Changes In Microvascular Permeability Research Articles

Attenuation of Inhaled Allergen-induced Airway Microvascular Leakage and Airflow Obstruction in Guinea Pigs by a 5-Lipoxygenase Inhibitor (A-63162)

Leukotrienes, products of the 5-lipoxygenase pathway in the metabolism of arachidonic acid, are potent mediators of airway microvascular leakage and smooth muscle contraction in guinea pigs. We studied the effect of a specific 5-lipoxygenase inhibitor, A-63162, on airway microvascular leakage and airflow obstruction following inhaled ovalbumin in actively sensitized guinea pigs. Airway microvascular leakage was assessed by extravasation of Evans blue dye into airway tissues. Inhaled ovalbumin caused increased lung resistance (RL) with decreased dynamic compliance (CL) and increased extravasation of Evans blue dye at all airway levels. A-63162 reduced the changes in RL and CL at 1.0 mumol/kg (p less than 0.05) but not at lower doses of 0.1 and 0.3 mumol/kg. A-63162 reduced Evans blue dye extravasation in airway tissues at all three doses, however, being most effective in the distal airways (p less than 0.01), and these reductions were greater than those in RL and CL. A 5-lipoxygenase inhibitor thus reduced airway microvascular leakage to a greater extent than airflow obstruction, suggesting that leukotrienes have a larger contribution to changes in airway microvascular permeability than smooth muscle contraction following inhaled allergen challenge in actively sensitized guinea pigs in vivo.

Analyses of microvascular permeability in response to mediators of immediate hypersensitivity

Mediator-induced changes in microvascular permeability were studied in rodent skin. To monitor these changes, Evan's blue dye, iodinated rat albumin and IgG, and tritiated neutral dextran molecules having different molecular radii were used. After intradermal injections of serotonin, histamine, and bradykinin, the degree of radiolabeled tracer efflux was determined by measuring the extent of blueing and the level of radioactivity in skin biopsy specimens. Although the mediators varied in potency on a molar basis (serotonin > bradykinin > histamine), the efflux resulting from each was similar. Furthermore, kinetic studies revealed that each of these vasoactive agents caused a marked but transient increase in macromolecular permeability that lasted less than 30 minutes. To determine the pore size created and the effect of charge on the transudation of macromolecules into the interstitium, fractions of neutral [ 3H]dextrans with a known molecular size (average radii, 12 and 4.4 nm, respectively) were infused either singly or in combination with 125I-labeled rat albumin and/or IgG before intradermal injection of serotonin, histamine, bradykinin, or compound 48 80 . Regardless of the mediator used, no differences could be demonstrated in macromolecular efflux, as indicated by either the molecular size of the charge of the tracer used. Thus, all mediators of immediate hypersensitivity reactions that were studied produce venular gaps >12 nm in addition to displaying similar vasopermeable characteristics.

Gamma scintigraphic imaging of lung microvascular permeability in adult respiratory distress syndrome

The sequence of lung microvascular permeability (LMVP) changes in early direct posttraumatic and late indirect pancreatitis-induced adult respiratory distress syndrome (ARDS) was studied and compared with that of a control group, as well as non-ARDS ICU patients. A computerized large field of view gamma camera was used to measure LMVP simultaneously over both lungs by In 113m-labeled transferrin and Tc 99m-labeled erythrocytes. The LMVP index (LMVPI) (%/h) was used to quantify LMVP in the dynamic scintigraphic measurement. In the control group the LMVPI was 2.6 +/- 2.8%/h for the right and 2.0 +/- 2.8%/h for the left lung. Similar values were found in mechanically ventilated ICU patients without ARDS (group A) on admission (right LMVPI 3.2 +/- 2.6, left LMVPI 2.6 +/- 2.7%/h) and 4 days later (right LMVPI 3.9 +/- 2.6, left LMVPI 2.3 +/- 1.8%/h). Interestingly, the initial evaluation of patients with direct early posttraumatic ARDS (lung contusion) (group B) showed significantly (p less than .01) elevated LMVP for the contused side (LMVPI 10.8 +/- 5.1%/h), but normal values for the nontraumatized lung (LMVPI 3.9 +/- 3.4%/h), whereas 4 days later the LMVP increased significantly (p less than .05) on the primarily healthy side (LMVPI 8.0 +/- 5.0%/h) while remaining elevated for the traumatized lung (LMVPI 10.9 +/- 6.0%/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in pulmonary microvascular permeability accompanying re-expansion oedema: evidence from dual isotope scintigraphy.

The pathophysiological mechanism of pulmonary oedema following rapid re-expansion of a collapsed lung is poorly understood. It has been suggested that the period of collapse or subsequent reinflation produces an increase in pulmonary microvascular permeability. To investigate this, the pulmonary accumulation of the plasma protein transferrin was measured by radiolabelling it in vivo with indium-113m. Plasma protein accumulation was calculated after correcting the accumulation of transferrin for changes in intrathoracic blood distribution by simultaneously monitoring technetium-99m labelled red blood cells. Functional images of plasma protein accumulation were constructed for the lung fields on a pixel by pixel basis. Investigations were performed on 14 subjects after drainage of a pleural effusion (n = 9) or evacuation of a pneumothorax (n = 5), and on 11 control subjects. Plasma protein accumulation was greater over the regions of lung re-expansion (-0.1-9.6, mean 2.9 x 10(-3)/min) than over the corresponding region of the contralateral lung (-1.2-0.8, mean 0.01 x 10(-3)/min; p less than 0.001). Patients who had undergone re-expansion procedures also had significantly greater plasma protein accumulation than normal controls. Nine of the 14 patients in the re-expansion group had clearly identifiable areas of increased plasma protein accumulation that corresponded to the part of the lung that had been re-expanded; no regional abnormalities were recorded in the control group. These results suggest that the reinflated lung displays abnormal microvascular permeability.

Changes in microvascular permeability with acceleration of edema in dog lungs

Elevation of left atrial pressure to 25-40 mmHg causes continuous pulmonary edema formation in dog lungs. However, after 5-120 min, the rate of edema formation often increases (acceleration of edema). Acceleration of edema could be associated with an increase in microvascular membrane permeability because an increase in permeability would cause fluid to filter through the microvascular membrane more rapidly. To test the hypothesis that acceleration is associated with increased permeability, we used the continuous weight-gain technique to estimate the pulmonary microvascular membrane filtration coefficient (Kf) before and after acceleration of edema in 10 dogs. Acceleration occurred 36 +/- 38 (SD) min after elevation of left atrial pressure to 35.2 +/- 5.4 mmHg. Rate of weight gain increased from 0.47 +/- 0.17 g/min before acceleration to 0.88 +/- 0.26 g/min (P less than 0.05) after acceleration of pulmonary edema. Kf was increased from initial values of 0.058 +/- 0.027 to 0.075 +/- 0.029 ml.min-1.mmHg-1 (P less than 0.05) after acceleration. In five additional dogs we cannulated lung lymphatics and determined the lymph to plasma protein concentration ratio (CL/CP) before and after acceleration. CL/CP increased from base-line values of 0.37 +/- 0.07 to 0.44 +/- 0.06 (P less than 0.05) after acceleration. Both the increase in Kf and CL/CP data support the hypothesis that acceleration of edema is due, in part, to a slight increase in microvascular membrane permeability. However, the findings could also have been caused by an increase in interstitial conductance, washout of interstitial proteins, or alveolar flooding.

Effect of ibuprofen on the pulmonary and systemic response to repeated doses of endotoxin

We infused 10 doses of Escherichia coli endotoxin, 1 microgram/kg, during a 5-day period, into eight unanesthetized sheep with lung and systemic lymph fistulas. The animals were then monitored for an additional 5 days. We noted an attenuation of the lung microvascular permeability changes with the later endotoxin doses. However, a 50% increase in cardiac index and oxygen consumption and a leukocytosis were seen beginning with the ninth endotoxin injection; these persisted throughout the 15-day postendotoxin period, as did an increase in pulmonary artery pressure. The hyperdynamic state was present when plasma prostanoids were only modestly increased, and there was no evidence of increased lung or systemic vascular permeability. Postmortem lung findings, 5 days after endotoxin administration, showed a marked interstitial inflammatory response, with infiltration of macrophages, neutrophils, and some lymphocytes and an increase in interstitial fibrous tissue. Six sheep were then given ibuprofen, 12.5 mg/kg, intravenously before the ninth and tenth doses and on the subsequent day. Ibuprofen significantly attenuated the hyperdynamic state and the pulmonary hypertension. In addition, the lung inflammation and fibrous tissue deposition was markedly attenuated. We conclude that a systemic hyperdynamic state develops that corresponds in time with lung inflammation but not with increased permeability. The lung and systemic changes may be blocked by ibuprofen. The ibuprofen effect may be due to a response other than prostanoid production.

Analysis of noninvasive macromolecular transport measurements in the lung.

Several groups of investigators are measuring transcapillary protein flux in the lung using noninvasive methods. Results from these studies are reported using several different protein transport indexes, including pulmonary transvascular transfer coefficient, relative extravascular protein, pulmonary transcapillary escape rate, protein leak index, lung transferrin index, slope index, and lung-to-heart count ratios. The purpose of this study is to discover the relationships between these indexes by employing a two-compartment theory of protein transcapillary transport in the lung. We found that all the above indexes can be related to a single index, which we call the normalized slope index. This index is the time rate of change of radioactivity originating from protein in lung interstitium divided by radioactivity arising from protein in lung plasma, normalized by this ratio at time 0, and corrected for blood volume changes. In particular the normalized slope index is shown to be the same as pulmonary transcapillary escape rate under normal sampling conditions and is relatively unaffected by changes in interstitial volume. The response of the normalized slope index to changes in microvascular pressure and microvascular permeability is explored by applying a two-pore model of the microvascular barrier. Results indicate that the normalized slope index is relatively insensitive to changes in microvascular pressure but is greatly affected by changes in microvascular permeability (i.e., changes in large-pore size or number). Since all published leak indexes are related, we would encourage all investigators in the field to adopt a single leak index. We recommend that when a two-compartment model is applied to external detection data, the results be expressed as pulmonary transcapillary escape rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Immediate hypersensitivity reactions in the guinea-pig conjunctiva: studies with a second-generation leukotriene D4 receptor antagonist, MK-571

The role of leukotriene D4 (LTD4) as a mediator of immediate hypersensitivity reactions in the guinea-pig conjunctiva was examined using a potent, second-generation LTD4 receptor antagonist, MK-571 (also known as L-660,711). The microvascular permeability changes in the guinea-pig conjunctiva following challenge with either LTD4 or antigen were measured through accumulation of intravenously administered 99mtechnetium-labeled albumin. Topical application of MK-571 (up to 2 h pretreatment) significantly inhibited the conjunctival responses to LTD4 (ED50 of 18-60 ng/eye) but not to histamine. The responses to a single topical antigen challenge in ovalbumin-sensitized guinea pigs were significantly inhibited (44%) by topical treatment with MK-571, in contrast to the lack of effect previously observed with prototypic antagonists. The inhibitory effects of MK-571 did not involve an action on conversion of [3H]LTC4 to LTD4 and LTE4. Following a second antigen challenge (24 h after the first), MK-571 inhibited the resultant permeability changes by 78%. Specific histamine H1 and H2 antagonists similarly inhibited the responses to the first and second challenges (63 and 74%, respectively). The present study suggests that LTD4 is involved in conjunctival hypersensitivity reactions and that potent LTD4 receptor antagonists may be of therapeutic value in the treatment of allergic conjunctivitis.

Oleic acid reduces pulmonary microvascular sieving capacity in sheep

Changes in pulmonary microvascular permeability in sheep, after oleic acid injection, were studied using estimations of the osmotic reflection coefficient (sigma d) for total protein, albumin, immunoglobulins (Ig) G and M and calculation of the equivalent small and large pores of the microvessels. A chronic lung fistula was prepared in eight sheep. After a base-line period, left atrial pressure (Pla) was increased. Oleic acid (0.05 mg/kg body wt) was injected after a filtration-independent state had been obtained, and the spontaneously ventilating animals were then followed for 2 h. The sigma d for the normal lung was 0.65 +/- 0.03, 0.59 +/- 0.02, 0.72 +/- 0.04, and 0.84 +/- 0.02 for total protein, albumin, IgG, and IgM, respectively. The equivalent pore radii were 54 and 225 A. After oleic acid infusion, arterial pressure and arterial O2 tension decreased and leukocytes and platelets were consumed. At the end of the experiment, sigma d's were 0.27 +/- 0.04, 0.24 +/- 0.07, 0.33 +/- 0.06, and 0.55 +/- 0.04 for total protein, albumin, IgG, and IgM, respectively. The equivalent pore radii were 54 and 275 A, and the number of large pores was increased by 195%. The results indicate that oleic acid produces an increased vascular permeability by increasing the size and the numbers of large pores of the pulmonary microvascular walls.

Pulmonary vascular permeability and resistance measurements in control and ANTU-injured dog lungs

Because questions have arisen regarding pulmonary vascular permeability and resistance measurements in isolated, perfused lungs, we sought to determine the 1) stability of repeated measurements of permeability and resistance in control lungs; and 2) magnitude of change in these measurements when permeability was greatly increased. Using blood-perfused dog lungs, we measured filtration coefficient (Kf) and isogravimetric capillary pressure (Pci) as indexes of vascular permeability, and we also determined total vascular resistance (Rt) as well as the segmental resistances using the double-occlusion pressure (Pdo). In a control group (n = 8), the base-line measurement of Kf (0.21 +/- 0.02 ml.min-1.cmH2O-1.100 g-1) and Pci (10.2 +/- 0.9 cmH2O) did not change over 4 h, indicating no changes in endothelial barrier function. Base-line Rt (13.9 +/- 2.6 cmH2O.l-1.min.100 g) also did not significantly increase. In a second group (n = 5), alpha-naphthylthiourea (ANTU) increased the initial Kf more than eight times (from 0.17 +/- 0.03 to 1.40 +/- 0.32 ml.min-1.cmH2O-1.100 g-1) and decreased Pci by 56% (from 9.4 +/- 0.6 to 4.1 +/- 0.4 cmH2O) at 1 h, indicating severely damaged endothelium. In addition, the Pdo determined during isogravimetric conditions correlated very well with Pci not only in control lungs (observed previously) but also in very permeable lungs (not previously reported). We conclude that this experimental model provides an excellent means of assessing changes in pulmonary microvascular permeability, with a spectrum ranging from no changes in hourly measurements for 4 h to obvious changes in permeability by 1 h.

Effect of antibody-mediated neutropenia on the cardiopulmonary response to endotoxemia

An ovine anti-neutrophil antibody has been produced by immunizing rabbits with purified sheep neutrophils. Serial intraarterial infusions of anti-neutrophil antibody in awake instrumented sheep produced selective and profound neutropenia. Intravascular infusion of endotoxin ( Escherichia coli, 1.5 μg/kg/30 min) resulted in significant and equivalent increases in pulmonary artery pressure, peripheral vascular resistance, and protein-rich pulmonary lymph flow in an endotoxin group ( n = 9) and a depletion + endotoxin group ( n = 4). Changes in cardiopulmonary parameters were most pronounced 2 to 8 hr after endotoxin administration in both groups. Cardiac index (CI) showed a precipitous and transient fall in both experimental groups at 0.5 to 1 hr after endotoxin infusion; however, by 8 hr CI rose significantly in the endotoxin group, while it remained unchanged in the depletion + endotoxin group. A significant rise in the peripheral neutrophil count was associated with the increase in CI in the endotoxin group. Plasma and pulmonary lymph levels of thromboxane -B 2 were unchanged during the depletion period with a significant increase 1 hr after endotoxin infusion. In this study questions arise regarding the exclusive role of circulating neutrophils in the microvascular permeability changes seen in sepsis-mediated adult respiratory distress syndrome.

Microvascular changes in the heart during chronic arterial hypertension.

Changes of myocardial microvascular permeability in chronic renovascular arterial hypertension were studied. Hypertension was induced in dogs utilizing a one-kidney, one-clip Goldblatt model. Systemic arterial pressure, coronary sinus pressure, systemic venous pressure, myocardial lymph flow rate, myocardial interstitial fluid pressure, and the lymph-to-plasma protein concentration ratio for total plasma proteins and for beta-lipoprotein (CL/CP) were determined in control animals and 4-6 weeks following the Goldblatt procedure in hypertensive animals. Control values for the normotensive animals were 123 +/- 17 mm Hg, 7.3 +/- 1.3 mm Hg, 2.5 +/- 2.1 mm Hg, 3.1 +/- 2.1 ml/hr, 14.9 +/- 3.1 mm Hg, 0.82, and 0.33, respectively, while control values for the chronically hypertensive dogs were 160 +/- 20 mm Hg, 7.8 +/- 1.9 mm Hg, 2.9 +/- 2.5 mm Hg, 10.5 +/- 2.5 ml/hr, 24.8 +/- 3.7 mm Hg, 0.87, and 0.31, respectively. Under control conditions, myocardial lymph flow rate was significantly higher in the hypertensive group while no difference could be demonstrated in CL/CP between the two groups. This is indicative of either a change in myocardial microvascular permeability or an increase in microvascular exchange surface area. Coronary sinus pressure was elevated in both groups in order to increase transmicrovascular fluid flux and determine the filtration-independent reflection coefficient (sigma) for each group. Sigma is a surface area-independent indicator of microvascular permeability when determined for specific protein molecules at high transmicrovascular fluid fluxes.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoactive drugs, microvascular permeability, and hemorrhagic pancreatitis in cats

We investigated the mechanisms by which 16,16-dimethyl prostaglandin E2 and histamine induced pancreatic hemorrhage in an experimental model of acute pancreatitis in cats. In normal animals, when large molecular weight dextran molecules were infused into the systematic circulation, they were recovered in secretin-stimulated pancreatic juice in low concentrations. Both 16,16-dimethyl prostaglandin E2 (in a dose that increased splenic artery blood flow and microvascular permeability]and histamine fin (in a dose that increased permeability only) increased the amount of dextran recovered in pancreatic juice. Isoproterenol, in a dose that produced the same increase in blood flow as 16,16-dimethyl prostaglandin E2 but which did not increase microvascular permeability, did not alter the amount of dextran recovered. This suggested that the increase in dextran output after 16,16-dimethyl prostaglandin E2 was primarily due to the increase in microvascular permeability caused by the drug. In other experiments, a combination of H1- and H2-receptor antagonists (mepyramine and cimetidine) protected against the development of pancreatic hemorrhage in both the prostaglandin- and histamine-treated animals. Indomethacin (a cyclooxygenase inhibitor) protected against the development of hemorrhage in the histamine-treated animals. Our results support the hypothesis that changes in microvascular permeability may be important in the pathogenesis of parenchymal hemorrhage in this model.

5-Lipoxygenase inhibitors and allergic conjunctivitis reactions in the guinea-pig

The role of leukotrienes as mediators of microvascular permeability changes (assessed through the accumulation of [ 99mTc]albumin) associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva was investigated by means of two novel, structurally dissimilar 5-lipoxygenase inhibitors, L-651,392 and L-651,896. Both compounds, when applied topically in vivo to the eyes of sensitized guinea-pigs as a 0.1% suspension significantly inhibited 5-lipoxygenase in the conjunctiva as assessed by ex vivo challenge with either antigen or ionophore A23187 and measurement of the release of leukotriene B 4-immunoreactive material. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs produced changes in conjunctival permeability which were blocked in part by either mepyramine (H 1-receptor antagonist) or the 5-lipoxygenase inhibitors. Combinations of mepyramine and L-651,896 resulted in near complete suppression of the permeability response, suggesting that the reaction is mediated only by histamine and leukotrienes.

Serotonin receptor blockade improves cardiac output and hypoxia in porcine ARDS

The effects of the serotonin receptor blocker, ketanserin, were studied in a porcine Pseudomonas adult respiratory distress syndrome model. Swine, weighing 14–30 kg, were anesthetized and ventilated with 0.5 FiO 2 and 5 cm H 2O positive end expiratory pressure. Three groups were studied: saline control (C, n = 9), continuous intravenous Pseudomonas aeruginosa, 5.0 × 10 8 CFU/kg/min (Ps, n = 8), and Pseudomonas and intravenous ketanserin, 0.2 mg/kg, given at 20 and 120 min after the onset of the Pseudomonas infusion (KET, n = 5). Pulmonary arterial (PAP) and systemic arterial (SAP) pressures, cardiac index (CI), thermal Cardio-Green extravascular lung water (EVLW), pulmonary albumin flux (slope index, SI), arterial blood gases, and whole blood serotonin levels were measured and pulmonary shunt and pulmonary (PVRI) and systemic (SVRI) vascular resistance indices were calculated. At 3 hr the Ps group demonstrated significant ( P < 0.05) increases in PAP (34 ± 1 vs C 13 ± 2 mm Hg), EVLW (14.4 ± 2.2 vs C 4.3 ± 1.2 ml/kg), SI (2.05 ± 0.23 × 10 −3 vs C 0.38 ± 0.09 × 10 −3 U/min), pulmonary shunt (67 ± 15% vs C 9 ± 3%), PVRI (1599 ± 89 vs C 184 ± 14 dyn · sec · cm −5/m 2), and SVRI (4542 ± 774 vs C 2087 ± 129 dyn · sec · cm −5/m 2) and decreases in CI (0.9 ± 0.1 L/min/m 2 vs C 2.8 ± 0.2 L/min/m 2), P aO 2 (93 ± 17 Torr vs C 203 ± 15 Torr) and arterial blood serotonin concentration (23.5 ± 13% decrease from basal). Treatment with ketanserin was associated with maintenance of P aO 2 (KET 207 ± 5 mm Hg vs C 203 ± 15 mm Hg), pulmonary shunt (KET 8 ± 3% vs C 9 ± 3%), and CI (KET 2.3 ± 0.1 L/min/m 2 vs C 2.8 ± 0.2 L/min/m 2) at control levels and attenuated the Pseudomonas-induced increase in PVRI (873 ± 37 vs Ps 1599 ± 89 dyn · sec · cm −5/m 2) and SVRI (2089 ± 287 vs Ps 4542 ± 774 dyn · sec · cm −5/m 2), but did not alter the development of pulmonary edema. These data indicate that serotonin plays a role in the development of the V Q mismatch and arterial hypoxemia observed in this model by a mechanism independent of changes in microvascular injury and permeability and was probably a result of reduced peripheral bronchiolar constriction.

Change in (dP/dt)max as an index of myocardial microvascular permeability.

We frequently study processes that alter microvascular permeability in the heart. Myocardial microvascular permeability has been estimated by determining the filtration independent reflection coefficient for beta-lipoprotein (sigma beta-LIPO). This technique requires the measurement of myocardial lymph flow rate and the lymph-to-plasma protein concentration ratio. Unfortunately, it is a nonsurvival procedure. An index of myocardial microvascular permeability was needed that could be determined in experimental preparations without sacrificing valuable chronically instrumented animals. We attempted to relate changes in myocardial microvascular permeability and myocardial edema formation to some index of myocardial performance. In 33 acute, anesthetized dogs (with normal or disrupted myocardial microvasculatures), we measured systemic arterial pressure, systemic venous pressure, coronary sinus pressure, left ventricular pressure, the maximum rate of change in left ventricular pressure (dP/dt)max, myocardial lymph flow rate, and myocardial extravascular fluid volume. Following an increase in coronary sinus pressure, the amount of edema fluid entering the myocardium varied as a function of myocardial microvascular permeability. Further, as the heart became edematous, (dP/dt)max changed with respect to time [delta(dP/dt)max/delta t]. Finally, a significant relation was found between sigma beta-LIPO and delta(dP/dt)max/delta t. Since coronary sinus pressure can be elevated and delta(dP/dt)max/delta t can be measured in chronic animals, this technique may be useful for evaluating myocardial microvascular permeability on a long-term survival basis.

Assessment of ischemia reperfusion injury in skeletal muscle by macromolecular clearance

Qualitative changes in skeletal muscle injury after ischemia are well known; however, quantitative assessments have not been well documented. We have determined microvascular permeability changes by measuring the clearance of fluorescein-labeled dextran of MW 150,000 (FITC-Dextran-150). The cremaster muscle of anesthetized rats was fashioned as a single layer, splayed on a lucite chamber and suffused with bicarbonate buffer solution at 35°C. Clearance is the product of suffusion rate times the ratio of suffusate to plasma concentrations of FITC-Dx 150. After a 1-hr period of baseline data collection, ischemia was produced by cross-clamping the cremasteric vascular pedicle for periods of 30 min and 2 hr in separate experiments. Clearance of FITC-Dx 150 increased from a control value (mean ± SE) of 8.3 ± 2.7 to 29.9 ± 8.1 μl/min/g after reperfusion following a 30-min period of ischemia, and from a control value of 36.2 ± 13.6 to 274 ± 94.5 after 2 hr of ischemia. The differences were statistically significant ( P < 0.05). Our results show a significant increase in microvascular permeability occurring after only 30 min of ischemia. They also demonstrate a direct relationship between the extent of the permeability change and the duration of the ischemic period.

Sepsis in sheep reduces pulmonary microvascular sieving capacity.

The changes in pulmonary microvascular permeability in sheep, after infusion of live Escherichia coli, were studied using estimations of the osmotic reflection coefficients (sigma) for total protein, albumin, immunoglobins (Ig) G and M and based on these estimations equivalent pore dimensions were calculated. A chronic lung lymph fistula was prepared in seven sheep. After a base-line period, left atrial pressure (Pla) was increased. E. coli (10(9) X kg body wt) were given after attaining filtration independent L/P values. The sigma's for the normal lung were calculated to 0.73 for total protein and to 0.65, 0.76, and 0.91 for albumin, IgG, and IgM, respectively. The equivalent pore radii were determined to 50 and 175 A with 35% of the filtration accounted for by the large pores. After bacterial infusion, the sigma's for total protein, albumin, IgG, and IgM decreased significantly from preseptic values to 0.58, 0.50, 0.64, and 0.83, respectively. After sepsis the small pores were 50 A and the large pores 200 A with 49% of total volume flow at maximum lymph flows occurring through the large pores. Assuming a constant small-pore population the large-pore number increased 32% after bacterial infusion. These results indicate that pulmonary microvascular permeability may have increased due to the sepsis.

Histamine as a Modulator of Airway Hyperreactivity L'histamine comme médiateur de l'hyperreactivité des voies aériennes

Histamine has long been known as a bronchoconstrictor agonist, but its role in asthma and airway inflammation is not as clear. Histamine release occurs in response to allergic challenge of mast cells. However, it is now known that mast cells are heterogeneous in responsiveness and sensitivity to antiallergic agents. Other cells, such as alveolar macrophages, neutrophils, eosinophils, and lymphocytes, can also be activated during allergic and inflammatory reactions. Damage to the airway epithelium would reduce the release of an epithelium-derived relaxant factor and thus increase airway smooth muscle tone. Released mediators, including eicosanoids, platelet-activating factor (PAF), complement fragments, and neurotransmitters, also contribute to inflammation in the airways and the interaction of all these mediators complicates the interpretation of the role of individual mediators. Not only can individual mediators affect the biological activity of other mediators, but their synthesis and release can be modulated as well.The present symposium was organized to examine the putative role of histamine in airway hyperreactivity and how it might interact with other mediators. Papers were presented on the role of mast cells and epithelial cells in allergic bronchoconstriction. The interaction of mast cells with other inflammatory cells was also reviewed. Further information was presented on the biological characteristics of epithelium-derived relaxant factor. Other papers reviewed the interaction of mediators on bronchoconstrictor activity and in inflammation-induced changes in microvascular permeability. The speakers emphasized that asthma and other forms of airway inflammation are complex disease entities and that a systematic analysis of interactions between the cells and mediators in the airways is necessary to understand the aetiology of these diseases and to develop improved therapeutic regimens.This symposium was supported by the Pharmacological Society of Canada, the Canadian Histamine Association, the Upjohn Company of Canada, and Merck Frosst Canada Inc.

The role of leukotriene D 4 as a mediator of allergic conjunctivitis in the guinea-pig

The role of leukotriene D 4 (LTD 4) as a mediator of conjunctival microvascular permeability changes associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva has been investigated using two novel, selective LTD 4 receptor antagonists, L-648,051 and L-649,923. Changes in microvascular permeability were measured through the accumulation of [ 99mTc]albumin. LTD 4 administered intravenously produced dose-related increases in conjunctival microvascular permeability through a mechanism which does not involve the generation of prostaglandis as indicated by the failure of indomethacin to attenuate the response. The response the to LTD 4 was significant blocked by the receptor antagonists, L-648,051 and L-649,923. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs caused significant increases in conjunctival microvascular permeability. Following a single challenge, the antigen response was largely blocked by mepyramine (H 1 receptor antagonist), but was unaffected by L-648,051 and L-649,923. Following a second challenge (24 h later) a substantial portion of the response was inhibited by L-648,051 and L-649,923. Indomethacin failed to inhibit either challenge. These results suggest that LTD 4 may have a role in chronic allergic conjunctivitis.