in the pathogenesis. The present study examined the concurrent changes in plasma fibronectin, RES phagocytic function, organ localisation of bacterial and non-bacterial particles and the levels of circulating endotoxin and fibrin degradation products in a clinically relevant murine model of severe intra-abdominal infection. Progressive sepsis was associated with deteriorating RES phagocytic function to 45% of control values within 48 h of sepsis induction. There was decreased hepatosplenic uptake and increased pulmonary localisation of bacterial and lipid emulsion particles. Plasma fibronectin increased in septic animals within 48 h suggesting increased fibronectin production. These changes would support the hypothesis that altered RES function may facilitate pulmonary microembolisation in the pathogenesis of septic multiple organ failure.

Kinetics of pulmonary platelet deposition and clearance during thrombin-induced microembolism in rabbits.

Using 111In-labeled autologous platelets, we studied the kinetics of pulmonary platelet deposition and clearance in relation to hemodynamic and structural events during thrombin-induced pulmonary microembolism in rabbits. Autologous platelets were radiolabeled and returned to animals prior to infusion of thrombin (100 units/kg over 15 min) (n = 20) or saline (n = 6). All animals were pretreated with tranexamic acid, an inhibitor of fibrinolysis. Thrombin-treated animals manifested progressive increases in mean pulmonary platelet activity, reaching a maximum of 38% above baseline (p less than .0001), whereas no change was observed in saline-treated controls. Animals that died during, or immediately following, thrombin infusion manifested significantly greater increases in pulmonary platelet uptake (mean 1.55 +/- 0.47 times baseline), compared to surviving animals (1.14 +/- 0.16; p less than .05 survivors vs. nonsurvivors). In surviving animals, following cessation of thrombin, pulmonary platelet activity cleared gradually, with a half-time of approximately 12 min. Thrombin reduced circulating platelet counts (p less than .001), increased mean pulmonary artery pressure (13 +/- 3 mm Hg to 18 +/- 6 mm Hg; p less than .0001), and reduced mean systemic arterial pressure (55 +/- 10 mm Hg to 44 +/- 7 mm Hg; p less than .001). The time courses of these events approximated that of thrombin-induced pulmonary platelet uptake. Furthermore, the increase in pulmonary artery pressure occurred predominantly in the group of animals in which the increase in pulmonary radiolabeled platelet activity exceeded the median value of 20%. Postmortem histology showed extensive pulmonary thrombus extending from small arterial to capillary levels in animals that died during, or immediately following, thrombin infusion, but not in surviving animals. Our findings suggest that platelet aggregation plays an important role in the pathogenesis of hemodynamic change following thrombin-induced pulmonary embolization.

Lipoxygenase products induce neutrophil activation and increase endothelial permeability after thrombin-induced pulmonary microembolism.

We examined the mechanism of the neutrophil (PMN)-dependent increase in pulmonary vascular permeability to protein after thrombin-induced pulmonary microembolism. Humoral factors that activate PMNs after thrombin-induced pulmonary microembolism were characterized in pulmonary lymph obtained from unanesthetized sheep challenged with intravenous infusion of alpha-thrombin. Time-dependent increases in PMN migration, aggregation, and superoxide anion (O2-) generation were induced by the pulmonary lymph obtained within 20 minutes after thrombin infusion. The pulmonary lymph neutrophil activating factors present in ether extracts of lymph had retention times of leukotriene B4 (LTB4) and monohydroxyeicosatetraenoic acids (HETEs) by high-performance liquid chromatography. The postthrombin lymph samples containing the LTB4 and HETEs increased PMN O2- generation and endothelial monolayer permeability to 125I-albumin in the presence of PMNs layered on the endothelial monolayers. Control lymph samples replete with LTB4, 5-HETE, and 15-HETE induced increases in PMN O2- generation and endothelial monolayer permeability to 125I-albumin in the presence of PMNs layered on the endothelial monolayers. Maximal increases in PMN O2- production and endothelial permeability occurred when LTB4, 5-HETE, and 15-HETE were coincubated with PMNs, indicating a synergistic action of these mediators in inducing PMN activation. Endothelial monolayer permeability to 125I-albumin did not increase with postthrombin lymph samples obtained after pretreatment with the 5-lipoxygenase inhibitor, L-651,392. The results indicate that lipoxygenase products generated in the lungs after thrombin-induced microembolism contribute to increased endothelial permeability secondary to PMN activation.

肺小細胞癌による微小腫よう肺塞栓症を合併した高齢者拡張型心筋症の１例

肺小細胞癌による微小腫よう肺塞栓症を合併した高齢者拡張型心筋症の１例

Pulmonary microembolization in experimental aortic surgery.

Pulmonary dysfunction frequently follows major surgery and has many features identical to "shock lung'. A porcine model of aortic surgery is described in which 111In-labelled platelet kinetics were related to subsequent pulmonary function. In 14 pigs, standardized aortic surgery resulted in reproducible shock and a 50 per cent mortality at 3 days. Cardiac output fell from 2.3 +/- 0.2 to 1.0 +/- 0.1 litres min-1 following removal of the aortic clamp and mean platelet and leucocyte counts fell from 437 +/- 48 to 252 +/- 39 x 10(9) litres-1 and 21.7 +/- 1.5 to 12.9 +/- 1.2 x 10(9) litres-1 respectively (P less than 0.01). Aggregate levels in inferior vena caval blood were maximal at this time and radiolabelled platelets accumulated in the lung with a rise in pulmonary vascular resistance. Alveolar-arterial oxygen difference subsequently increased from initial values of 13.7 +/- 2.0 to 23.4 +/- 3.5 mmHg (P less than 0.01) following resuscitation and to 32.5 +/- 3.4 mmHg at 3 days following surgery (P less than 0.01). This clear sequence suggests that pulmonary platelet microembolization occurs during surgical shock and may be responsible for subsequent pulmonary dysfunction.

Determinants of platelet kinetics: effects of pulmonary microembolism.

We examined the mechanisms of platelet uptake in the lungs after alpha-thrombin-induced pulmonary microembolism. Platelets labeled with 111In-oxine were reinfused into chronically prepared sheep. Pulmonary microembolism resulted in an increase in lung platelet radioactivity (95.5 +/- 15.3%; n = 4), which was followed by an exponential washout (half-life = 115 +/- 4 min). Platelet uptake in the lungs was more sustained after prior fibrinolytic inhibition with tranexamic acid (half-life = 178 +/- 11 min), although the initial increase was similar (90.7 +/- 9.6%; n = 7). Prior depletion of fibrinogen with ancrod (Arvin), blunted the initial increase in lung platelet uptake after alpha-thrombin challenge (31.7 +/- 11.3%, n = 5), indicating that the effect of thrombin was markedly dependent on fibrinogen. We examined the role of circulating granulocytes, since platelets may bind to subendothelial matrix exposed after granulocyte-mediated lung vascular injury. Maximal pulmonary platelet uptake after thrombin in granulocytopenic sheep was not different from control (71.7 +/- 14.4%; n = 4). The results indicate that pulmonary microembolism results in lung platelet sequestration. Platelet uptake is not dependent on granulocyte-mediated vascular injury but requires fibrin deposition and is sustained if fibrinolysis is inhibited.

A new model of pulmunary microembolism in the mouse

The method of infusion of hardened red blood cells described by Clement et al. (1983) to induce pulmonary hypertension in the minipig has been modified to obtain a model of pulmonary microembolism in the mouse. In this model, the infusion of hardened red blood cells causes the death of about 90% of control animals in 2–5 min, and the efficacy of a given pharmacological treatment can be assessed in terms of the percentage of animals protected from death 15 min after the infusion. Platelets are not apparently involved, since the number of circulating platelets, plasma levels of TxB 2, and PF-4 are not modified, and the mortality in thrombocytopenic animals is not different from controls. Furthermore, aspirin and heparin are totally inactive in this model. Preliminary results with some Ca ++ channel blockers (nitrendipine and nicardipine) indicate that these compounds may be active. This experimental model offers an easy and relatively inexpensive test for the characterization of compounds to prevent pulmonary microembolism, acting via a platelet-independent mechanism.

Diameter and flow velocity changes in small pulmonary vessels due to microembolization

The pulmonary vascular bed was embolized with glass beads in small doses that induced no significant changes in pulmonary arterial pressure in anesthetized cats. We analyzed changes in internal diameter (ID), flow velocity, and volume flow of embolized and nonembolized arteries simultaneously with ID changes of small veins. In embolized arteries, with 180-, 300-, and 500-microns beads, ID constricted maximally in just proximal portions of the plug by 22, 23, and 17%, respectively, but with 840-microns beads, no ID constriction occurred. With 50-microns beads, the maximum ID constriction occurred in arteries of 200-300 microns but not in those of 100-200 microns. The constriction decreased in the upstream larger arteries and disappeared in those greater than 800 microns ID. In the nonembolized arteries no ID change occurred. Veins constricted slightly compared with arteries. By heparin pretreatment, ID constriction was slightly attenuated in arteries and was almost abolished in veins, whereas it was not affected with hexamethonium bromide. At a branching site, volume flow to an embolized artery decreased because of a decrease in ID and flow velocity, whereas volume flow to a nonembolized artery increased because of an increase in flow velocity. We concluded that pulmonary microembolization induced a vasoconstriction chiefly in small pulmonary arteries upstream to the plug. After embolization, blood flow was locally redistributed from an embolized to a nonembolized artery at a branching site. Arterial vasoconstriction may be mediated chiefly by local mechanical factors.

Thromboxane increases pulmonary vascular resistance and transvascular fluid and protein exchange after pulmonary microembolism

We compared the effects of inhibition of thromboxane synthetase with antagonism of thromboxane A 2 (TxA 2)/ prostaglandinH 2 receptors on the changes in pulmonary hemodynamics and pulmonary transvascular fluid and protein exchange following thrombin-induced pulmonary microembolism. Studies were made in chronically instrumented unanesthetized sheep prepared with lung lymph fistulas. Control thrombin challenged sheep (n=5) were compared to animals pretreated with Dazoxiben (the Dazoxiben-thrombin group, n=8) or animals pretreated with L-640,035 (the L-640,035-thrombin group, n=5). In the control-thrombin sheep, plasma TxA 2 concentrations rose after thrombin and the response was inhibited in the Dazoxiben-thrombin group. The rise in the plasma TxA 2 concentrations was greater in the L-640,035-thrombin group than in the control-thrombin group. In the control-thrombin group, thrombin produced a sustained increase in the pulmonary transvascular protein clearance (pulmonary lymph flow × lymph/plasma protein concentration ratio) and pulmonary vascular resistance (PVR). In the Dazoxiben-thrombin group, increases in both pulmonary transvascular protein clearance and PVR after thrombin were less than in the control-thrombin group. In the L-640,035-thrombin group, thrombin initially increased pulmunary transvascular protein clearance and PVR to the same levels as the control group; however, both protein clearance and PVR declined with time, in contrast to the sustained responses in the control-thrombin group. These differences may be related to the initially greater increase in plasma TxA 2 concentrations after thrombin in the L-640,035-treated animals. The results indicate that TxA 2 plays a role in mediating the increases in PVR and contributes to increases in pulmonary transvascular fluid and protein exchange after thrombin-induced pulmonary microembolism.