Proteolytic and lysosomal enzymes in acute trauma-induced lung injury in sheep

Surgical preparation of a lung lymph fistula in sheep was previously shown to induce temporary permeability disturbance of pulmonary microvessels. Flow and composition of lung lymph were compared in 19 sheep with acute, and 16 with chronic lymph fistula. Lymph and plasma were analyzed regarding activities of prothrombin, antithrombin III, prekallikrein, kallikrein, functional kallikrein inhibitors and 11 acid hydrolases of lysosomal origin. Levels of prothrombin and antithrombin III fell postoperatively in plasma and reached even lower values in lymph, indicating systemic activation of the coagulation system as well as local activation in the lung. The studied components of the plasma-kallikrein system were unchanged. Lysosomal enzymes were released in lung lymph, reflecting cell injury in the lung. Local activation of proteolytic enzyme systems thus occurs in the lung after trauma. Analysis of organ-specific lymph (= interstitial fluid) may contribute to better understanding of the pathophysiology of trauma.     

Complement and endotoxin-induced lung injury in sheep

Intravenous infusions of endotoxin in sheep cause lung injury characterized by edema due to increased microvascular permeability. Similar increases in pulmonary microvascular permeability are seen in septic patients with the adult respiratory distress syndrome. Since endotoxin-induced lung injury may be mediated by interactions between products of complement activation and polymorphonuclear leukocytes, plasma and lung lymph from six unanesthetized sheep infused with Escherichia coli endotoxin (1.0 micrograms/kg over 30 min) were examined for complement-derived chemotactic activity. By 2-3 hr following infusion of endotoxin, all animals had the increased lung lymph fluid and protein flows characteristic of permeability edema. Preinfusion samples of plasma and lung lymph did not contain chemotactic activity for polymorphonuclear leukocytes. Following infusion of endotoxin, however, significant chemotactic activity was detected in plasma at 0.5-3.5 hr (P less than 0.05) and in lymph at 1.5-6.5 hr (P less than 0.025). The chemotactic activity was heat stable (56 degrees C for 30 min) but was abolished by treatment with antibodies to C5. These data indicate that infusions of endotoxin lead to the generation in plasma, and the appearance in lung lymph, of C5-derived peptides with chemotactic activity for polymorphonuclear leukocytes. C5-derived peptides may account for the pulmonary microvascular leukostasis and endothelial injury that lead to increased permeability edema after infusions of endotoxin.     

Pulmonary and systemic fluid filtration after continuous versus bolus interleukin-2 infusion

Interleukin-2 has been widely investigated as adjuvant therapy for advanced cancer and is administered by either bolus or continuous infusion. We compared the effects of bolus and continuous interleukin-2 infusion on pulmonary (QL) and systemic microvascular fluid filtration in 11 adult sheep prepared with chronic lung and soft-tissue lymph fistulas. Interleukin-2 was administered as a bolus infusion (100,000 units/kg) every 8 hours for 3 days or as a continuous infusion at the same dose for 3 days. No significant changes in pulmonary hydrostatic pressures or pulmonary vascular resistance were noted after either bolus or continuous interleukin-2 infusion. However, significantly decreased (p less than or equal to 0.05) systemic vascular resistances were observed in both groups. QL increased steadily throughout the infusion period in both groups, peaking at three times baseline on the third infusion day. The plasma/interstitial protein clearance (QL X lymph/plasma protein ratio) rose similarly in both groups, indicating increased barrier permeability. Increased lymphocyte clearance into lung lymph occurred by day 3 but was not associated with lymphocytic sequestration in the lung interstitium. We conclude that pulmonary and systemic microvascular fluid and protein flux exhibit similar changes after bolus or continuous interleukin-2 infusion. These changes are associated with increased clearance of lymphocytes into lung lymph that are not sequestered in the pulmonary interstitium after infusions of shorter duration.     

Activation of cascade systems by hip arthroplasty. No difference between fixation with and without cement

The acrylic bone cement has been regarded as a very potent activator of the hemostatic mechanisms. A battery of coagulation, fibrinolytic, and kallikrein variables were studied perioperatively in 21 patients undergoing hip arthroplasty with fixation of the prosthesis either with (Charnley) or without (HP-Garches) cement. Epidural analgesia was used and dextran 6 per cent as thromboprophylaxis. The HP-Garches procedure was shorter and caused less blood loss. No differences were found between the two surgical procedures regarding the activation of the cascade systems. The coagulation and fibrinolytic systems were activated early, but a week postoperatively the latter seems to predominate. A marked activation of the kallikrein system was apparent. Our study shows that despite thromboprophylaxis a marked activation of the coagulation, fibrinolytic, and kallikrein systems occurs in relation to hip arthroplasty irrespective of the use or nonuse of cement and irrespective of the volume of blood loss during surgery. It may be the reaming of the bone marrow that initiates the activation of the cascade systems.     

Activation of cascade systems by hip arthroplasty: No difference between fixation with and without cement

The acrylic bone cement has been regarded as a very potent activator of the hemostatic mechanisms. A battery of coagulation, fibrinolytic, and kallikrein variables were studied perioperatively in 21 patients undergoing hip arthroplasty with fixation of the prosthesis either with (Charnley) or without (HP-Garches) cement. Epidural analgesia was used and dextran 6 per cent as thromboprophylaxis. The HP-Garches procedure was shorter and caused less blood loss. No differences were found between the two surgical procedures regarding the activation of the cascade systems. The coagulation and fibrinolytic systems were activated early, but a week postoperatively the latter seems to predominate. A marked activation of the kallikrein system was apparent. Our study shows that despite thromboprophylaxis a marked activation of the coagulation, fibrinolytic, and kallikrein systems occurs in relation to hip arthroplasty irrespective of the use or nonuse of cement and irrespective of the volume of blood loss during surgery. It may be the reaming of the bone marrow that initiates the activation of the cascade systems.     

Effect of ablated airway blood flow on systemic and pulmonary microvascular permeability after smoke inhalation in sheep

The bronchial circulation plays a significant role in the pathogenesis of smoke inhalation. We investigated the physiological manifestations in both the systemic and the pulmonary circulation after smoke inhalation injury, and determined whether ablation of the bronchial circulation had any effect on these changes. We used a chronically instrumented ovine model with lung and prefemoral lymph fistulae to determine the changes in pulmonary and systemic microvascular permeability. Fourteen animals were divided into two groups. The injection group had bronchial circulation ablation with an ethanol injection into the bronchial artery, whereas it was left intact in the sham group. The sham group showed a four-fold increase in lung lymph flow (l-Q(L)) and a two-fold increase in prefemoral lymph flow (s-Q(L)) 24 h after injury. The increase in s-Q(L) was associated with a decrease in lymph oncotic pressure. Therefore, systemic colloid clearance (s-CC), an indicator of systemic microvascular permeability to protein, was unchanged. The ablated bronchial circulation reversed the pulmonary but not the systemic manifestations after smoke inhalation. In conclusion, the pathophysiological events occurring after smoke inhalation were confined to the lung with increased bronchial blood flow delivering inflammatory mediators directly to the lung parenchyma.     

Effects of interleukin-2 on pulmonary and systemic transvascular fluid filtration

Interleukin-2 (IL-2) therapy for patients with advanced cancer may be compromised by dose-limiting and life-threatening pulmonary and systemic edema. We studied the effects of bolus IL-2 infusion on lung and soft-tissue transvascular fluid and protein filtration in six sheep with chronic lung and soft-tissue lymphatic cannulation. Changes in lung (QL) and soft-tissue (QS) lymph flow were used as indicators of transvascular fluid filtration. A dose of 100,000 U/kg IL-2 was administered every 8 hours for 3 days. A significant increase (p less than or equal to 0.05) in both QL and QS was observed after each IL-2 infusion, with maximal flow occurring 2 to 3 hours after infusion. After 72 hours of IL-2 infusion, a fourfold maximal increase in QL occurred, which recovered to near-baseline values within 24 hours. Elevations in QL and QS were not associated with increases in pulmonary arterial or pulmonary arterial wedge pressures, but these elevations were associated with significant (p less than or equal to 0.05) increases in cardiac output (7.7 +/- 0.5 to 11.4 +/- 0.4 L/min) and a consistent decrease in systemic vascular resistance. A significant increase in lung lymph/plasma protein ratio (0.49 +/- 0.06 to 0.93 +/- 0.04 for albumin) revealed a marked increase in pulmonary microvascular porosity. This change, however, was not observed in the systemic microcirculation. Serum concentrations of tumor necrosis factor did not increase with the observed changes in pulmonary microvascular porosity. We conclude that IL-2 increases both pulmonary and systemic microvascular fluid flux. In addition, there is a marked increase in pulmonary, but not systemic, protein permeability that is not a consequence of changes mediated by tumor necrosis factor.     

Lung vascular injury with protease infusion. Relationship to plasma fibronectin.

Fibronectin exists in a soluble form in plasma and in an insoluble form in tissues. Plasma fibronectin can modulate phagocytic function as well as incorporate into the tissue matrix where it is believed to influence microvascular integrity and tissue repair. The temporal alterations in plasma and lung lymph fibronectin were studied in relation to increased pulmonary vascular permeability induced by protease infusion. The acute sheep lung lymph fistula model was used. A 39% decrease in plasma fibronectin (control = 421 +/- 67 micrograms/ml) was observed 2.5 hours (255 +/- 43 micrograms/ml) after protease infusion. There was an elevation of lymph fibronectin early after protease infusion, followed by a progressive decline. Concomitant with the decrease in plasma fibronectin, an increase in lymph flow (QL) of greater than 200% (from a control of 6.7 +/- 1.0 ml/hr to 13.9 +/- 1.4 ml/hr) was observed within 2.5 hours. Also, there was a sustained elevation in the total protein lymph/plasma concentration (L/P) ratio, which was maximal at 2.5 hours. The transvascular protein clearance (TVPC = QL X L/P) was 4.5 +/- 0.7 ml/hr at the control period and 13.1 +/- 2.0 ml/hr by 2.5 hours. This was indicative of increased flux of protein-rich fluid across the pulmonary endothelial barrier. Lung vascular permeability stabilized after 2.5 hours as manifested by a slowly declining L/P ratio. Thus, plasma fibronectin deficiency may contribute to the etiology of increased lung vascular permeability with protease infusion. Since the progressive decline in plasma fibronectin was not reflected in a proportional increase in lymph fibronectin, plasma fibronectin may have sequestered in tissues such as the lung, or perhaps in reticuloendothelial cells during the injury phase. Whether the progressive decrease in plasma fibronectin reflects its incorporation into the endothelial barrier matrix where it may mediate stabilization of the pulmonary microvascular barrier remains to be determined.     

Pharmacologic strategies for combating the inflammatory response

The "systemic inflammatory response" is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial--or promiscuous--pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.     

Dynamic changes of lung lymph flow and the release of lysosomal enzyme from the lungs after severe steam inhalation injury in goats

Chronic lung lymph fistulae were produced in six goats according to Winn's and Stothert's methods with our modification to define the pathophysiology of pulmonary oedema after severe steam inhalation injury. Arterial blood gas, lung lymph flow (QLym), lymph/plasma total protein concentration ratio (L/P), and beta-glucuronidase (beta-G) in plasma and lung lymph were monitored for 24 h post-injury. The pathological changes in the lung tissues were also determined at the end of the study. It was found that directly after injury, QLym increased steadily to a peak value at 6 h, followed by declining values at 18 and 24 h. L/P decreased promptly during the 60 min after injury and then also steadily increased to a peak value at 4 h (P less than 0.05). A significant increase in plasma beta-G was only observed at 4 h post-burn. However, lung lymph beta-G activities and lymph beta-G transport increased immediately after injury, reaching a peak at 4 h (5 and 12 times above baseline values, respectively, P less than 0.01). Significant hypoxaemia and hypocapnia occurred at 2 h post-burn and deteriorated progressively throughout the study. There were obvious pulmonary interstitial and alveolar oedema microscopically. This study demonstrates that the increase in transvascular fluid and protein flux after steam inhalation injury is mainly due to increased pulmonary microvascular permeability. Nevertheless, a hydrostatic pressure effect can not be completely excluded, especially in the first hour post-burn. Lysosomal enzyme release is considered to be one of the important factors which damage lung microvascular elements and induce an increase in their permeability.     

Evidence for tumor necrosis factor-induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury.

Acute lung injury characterized by increased microvascular permeability is one feature of multiple-organ system failure and the adult respiratory distress syndrome. Intestinal ischemia-reperfusion injury has been linked to this type of acute lung injury. The purpose of these experiments was to examine the pathogenic mediators that link the two processes, with particular emphasis on the roles of endotoxin and tumor necrosis factor alpha (TNF alpha). Previously described characteristics of the acute lung injury in this rat model of intestinal ischemia-reperfusion include pulmonary neutrophil sequestration, depletion of lung tissue ATP, alveolar endothelial cell disruption, and increased microvascular permeability. Plasma levels of TNF in the systemic circulation of sham-operated animals and those with intestinal ischemic injury less than 60 minutes in duration were very low or undetectable. Intestinal ischemia for 120 minutes was associated with TNF elevation to 1.19 +/- 0.50 U/mL. Reperfusion for periods of 15 and 30 minutes generated 5- to 10-fold increases in circulating TNF levels (6.61 +/- 3.11 U/mL, p greater than 0.05 and 10.41 +/- 5.41 U/mL, p = 0.004 compared to sham); however this increase in circulating TNF was transient and largely cleared within 60 minutes after initiating reperfusion. Portal vein endotoxin levels were found to increase significantly before the appearance of TNF in systemic plasma, suggesting that gut-derived endotoxin may induce TNF release from hepatic macrophages into the systemic circulation. Anti-TNF antibody attenuated the increase in pulmonary microvascular permeability in this preparation but did not prevent pulmonary neutrophil sequestration. These observations suggest that endotoxin and TNF have pathogenic roles in this acute lung injury, but that mechanisms of adherence of neutrophils to endothelial cells independent of TNF may be involved. The accumulation of neutrophils in the lung but the prevention of a vascular permeability increase in the presence of antibody to TNF may imply an in vivo role for TNF in the process of neutrophil activation. These studies provide additional evidence of the importance of the endogenous inflammatory mediators in the development of systemic injury in response to local tissue injury.     

Intravenous injection of trauma-hemorrhagic shock mesenteric lymph causes lung injury that is dependent upon activation of the inducible nitric oxide synthase pathway

OBJECTIVE: To test the hypothesis that gut-derived factors carried in trauma-hemorrhagic shock (T/HS) lymph is sufficient to induce lung injury. Additionally, because our previous studies showed that T/HS-induced nitric oxide production was associated with lung injury, we examined whether T/HS lymph-induced lung injury occurs via an inducible nitric oxide synthase (iNOS)-dependent pathway. BACKGROUND: We have previously shown that T/HS-induced lung injury is mediated by gut-derived humoral factors carried in the mesenteric lymph. However, it remains unclear whether T/HS lymph itself is sufficient to induce lung injury, or requires the activation of other factors during the T/HS period to exert its effect. METHODS: Mesenteric lymph collected from T/HS or trauma-sham shock (T/SS) animals was injected intravenously into male rats at a rate of 1 mL/h for 3 hours. At the end of infusion, lung injury was assessed by lung permeability and lung histology. The effect of iNOS inhibition on T/HS lymph-induced lung injury was studied and this was further confirmed in iNOS knockout mice. Finally, iNOS immunohistochemistry was performed to identify the cells of origin of iNOS. RESULTS: The injection of T/HS lymph, but not sham shock lymph, caused lung injury. This was associated with increased plasma nitrite/nitrate levels as well as induction of iNOS protein in the lung, liver, and gut. Treatment with the selective iNOS inhibitor aminoguanidine prevented T/HS lymph-induced lung injury. iNOS knockout mice, but not their wild-type controls, were resistant to T/HS lymph-induced lung injury. By immunohistochemistry, neutrophils and macrophages, rather than parenchymal cells, were the source of T/HS lymph-induced lung iNOS. CONCLUSIONS: These results indicate that T/HS lymph is sufficient to induce acute lung injury and that lymph-induced lung injury occurs via an iNOS-dependent pathway.     

Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma?

OBJECTIVE: To measure plasma levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF) early after trauma and to determine their clinical significance. BACKGROUND: Angiopoietins and VEGF play a central role in the physiology and pathophysiology of endothelial cells. Ang-2 has recently been shown to have pathogenetic significance in sepsis and acute lung injury. Little is known about the role of angiopoietins and VEGF early after trauma. METHODS: Blood specimens from consecutive major trauma patients were obtained immediately upon arrival in the emergency department and plasma samples assayed for Ang-1, Ang-2, VEGF, markers of endothelial activation, protein C pathway, fibrinolytic system, and complement. Base deficit was used as a measure of tissue hypoperfusion. Data were collected prospectively. RESULTS: Blood samples were obtained from 208 adult trauma patients within 30 minutes after injury before any significant fluid resuscitation. Plasma levels of Ang-2, but not Ang-1 and VEGF were increased and correlated independently with severity of injury and tissue hypoperfusion. Furthermore, plasma levels of Ang-2 correlated with markers of endothelial activation, coagulation abnormalities, and activation of the complement cascade and were associated with worse clinical outcome. CONCLUSIONS: Ang-2 is released early after trauma with the degree proportional to both injury severity and systemic hypoperfusion. High levels of Ang-2 were associated with an activated endothelium, coagulation abnormalities, complement activation, and worse clinical outcome. These data indicate that Ang-2 is a marker and possibly a direct mediator of endothelial activation and dysfunction after severe trauma.     

Metabolic effects of pretreatment with Escherichia coli J5 antiserum on guinea pig gram-negative bacterial sepsis

Antiserum raised to a rough mutant Escherichia coli, termed J5 (anti-J5 RS), protected against lethal gram-negative bacterial sepsis in a guinea pig model when animals were pretreated with both antiserum and heparin. This same model was used to examine and compare the effects of pretreatment with anti-J5 RS, normal rabbit serum (NRS), or saline, each +/- heparin on physiologic and metabolic parameters during a septic insult. Results demonstrated that leukopenia and thrombocytopenia occurred to a similar degree in all pretreatment groups; no significant leuko- or thrombostasis was noted on examination of histologic specimens; complement activation was maximal in those animals receiving anti-J5 RS alone without heparin; the most abnormal amino acid profile was present in the NRS + heparin group; and only the anti-J5 RS + heparin group did not develop glomerular lesions indicative of disseminated intravascular coagulation. A complement-mediated cell aggregation-type injury does not appear to occur in this model. It is hypothesized that both excessive complement and coagulation system activation occur after bacterial challenge when antibody directed against the bacteria is present (anti-J5 RS) leading to antigen-antibody complex formation and complement and coagulation cascade activation. Heparin may block either or both these cascade systems allowing enhanced, antibody-mediated opsonization and clearance of blood-borne bacteria, thus preventing end-organ alterations and organ failure during sepsis when combined with anti-J5 RS.     

Neutrophil-dependent, oxygen-radical mediated lung injury associated with acute pancreatitis.

Cerulein-induced acute pancreatitis in rats is associated with a reversible lung injury that is characterized by alveolar capillary endothelial-cell injury, increased microvascular permeability, interstitial edema formation, and intraalveolar hemorrhage and fibrin deposition. The role of mediators in this injury was analyzed using gravimetric data, microvascular permeability indices, electron microscopy, and a quantitative morphometric analysis. Neutrophil depletion induced by a specific antibody was highly protective against lung injury. Interruption of the complement pathway (using low dose Naja naja cobra venom factor) also protected against lung injury. Catalase and superoxide dismutase were also protective. The iron chelator deferoxamine and the hydroxyl radical scavenger, dimethylsulfoxide, were not protective against acute lung injury. These data suggest that complement, neutrophils, and neutrophil-derived (H2O2-dependent) oxygen products mediate lung injury that occurs secondary to cerulein-induced pancreatitis. In contrast to other models of neutrophil-dependent, oxygen-radical-mediated lung injury, this lung injury does not appear to be an iron-dependent and hydroxyl-radical mediated injury. We postulate that the process of acute pancreatitis leads to complement activation followed by neutrophil recruitment, sequestration, and adherence to alveolar capillary endothelial cells. Ultimately lung injury appears to result from local endothelial-cell injury secondary to neutrophil-generated oxygen products that may be myeloperoxidase dependent.     

Enterococcal sepsis and lung microvascular injury in sheep

In a common bile duct contamination model, we studied the effect of Streptococcus faecalis compared with Escherichia coli in sheep with chronic lymph fistulas to investigate the role of enterococcus in acute lung injury and acute sepsis. Early pulmonary hypertension in the E coli group was not expressed in the S faecalis group, probably due to a failure of S faecalis to illicit a thromboxane A2 response. In the late period, E coli was associated with significantly greater lung microvascular damage compared with S faecalis. The lack of difference between groups with respect to complement activation suggests the action of chemotactic factors, in addition to complement, mediating granulocyte aggregation, and neutropenia. In this model, S faecalis demonstrated limited pathogenicity as expressed in lung microvascular injury compared with E coli.     

Aprotinin and the systemic inflammatory response after cardiopulmonary bypass

Cardiopulmonary bypass is associated with a systemic inflammatory response, a spectrum of pathophysiologic changes ranging from mild organ dysfunction to multisystem organ failure. Complications include coagulation disorders (bleeding diathesis, hyperfibrinolysis) from platelet defects and plasmin activation, as well as pulmonary dysfunction from neutrophil sequestration and degranulation. Diverse injuries are a consequence of multiple inflammatory mediators (complement, kinins, kallikrein, cytokines). Both plasmin and kallikrein amplify the inflammatory response by activating components of the contact activation system. The full-Hammersmith (high dose) of aprotinin, a serine protease inhibitor approved for reducing blood loss and transfusion requirements in cardiopulmonary bypass, inhibits kallikrein and plasmin, resulting in suppression of multiple systems involved in the inflammatory response. Specifically, inhibition of factor XII, bradykinin, C5a, neutrophil integrin expression, elastase activity, and airway nitric oxide production are observed. Clinical correlates include reduced capillary leak, preserved systemic vascular resistance and blood pressure, and improved myocardial recovery following ischemia. Overall, evidence indicates that aprotinin attenuates the systemic inflammatory response associated with cardiopulmonary bypass.     

Hydroxyethyl starch pretreatment in bacteremic sheep.

Live bacteria were infused in a chronic ovine lung lymph model to determine if a preceding infusion of the colloid, hydroxyethyl starch (HES), exaggerated the cardiopulmonary dysfunction or impaired removal of bacteria by macrophages in the pulmonary circulation. HES was infused (3 mL/kg/hr; n = 6) from 24 to 12 hr before the bacteria and decreased plasma protein content and increased pulmonary lymph to plasma protein concentration because of its oncotic properties. Ringer's lactate (2 mL/kg/hr) was given after stopping HES and also to the control group (n = 6). Infusion of live Ps. aeruginosa (2.5 x 10(8) Ps./min for approximately 30 min) induced equivalent pulmonary hypertension, increased pulmonary microvascular permeability, and cardiovascular depression in the two groups. The removal of bacteria in the lungs was not affected, indicating that this measurement of the function of the mononuclear phagocytic system was not impaired by the preceding HES.     

The pathophysiology of smoke inhalation injury in a sheep model

This study describes an experimental model of smoke inhalation injury in sheep, in which the same pathophysiologic alterations occur as with clinical inhalation in man. Both the patients and the experimental sheep develop diffuse pulmonary mucosal sloughing, pulmonary edema, and a decrease in systemic oxygen tension. The results of this study indicate that the pulmonary edema is the result of an increase in microvascular permeability, characterized by increases in lung lymph flow (Qlym), lymph-to-plasma protein concentration ratio (L/P), and transvascular protein flux (Qlym X lung lymph protein concentration), while pulmonary vascular pressures remain constant. Neutrophil degranulation may contribute to the increased microvascular permeability.     

Effect of smoke inhalation injury on thromboxane levels and platelet counts

Thirteen goats with chronic lung lymph fistula suffering from smoke inhalation injury were studied for a 6-h period. All animals were found to have acute respiratory failure after injury, the arterial TXA₂ (thromboxane A₂) levels had increased by 5 min after injury, they peaked at 2 h, and then subsequently declined. Peripheral platelet counts decreased progressively within 2 h, then gradually recovered but were still lower than baseline values at 6 h after injury. EVLW (extravascular lung water), Q1 (lung lymph flow rate) and L/P (total lymph protein/plasma protein concentration), all increased and peaked at 2 h after injury. A negative linear correlation was observed between the TXA₂ levels and the platelet counts. Furthermore, differences between the venous and arterial platelet counts were markedly increased. All these observations suggested that the increased TXA₂ triggered the formation of platelet microaggregates which were then trapped in the microvasculatures of viscera such as the lung. This might be one of the causes of the decreased platelet counts in peripheral blood. Both TXA₂ levels and platelet counts were closely correlated with EVLW, suggesting that TXA₂ may indirectly cause the increased pulmonary microvascular permeability by promoting platelet aggregation and microaggregate formation in the pulmonary microvasculature. This may be one of the reasons for the developing pulmonary oedema in goats following smoke inhalation injury.