Role of lipids in bone marrow-induced pulmonary edema

We examined the mechanism of the bone marrow-induced pulmonary edema in the isolated Ringer-perfused rabbit lung. Bone marrow administration (0.2 ml/kg body wt) increased pulmonary arterial pressure, capillary pressure, arterial resistance, and venous resistance within 2-4 min. Bone marrow also produced marked increases in lung wet weight and the capillary filtration coefficient but at later time points (90-120 min) during the perfusion. Only the triglyceride-containing lipid component of the bone marrow produced increases in pulmonary hemodynamics, lung wet weight, and the capillary filtration coefficient comparable to those observed after bone marrow. Bone marrow and the lipid component of bone marrow both produced increases in venous effluent lipoprotein lipase activity (the enzyme responsible for hydrolysis of triglycerides to free fatty acids). Bone marrow also stimulated the production of thromboxane B2 but not 6-ketoprostaglandin F1 alpha in the perfused lung. Both meclofenamate (1 microM), a cyclooxygenase inhibitor, and U-60,257 (10 microM), a lipoxygenase inhibitor, attenuated the bone marrow-induced pulmonary hemodynamic response, whereas only U-60,257 attenuated the increases in lung wet weight and the capillary filtration coefficient. In conclusion, pulmonary embolization induced by bone marrow results in increases in lung weight and the capillary filtration coefficient in the isolated Ringer-perfused rabbit lung. Pulmonary vasoconstriction is partially dependent on arachidonic acid metabolites but appears to be independent of circulating blood-formed elements. The lipid component of bone marrow or products derived from this component (e.g., free fatty acids and lipoxygenase products) may mediate the bone marrow-induced pulmonary edema.     

Enhanced microvascular permeability of PMA-induced acute lung injury is not mediated by cyclooxygenase products.

Products of cyclooxygenase activity have been proposed to mediate the pulmonary hypertension and increased microvascular permeability associated with phorbol myristate acetate- (PMA) induced acute lung injury. Previously, we reported that thromboxane (Tx) does not mediate PMA-induced pulmonary hypertension in intact anesthetized dogs. In the present study, PMA was administered to isolated canine lungs perfused with autologous blood at constant flow to investigate a possible role for Tx in the PMA-induced increase in microvascular permeability. Changes in permeability were assessed by determining changes in the capillary filtration coefficient (Kfc). In lobes pretreated with papaverine to prevent PMA-induced increases in pulmonary vascular resistance, Kfc increased from a baseline value of 0.2 +/- 0.03 to 1.5 +/- 0.29 ml.min-1.cmH2O-1.100 g wet lobe wt-1 (P < 0.01) 30 min after PMA (5.8 x 10(-8) M, n = 10). Concomitantly, TxB2, the stable metabolite of TxA2, increased from 138 +/- 44 to 1,498 +/- 505 pg/ml (P < 0.05) in the blood. Both the selective Tx synthase inhibitor, OKY-046 (7 x 10(-4) M, n = 6), and the cyclooxygenase inhibitor, indomethacin (10(-4) M, n = 7), prevented the PMA-induced increase in TxB2, but neither compound attenuated the PMA-induced increase in Kfc. ONO-3708 (10(-6) M), a selective prostaglandin (PG) H2/TxA2 receptor antagonist, prevented the vasoconstriction resulting from administration of U-46619, a stable PGH2/TxA2 receptor agonist, but it did not prevent the PMA-induced increases in Kfc (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chest wall restriction limits high airway pressure-induced lung injury in young rabbits

High peak inspiratory pressures (PIP) during mechanical ventilation can induce lung injury. In the present study we compare the respective roles of high tidal volume with high PIP in intact immature rabbits to determine whether the increase in capillary permeability is the result of overdistension of the lung or direct pressure effects. New Zealand White rabbits were assigned to one of three protocols, which produced different degrees of inspiratory volume limitation: intact closed-chest animals (CC), closed-chest animals with a full-body plaster cast (C), and isolated excised lungs (IL). The intact animals were ventilated at 15, 30, or 45 cmH2O PIP for 1 h, and the lungs of the CC and C groups were placed in an isolated lung perfusion system. Microvascular permeability was evaluated using the capillary filtration coefficient (Kfc). Base-line Kfc for isolated lungs before ventilation was 0.33 +/- 0.31 ml.min-1.cmH2O-1.100g-1 and was not different from the Kfc in the CC group ventilated with 15 cmH2O PIP. Kfc increased by 850% after ventilation with only 15 cmH2O PIP in the unrestricted IL group, and in the CC group Kfc increased by 31% after 30 cmH2O PIP and 430% after 45 cmH2O PIP. Inspiratory volume limitation by the plaster cast in the C group prevented any significant increase in Kfc at the PIP values used. These data indicate that volume distension of the lung rather than high PIP per se produces microvascular damage in the immature rabbit lung.     

Vascular pressure effects on lung edema formation after glass bead embolism

The canine lung lobe was embolized with 100-micron glass beads before lobectomy and blood anticoagulation. The lobe was isolated, ventilated, and pump-perfused with blood at an arterial pressure (Pa) of about 50 (high pressure, HP, n = 9) or 25 Torr (low pressure, LP, n = 9). Rus/PVR, the ratio of upstream (Rus) to total lobar vascular resistance (PVR), was determined by venous occlusion and the isogravimetric capillary pressure technique. The capillary filtration coefficient (Kf), an index of vascular permeability, was obtained from rate of lobe weight gain during stepwise capillary pressure (Pc) elevation. The embolized lobes became more edematous than nonembolized controls, (C, n = 11), (P less than 0.05), with Kf values of 0.20 +/- 0.04, 0.25 +/- 0.06, and 0.07 +/- 0.01 ml X min-1 X Torr-1 X 100 X g-1 in LP, HP, and C, respectively (P less than 0.05). The greater Rus/PVR in embolized lobes (P less than 0.05) protected the microvessels and, although Pc was greater in HP than in controls (P less than 0.05), Pc did not differ between HP and LP (P greater than 0.05). Although indexes of permeability did not differ between embolized groups (P greater than 0.05), HP became more edematous than LP (P less than 0.05). The greater edema in HP did not appear due to a greater imbalance of Starling forces across the microvessel wall or to vascular recruitment. At constant Pc and venous pressure, elevating Pa from 25 to 50 Torr in embolized lobes resulted in greater edema to suggest fluid filtration from precapillary vessels.     

Effects of anti-tumor necrosis factor-alpha and anti-intercellular adhesion molecule-1 antibodies on ischemia/reperfusion lung injury

Inhibition of neutrophil activation and adherence to endothelium by antibodies to tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecules (ICAM-1), respectively, might attenuate ischemia-reperfusion injury (I/R). I/R was conducted in an isolated rat lung model. Anti-TNF-alpha antibody and/or anti-ICAM-1 antibody were added before ischemia or after reperfusion. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficients (Kfc), and pathologic changes were assessed to evaluate the severity of I/R. The LWG, Kfc, pathological changes and lung injury score of treatment groups with anti-TNF-alpha antibody treatment, either pre-ischemia or during reperfusion, were less than those observed in control groups. Similar findings were found in group treated with anti-ICAM-1 antibody or combination therapy during reperfusion. In contrast, pre-I/R treatment with anti-ICAM-1 antibody induced severe lung edema and failure to complete the experimental procedure. No additional therapeutic effect was found in combination therapy. We conclude that TNF-alpha and ICAM-1 play important roles in I/R. Anti-TNF-alpha antibody has therapeutic and preventive effects on I/R. However, combined therapy with anti-TNF-alpha antibody and anti-ICAM-1 antibody may have no additive effect and need further investigation.     

Relationship of fluid filtration to lung vascular pressure during edema

Effect of edema on the relationship between rate of fluid filtration and vascular pressure was studied in ventilated isolated dog lung lobes blood-perfused at constant flow. Constant rate of lobe weight gain (S), representing transvascular fluid flux, was obtained at different venous pressures (Pv) as Pv was increased stepwise from 2 to 40 and then similarly decreased from 40 to 2 Torr (n = 6). In another group (n = 6), edema was maximized by reversing the sequence of Pv change; S was obtained during similar Pv steps as Pv was decreased from 40 to 2 and then returned to 40 Torr. In both groups, delta S was disproportionately greater for delta Pv at higher Pv's, with S vs. Pv fit by an exponential curve (P less than 0.001). The exponential relationship was independent of lung hydration inasmuch as greater edema on the second limb of Pv change did not alter the curve (P greater than 0.05). At 144% weight gain, interstitial compliance was 55.5 +/- 26.8 ml.100 g-1.Torr-1 (n = 10). Interstitial pressure reportedly remains constant, i.e., fails to increase to further buffer fluid filtration, after transition of the lung interstitium from low to high compliance at approximately 40% lung weight gain. If so, then the exponential S vs. Pv relationship observed in the present study at elevated interstitial compliance does not appear related to tissue pressure-buffering effects.     

Reversal of increased microvascular permeability associated with ischemia-reperfusion: role of cAMP.

Ischemia-reperfusion (IR) is a form of oxidant injury known to increase microvascular permeability in the lung. Agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) levels have been shown to have beneficial effects in several models of oxidant lung injury associated with increased microvascular permeability. We investigated the role of adenylate cyclase activation with isoproterenol (ISO) or forskolin (FSK) in reversing the increased microvascular permeability associated with IR. ISO or FSK administered after 45 min of ischemia and 46 min of reperfusion caused a reduction in the capillary filtration coefficient (Kfc) from 1.25 +/- 0.13 to 0.53 +/- 0.08 and 0.55 +/- 0.10 ml.min-1.cmH2O-1.100 g tissue-1, respectively, at 90 min of reperfusion. This reduction in Kfc was accompanied by a rise in perfusate cAMP levels from 16.5 +/- 4.9 and 31.2 +/- 11.9 pmol/ml at 45 min of reperfusion to 444.2 +/- 147.8 and 276.1 +/- 91.0 pmol/ml at 105 min of reperfusion in lungs treated with ISO or FSK, respectively, at 46 min of reperfusion. Dibutyryl cAMP (DBcAMP), a membrane-permeable cAMP analogue, mimicked the permeability effect by reducing Kfc to 0.67 +/- 0.15 at 90 min of reperfusion. Significant hemodynamic changes occurred but were small and cannot explain the observed effect on Kfc. Photomicrographs from lungs treated with ISO or FSK revealed a reversal of the morphological manifestations of increased microvascular permeability. We conclude that the increased microvascular permeability associated with IR can be reversed by ISO, FSK, and DBcAMP and that cAMP produced by the lung contributes to the observed reversal.     

Effects of arachidonate on permeability and resistance distribution in canine lungs

In this study, 14 canine lung lobes were isolated and perfused with autologous blood at constant pressure (CP) or constant flow (CF). Pulmonary capillary pressure (Pc) was measured via venous occlusion or simultaneous arterial and venous occlusions. Arterial and venous pressures and blood flow were measured concurrently so that total pulmonary vascular resistance (RT) as well as pre- (Ra) and post- (Rv) capillary resistances could be calculated. In both CP and CF perfused lobes, 5-min arachidonic acid (AA) infusions (0.085 +/- 0.005 to 2.80 +/- 0.16 mg X min-1 X 100 g lung-1) increased RT, Rv, and Pc (P less than 0.05 at the highest dose), while Ra was not significantly altered and Ra/Rv fell (P less than 0.05 at the highest AA dose). In five CP-perfused lobes, the effect of AA infusion on the pulmonary capillary filtration coefficient (Kf,C) was also determined. Neither low-dose AA (0.167 +/- 0.033 mg X min-1 X 100 g-1) nor high-dose AA (1.35 +/- 0.39 mg X min-1 X 100 g-1) altered Kf,C from control values (0.19 +/- 0.02 ml X min-1 X cmH2O-1 X 100 g-1). The hemodynamic response to AA was attenuated by prior administration of indomethacin (n = 2). We conclude that AA infusion in blood-perfused canine lung lobes increased RT and Pc by increasing Rv and that microvascular permeability is unaltered by AA infusion.     

Effects of arterial pressure on lung capillary pressure and edema after microembolism

The effect of increased arterial pressure (Pa) on microvessel pressure (Pc) and edema following microvascular obstruction (100-micron glass spheres) was examined in the isolated ventilated dog lung lobe pump perfused with blood. Lobar vascular resistance (PVR) increased 2- to 10-fold following emboli when either Pa or flow was held constant. Microbead obstruction increased the ratio of precapillary to total PVR from 0.60 +/- 0.05 to 0.84 +/- 0.02 (SE) or to 0.75 +/- 0.06 (n = 6), as determined by the venous occlusion and the isogravimetric capillary pressure techniques, respectively. Isogravimetric Pc (5.0 +/- 0.7) did not differ from Pc obtained by venous occlusion (3.8 +/- 0.2 Torr, n = 6). After embolism, Pc in constant Pa decreased from 6.2 +/- 0.3 to 4.4 +/- 0.3 Torr (n = 16). In the constant-flow group, embolism doubled Pa while Pc increased only 40% (6.7 +/- 0.6 to 9.2 +/- 1.4 Torr, n = 6) with no greater edema formation than in the constant Pa groups. These data indicate poor transmission of Pa to filtering capillaries. Microembolism, even when accompanied by elevated Pa and increased flow velocity of anticoagulated blood of low leukocyte and platelet counts, caused little edema. Our results suggest that mechanical effects alone of lung microvascular obstruction cause minimal pulmonary edema.     

Interaction of chemical and high vascular pressure injury in isolated canine lung

Because both chemical and mechanical insults to the lung may occur concomitantly with trauma, we hypothesized that the pressure threshold for vascular pressure-induced (mechanical) injury would be decreased after a chemical insult to the lung. Normal isolated canine lung lobes (N, n = 14) and those injured with either airway acid instillation (AAI, n = 18) or intravascular oleic acid (OA, n = 25) were exposed to short (5-min) periods of elevated venous pressure (HiPv) ranging from 19 to 130 cmH2O. Before the HiPv stress, the capillary filtration coefficient (Kf,c) was 0.12 +/- 0.01, 0.27 +/- 0.03, and 0.31 +/- 0.02 ml.min-1.cmH2O-1 x 100 g-1 and the isogravimetric capillary pressure (Pc,i) was 9.2 +/- 0.3, 6.8 +/- 0.5, and 6.5 +/- 0.3 cmH2O in N, AAI, and OA lungs, respectively. However, the pattern of response to HiPv was similar in all groups: Kf,c was no different from the pre-HiPv value when the peak venous pressure (Pv) remained less than 55 cmH2O, but it increased reversibly when peak Pv exceeded 55 cmH2O (P less than 0.05). The reflection coefficient (sigma) for total proteins measured after pressure exposure averaged 0.60 +/- 0.03, 0.32 +/- 0.04, and 0.37 +/- 0.09 for N, AAI, and OA lobes respectively. However, in contrast to the result expected if pore stretching had occurred at high pressure, in all groups the sigma measured during the HiPv stress when Pv exceeded 55 cmH2O was significantly larger than that measured during the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Simultaneous measurement of fluid and protein permeability in isolated rabbit lungs during edema.

Fluid conductance and protein permeability have been studied in isolated perfused lung models of pulmonary edema. However, previous studies have not investigated changes of both fluid conductance and protein permeability in the same isolated lung preparation after injury. Arachidonic acid (AA) metabolites are involved in the inflammatory processes that lead to the development of pulmonary edema. The hemodynamic effects of AA have been well established; however, controversy exists concerning the ability of AA to alter the permeability of the pulmonary microvasculature to fluid and protein. The purpose of this study was to simultaneously determine whether transvascular fluid conductance and protein permeability are increased in isolated perfused rabbit lungs with pulmonary edema induced by AA. Indomethacin (80 microM) was added to the perfusate to inhibit the hemodynamic effects of AA and produce a pressure-independent model of pulmonary edema. Fluid conductance was assessed by determination of the capillary filtration coefficient (Kf), and protein permeability was evaluated by measurement of 125I-albumin clearance. The injection of AA (3 mg/200 ml of perfusate) into the pulmonary arterial catheter resulted in an increase in lung weight over the remaining 30-min experimental period. Kf (microliter.s-1 x cmH2O-1 x g dry lung-1) was increased (P < 0.05) in AA-treated lungs at 10 and 30 min post-AA injection when compared with control lungs and baseline values (determined 10 min before AA injection). Albumin clearance was also greater (P < 0.05) in lungs that received AA. 125I-albumin clearance was measured at different rates of fluid flux produced by elevation of venous pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sex-related effects on venous compliance and capillary filtration in the lower limb

Recent studies in humans have suggested sex differences in venous compliance of the lower limb, with lower compliance in women. Capillary fluid filtration could, however, be a confounder in the evaluation of venous compliance. The venous capacitance and capillary filtration response in the calves of 12 women (23.2 +/- 0.5 years) and 16 men (22.9 +/- 0.5 years) were studied during 8 min lower body negative pressure (LBNP) of 11, 22, and 44 mmHg. Calf venous compliance is dependent on pressure and was determined using the first derivative of a quadratic regression equation that described the capacitance-pressure relationship [compliance = beta1 + (2 x beta2 x transmural pressure)]. We found a lower venous compliance in women at low transmural pressures, and the venous capacitance in men was increased (P < 0.05). However, the difference in compliance between sexes was reduced and not seen at higher transmural pressures. Net capillary fluid filtration and capillary filtration coefficient (CFC) were greater in women than in men during LBNP (P < 0.05). Furthermore, calf volume increase (capacitance response + total capillary filtration) during LBNP was equivalent in both sexes. When total capillary filtration was not subtracted from the calf capacitance response in the calculation of venous compliance, the sex differences disappeared, emphasizing that venous compliance measurement should be corrected for the contribution of CFC.     

Essential fatty acid-deficient rats are resistant to oleic acid-induced pulmonary injury

Because leukotrienes and prostaglandins are inflammatory mediators derived from arachidonic acid, their potential role in oleic acid-induced lung injury was evaluated in control and in essential fatty acid-deficient (EFAD) rats depleted of arachidonic acid substrate. In control rats, oleic acid (0.06 ml/kg iv) increased the pulmonary permeability index (measured by scintigraphy) from -10 +/- 13 x 10(-6) s-1 to 217 +/- 20 x 10(-6) s-1 and 118 +/- 13 x 10(-6) s-1 at 5 and 50 min (P less than 0.05), respectively. It also caused arterial hypoxemia at 30 min (P less than 0.05). Compared with saline controls, oleic acid increased bronchoalveolar lavage fluid levels of immunoreactive (i) LTC4/D4, iLTB4, (P less than 0.01), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) (P less than 0.05). In EFAD rats, oleic acid failed to significantly increase the lung permeability index at 5 and 50 min. In contrast to control rats, oleic acid failed to cause hypoxemia in the EFAD rats. Bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha after oleic acid in EFAD rats were lower compared with oleic acid controls, whereas iLTC4/D4 in the oleic acid EFAD group was not decreased. Treatment with intraperitoneal ethyl arachidonate (400 mg over 2 wk) reversed the resistance of EFAD rats such that the pulmonary edema (P less than 0.05) was evident after oleic acid. This latter group also manifested a significant (P less than 0.05) rise in the bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha. These results suggest that arachidonic acid metabolites contribute to oleic acid-induced pulmonary permeability.     

Promethazine or DPPD pretreatment attenuates oleic acid-induced injury in isolated canine lungs

Oleic acid causes pulmonary edema by increasing capillary endothelial permeability, although the mechanism of this action is uncertain. We tested the hypothesis that the damage is an oxidant injury initiated by oleic acid, using isolated blood-perfused canine lung lobes. The lobes were dilated with papaverine and perfused in zone III with a constant airway pressure of 3 cmH2O. Changes in isogravimetric capillary pressure (Pc,i) and capillary filtration coefficient (Kf,C) were used as indices of alterations in microvascular permeability in lungs treated with silicone fluid (n = 3), oleic acid (n = 11), oleic acid after pretreatment with the antioxidants promethazine HCl (n = 11) or N,N'-diphenyl-p-phenylenediamine (DPPD; n = 4), or oleic acid following pretreatment with methylprednisolone (n = 4). Kf,C averaged 0.21 +/- 0.02 ml X min-1 X cmH2O-1 X 100 g-1 in control and increased to 0.55 +/- 0.05 and 0.47 +/- 0.05 when measured 20 and 180 min after the administration of oleic acid. When oleic acid was infused into lungs pretreated with promethazine, Kf,C increased to only 0.38 +/- 0.05 ml X min-1 X cmH2O-1 X 100 g-1 after 20 min and had returned to control levels by 180 min. Pretreatment with DPPD, but not methylprednisolone, similarly attenuated the increase in Kf,C following oleic acid. Silicone fluid had no effect on Kf,C. That oleic acid increases vascular permeability was also evidenced by a fall (P less than 0.05) in Pc,i from control when measured at 180 min in every group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fructose 1,6-diphosphate augments paraquat injury in isolated dog lungs.

Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridylium dichloride), a widely used herbicide, causes pulmonary edema by a cyclic oxidation and reduction reaction with oxygen molecules with the production of oxygen free radicals. Because fructose 1,6-diphosphate (FDP) has recently been shown to inhibit the generation of oxygen free radicals by activated neutrophils, we determined the effects of FDP on PQ-induced increase in microvascular permeability in isolated blood-perfused dog lungs. Vascular permeability was assessed using the capillary filtration coefficient (Kf,c) and isogravimetric capillary pressure (Pc,i). There was no change in these variables over 5 h in the control lungs treated with saline (n = 5). A significant increase in Kf,c and a decrease in Pc,i, both of which indicated increased vascular permeability, were observed at 5 h of perfusion with 4 x 10(-3) M PQ (n = 5). Unexpectedly, an increase in microvascular permeability occurred within 4 h after administration of PQ in the lungs that were pretreated with FDP (2.7-14.2 mM, n = 6). Moreover the increases of Kf,c in the FDP-pretreated lungs were significantly greater than those in the lungs treated with PQ alone. Also, the final-to-initial lung weight ratio of the FDP-pretreated group was greater than those of the other groups. Thus the FDP dose used in the present study accentuated rather than prevented the PQ lung injury.     

Retinoic acid induces nonuniform alveolar septal growth after right pneumonectomy.

To determine whether all-trans retinoic acid (RA) enhances compensatory lung growth in fully mature animals, adult male dogs (n = 4) received 2 mg x kg(-1) x day(-1) po RA 4 days/wk beginning the day after right pneumonectomy (R-PNX, 55-58% resection). Litter-matched male R-PNX controls (n = 4) received placebo. After 4 mo, the remaining lung was fixed by tracheal instillation of fixatives at a constant airway pressure for detailed morphometric analysis. After RA treatment compared with placebo, lung volume was slightly but not significantly lower. Volume density of septum to lung was 37% higher because of a 50 and 25% higher volume density of capillary and septal tissue, respectively. Mean septal thickness was 27% higher. Absolute volumes of endothelial cells and capillary blood were 31-37% higher, whereas epithelial and interstitial volumes were not different between groups. Absolute alveolar-capillary surface areas did not differ between groups, and alveolar septal surface-to-volume ratio was 20% lower in RA-treated animals. RA treatment exaggerated interlobar differences in morphometric indexes and caused alveolar capillary morphology to revert to a more immature state. Thus RA treatment during early post-R-PNX adaptation preferentially enhanced alveolar capillary and endothelial cell volumes consistent with formation of new capillaries, but the associated septal distortion precluded a corresponding increase in gas-exchange surface or morphometric estimates of lung diffusing capacity.     

Measurement of the filtration coefficient (Kfc) in the lung of Gallus domesticus and the effects of increased microvascular permeability

The filtration coefficient (Kfc) is a sensitive measure of microvascular hydraulic conductivity and has been reported for the alveolar lungs of many mammalian species, but not for the parabronchial avian lung. This study reports the Kfc in the isolated lungs of normal chickens and in the lungs of chickens given the edemogenic agents oleic acid (OA) or dimethyl amiloride (DMA). The control Kfc =0.04±0.01 ml min⁻¹ kPa⁻¹ g⁻¹. This parameter increased significantly following the administration of both OA (0.12±0.02 ml min⁻¹ kPa⁻¹ g⁻¹) and DMA (0.07±0.01 ml min kPa⁻¹ g⁻¹). As endothelial cadherins are thought to play a role in the dynamic response to acute lung injury, we utilized Western blot analysis to assess lung cadherin content and Northern blot analysis to assess pulmonary vascular endothelial (VE) cadherin expression following drug administration. Lung cadherin content decreases markedly following DMA, but not OA administration. VE cadherin expression increases as a result of DMA treatment, but is unchanged following OA. Our results suggest that the permeability characteristics of the avian lung are more closely consistent with those of the mammalian rather than the reptilian lung, and, that cadherins may play a significant role in the response to acute increases in avian pulmonary microvascular permeability.     

Sites of leakage in three models of acute lung injury

Fluid leaking from arterial and venous extra-alveolar vessels (EAV's) may account for up to 60% of the total transvascular fluid flux when edema occurs in the setting of normal vascular permeability. We determined if the permeability and relative contribution of EAV's was altered after inducing acute lung injury in rabbits by administering oleic acid (0.1 ml/kg) into the pulmonary artery, HCl (5 ml/kg of 0.1 N) into the trachea, or air emboli (0.03 ml.kg-1.min-1) into the right atrium for 90 min. Subsequently, the lungs were excised and continuously weighed while they were maintained in a warmed, humidified chamber with alveolar and pulmonary vascular pressures controlled and the lungs either ventilated or distended with 5% CO2 in air. The vascular system was filled with autologous blood and saline (1:1) to which papaverine (0.1 mg/ml) was added to inhibit vasospasm. Vascular pressures were referenced to the lung base. After a transient hydrostatic stress to maximize recruitment, vascular pressures were set at 5 cmH2O, and lungs were allowed to become isogravimetric (30-60 min). A fluid filtration coefficient (Kf) was determined by the use of a modification of the method of Drake and colleagues [Am. J. Physiol. 234 (Heart Circ. Physiol. 3): H266-H274, 1978]. EAV's were isolated by zoning techniques. In control preparations arterial and venous EAV's accounted for 26% (n = 9) and 38% (n = 11) of the total leakage, respectively. In all three models Kf increased two- to fourfold when the lungs were in zone 3 (alveolar vessels and arterial and venous EAV's contributing to the leakage).(ABSTRACT TRUNCATED AT 250 WORDS)     

Filtration coefficient obtained by stepwise pressure elevation in isolated dog lung

The base-line capillary filtration coefficient (Kf) obtained from rates of lobe weight gain during stepwise vascular pressure elevation is reported to be threefold greater in isolated than in intact dog lung. To further evaluate the stepwise pressure elevation technique, we obtained Kf in control and oleic acid-injured isolated lung. The left lower lung lobe was removed, placed on a balance, ventilated, and pump perfused with autogenous blood. Saline (n = 6) or oleic acid (n = 6) was infused, and rate of lobe weight gain was obtained during stepwise pressure elevation. Kf averaged 0.071 +/- 0.012 and 0.243 +/- 0.027 ml X min-1 X Torr-1 X 100 g-1 in the control and injured lobes, respectively. Stepwise pressure elevation can yield a base-line Kf in isolated lung similar to Kf's obtained from this and other gravimetric methods in intact and isolated lung. Furthermore, Kf increased severalfold following lung injury with oleic acid. The stepwise pressure elevation technique for Kf determination in isolated lung can be a useful tool for quantitating changes in vascular permeability.