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PubMed2005

Changes in plasma protein extravasation in rat skin during inflammatory challenges evaluated by microdialysis.

Docetaxel and prostaglandin E1 (PGE1) increase transcapillary albumin extravasation and reduce interstitial fluid pressure in the skin. In this study the microdialysate concentration (Cm) of 125I-labeled human serum albumin (125I-HSA) and different-sized endogenous plasma proteins (EPP) was compared to evaluate changes in transcapillary extravasation of plasma proteins. 125I-HSA was also used to estimate changes in the specific activity of albumin. Extravasation of 125I-HSA and EPP from plasma to interstitium in the rat skin was compared during continuous administration of docetaxel and PGE1 by using microdialysis in anesthetized rats. Also, 20 ml of Ringer solution (RS) were injected intravenously during 10 min in a separate group. Two hollow plasmapheresis fibers (3 cm, cut off 3,000 kDa), one acting as control, were placed subcutaneously on the back skin and perfused with RS (5 microl/min, 140 min, collected every 10 min). The size of the different EPP was estimated to be 73, 65, 56, 47, and 39 A, separated by a size-exclusion high-performance liquid chromatography column and quantified by UV detection (280 nm). Docetaxel (0.5 mg/ml, n = 5) increased Cm of 125I-HSA and EPP of sizes 73, 65, 56, and 39 A significantly (P < 0.05) compared with control. PGE1 (20 microg/ml, n = 6) increased Cm of 125I-HSA significantly (P < 0.05) but none of the different-sized EPP was increased compared with control. Intravenous RS (20 ml, n = 6) increased Cm of 125I-HSA and increased all the different-sized EPP significantly (P < 0.05) compared with control. Although the microdialysis method is able to monitor qualitative changes in capillary permeability, a quantitative determination of the capillary reflection coefficient or permeability-surface area product was not possible, because steady state between plasma and dialysate was not achieved during the measurement period. The different pattern of extravasation of EPP and 125I-HSA after docetaxel, PGE1, and RS indicates increased interstitial transport rate and/or increased capillary permeability after docetaxel and RS, whereas PGE1 seems to increase transcapillary fluid flux without altering the permeability.

Alprostadil↗
PubMed2005

Experimental modelling of drug membrane permeability by capillary electrophoresis using liposomes, micelles and microemulsions.

Capillary electrophoresis (CE) was evaluated as an in-vitro format for experimental modelling of membrane permeability using only nanogram quantities of drug compounds. The rationale for the CE technique emanates from emulation of a lipid-like pseudo-stationary phase that governs separations mainly as a result of differences in molecular size, lipophilicity, hydrogen bonding and charge, all of which also have a strong influence on in-vivo drug absorption. By means of micellar, microemulsion and liposome electrolytes, the migration behaviour was studied at 37 degrees C for 22 model drug compounds. The generated CE retention factor data were then compared with membrane permeability reference data. Both simple log D and more common Caco-2 cell parameters were evaluated. In addition, permeation through intestinal segments of rat ileum and rat colon was included. An improved correlation was obtained in the order: micellar < microemulsion < liposome systems. Although the correlation for the best liposome CE system was only R(2)=0.77, the evaluation results for all emphasized the strength and flexibility of CE for assessing specific drug-membrane interaction through tailor-made lipophilic media.

Animals↗
PubMed1996

[Clinical practice interpretation of oncotic pressure, serum albumin and protein determination and their ability for guiding therapeutics in cases of disturbances of capillary exchanges].

The osmotic pressure of the serum proteins, the colloid osmotic pressure (COP) or oncotic pressure, is one of the four Starling forces determining fluid movements across a capillary. Theoretical and empirical formulas considering plasma protein or albumin concentration have been used. However, such calculations are only approximations, being inadequate especially when protein fractionation pattern is abnormal or when artificial colloids are used. It is preferable to measure COP directly. In healthy standing adults COP is around 25 mmHg. It is influenced by age, position, blood pressure and pH. The interpretation of the COP must take into account, on the one hand the possible variations of the other factors involved in the Starling's equilibrium and, on the other hand the structural and functional differences between systemic and pulmonary circulations. When capillary permeability is not altered, a decreased COP is associated with an increased filtration rate across the capillaries, resulting in oedema in skeletal muscle, skin, subcutaneous tissue, intestine and heart. The lung is relatively insensitive to extravascular fluid shifts caused by lowering of the COP, due to the efficacy of the pulmonary lymph drainage and the high pulmonary interstitial protein concentration. The main determinant of fluid exchange in the lung is then the hydrostatic force, reflected by the pulmonary artery wedge pressure. When capillary permeability is altered, the decreased reflectance coefficient results in a smaller effect of the COP on interstitial oedema formation. Several studies demonstrated that oedema formation in the injured tissues seems unaffected by changes in COP. During fluid resuscitation, COP measurement is useful for assessing the risks of peripheral oedema formation and additional measurements of pulmonary artery wedge pressure for assessing the risks of pulmonary oedema. Therefore COP measurement can serve as a useful guide for selection of colloids or crystalloids in critically ill patients, avoiding expensive albumin administrations.

Blood Proteins↗
PubMed2006

Increased extravasation of macromolecules in skeletal muscles of the Zucker rat model.

OBJECTIVE: Assess whether changes in permeability of the muscle regional microcirculation occur in the obese Zucker rat model. RESEARCH METHODS AND PROCEDURES: Capillary permeability to albumin was assessed in vivo in Zucker rats (n = 15) and lean controls (n = 15) by quantifying the extravasation of albumin-bound Evans Blue (EB) in different organs. Unanaesthetized animals were injected with EB 20 mg/kg in the caudal vein, and EB was extracted by formamide from selected organs collected after exsanguination. RESULTS: Relative to control animals, Zucker rats had higher body weight (Delta = +33%; p < 0.001), plasma triglycerides (Delta = +244%; p < 0.001), and insulin (Delta = +240%; p < 0.001) concentrations. Plasma glucose concentrations were not different between the two groups (p = not significant). Using the EB technique, we showed a 30% to 50% (p < 0.01) increase in the extravasation of EB in the obese rats, regardless of the skeletal muscle group studied. This increase in skeletal muscle vasopermeability was not paralleled by any increase in the expression of the muscle endothelium-nitric oxide (NO) system because the total NO synthase (NOS) activity in skeletal muscle of the obese Zucker rat was significantly lower (p < 0.001), as was the endothelial NOS immunoreactive mass (p < 0.001), compared with lean controls. DISCUSSION: In conclusion, there seems to be dissociation between capillary permeability and local regulation of microcirculation in skeletal muscles of the obese Zucker rat. It is suggested that the increase in skeletal muscle vasopermeability (extravasation of macromolecules) is a compensation for the loss of NO-dependent vasodilation and capillary recruitment noted in this model of obesity and insulin resistance.

Albumins↗
PubMed1999

In vivo measurement of solute transport rates in a bioartificial organ.

A radioactive tracer technique was used to evaluate the in vivo mass transfer properties of a tissue engineered bioartificial organ. To obtain these measurements, bioartificial organs were first implanted in ten rats and allowed to vascularize for 4 weeks. After vascularization, radioactive inulin was placed within the cell chamber of the device. Following the addition of tracer, blood samples were taken over a 4-h time period and inulin levels were determined. The results of these experiments were interpreted using a compartmental model that describes the transport of inulin from the cell chamber, across the immunoisolation membrane, and into the neovascularized region contained within the adjacent scaffold material. Nonlinear regression analysis of the plasma inulin levels using a four-compartment pharmacokinetic model provided estimates of the membrane permeability, the product of the capillary wall surface area and capillary permeability, and the glomerular filtration rate (GFR). The permeability of the membrane was found to be 3.50 x 10(-5) +/- 1.15 x 10(-5) cm/sec (95% confidence interval, n = 10), which compares favorably to previous in vitro permeability data for this membrane. The capillary wall permeability was found to be 0. 0087 6 0.0029 cm(3)/sec/100 g of tissue. This compares well to a reported value for inulin of 0.01 cm(3)/sec/100 g of tissue. The GFR was found to be 0.44 +/- 0.07 ml/h/g BW, which compares well with a reported value of 0.40 ml/hr/g BW. The inulin tracer technique reported here is a useful tool for assessing the in vivo transport characteristics of a bioartificial organ as well as the vascularization within tissue engineered structures.

Animals↗
PubMed1995

Effect of adjuvants on immunization with dengue virus-induced cytotoxic factor.

Specific active immunization with dengue type 2 virus (DV)-induced cytokine, cytotoxic factor (CF), prevents CF-mediated pathology in mice. The present study was undertaken to determine the optimum dose of CF and the effect of different adjuvants on the immune response as assessed by the study of anti-CF antibody titre by ELISA and protection against increase in capillary permeability to challenging dose of 3 micrograms CF. The maximum protection of 94 +/- 4% against increase in capillary permeability was observed at week 4 after immunization with 5 micrograms dose of CF mixed with Freund's incomplete adjuvant (FIA), which gradually decreased to 21 +/- 10% on week 24. With a dose of 10 micrograms the protection obtained was 79 +/- 5%, but persisted for a longer time at a higher level. The response was poor with 1 microgram dose of CF. The mean anti-CF antibody titres gradually decreased after reaching the peak at week 4 after immunization. Mice immunized with different adjuvants emulsified with 5 micrograms CF were challenged at different intervals with 3 micrograms CF. Maximum protection observed with CF + tetanus toxoid (TT) and 84/246 was about 93 +/- 2% and 97 +/- 2%, while that with alhydrogel was 33 +/- 12% and with bacille Calmette-Guérin (BCG) was 67 +/- 4%. At week 24 after immunization, however, the best response was obtained with 10 micrograms of adjuvant 84/246. Intracerebral challenge with 10 or 100 LD50 dose of dengue type 2 virus showed significantly prolonged mean survival time and delayed onset of signs of sickness in immunized mice compared with normal mice. The maximum survival time was with adjuvant 84/246 even at week 24. The findings thus show that the optimum dose of CF is 5 micrograms and the adjuvant of choice is 84/246.

Adjuvants, Immunologic↗
PubMed2004

Role of COX-2 in microcirculatory disturbance in experimental pancreatitis.

AIM: To elucidate the role of COX-2 in the development of capillary leakage in rats with acute interstitial pancreatitis. METHODS: Rats with acute interstitial pancreatitis were induced by caerulein subcutaneous injection. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene expression of COX-2 in pancreatic tissues, spectrophotometry was used to assay the parameters of acute pancreatitis such as the serum amylase and plasma myeloperoxidase, and determination of capillary permeability in the pancreas by quantifying the permeability index (PI) assisted response of pancreatic microvascular via intravital fluorescence microscope video image analysis system. RESULTS: A significant increase of COX-2 expression, elevation of serum amylase, and plasma myeloperoxidase were detected in rats with acute edematous pancreatitis compared with control rats. The changes of pancreatic microvascular after caerulein injection were as following: (a) the decrease of pancreatic capillary blood flow (4th h, 0.56+/-0.09 nL/min, P<0.05; 8 th h, 0.34+/-0.10 nL/min, P<0.001); (b) reduction of functional capillary density (4 th h, 381+/-9 cm(-1), P>0.05; 8th h, 277+/-13 cm(-1), P<0.001); (c) irregular and intermittent capillary perfusion was observed at the 8th h and these vessels were also prone to permeation. CONCLUSION: COX-2 plays an important role in mediating capillary permeability in pancreatitis, thereby contributing to capillary leakage.

Animals↗
PubMed1998

Quantitative kinetic analysis of blood vessels in the outer membranes of chronic subdural hematomas.

Dynamic biologic modeling was used to calculate the transfer rate constant for gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) and capillary permeability in the outer membrane of chronic subdural hematomas and effusions. Following intravenous Gd-DTPA injection, Gd concentrations in the subdural fluid and in timed arterial blood samples were measured by ion-coupled plasma emission spectrometry in 53 chronic subdural hematomas and 18 chronic subdural effusions. The capillary surface area in outer membrane was assessed morphometrically. Transfer rate constants for subdural hematomas and subdural effusions were 12.4 +/- 1.0 and 20.6 +/- 1.7 (x 10(-4)min-1, respectively. Capillary permeabilities for subdural hematomas and subdural effusions were 16 +/- 1.2 and 19 +/- 3.7 ml.min-1(mm2/mm3)-1, respectively. The capillary surface areas for subdural hematomas and subdural effusions were 48 +/- 3 and 77 +/- 10 mm2/mm3, respectively. The high degree of infiltration of Gd into subdural effusions reflects the high capillary surface area in the outer membrane rather than greater permeability of individual capillaries. The value of transfer rate constant was correlated inversely with the duration of the chronic subdural fluid collection. Immature outer membrane has a high transfer rate constant which allows extravasation of plasma components into the subdural space, resulting in increasing volume of the subdural effusion. Delayed magnetic resonance imaging following Gd administration may be clinically useful for estimating the age of chronic subdural fluid accumulations.

Aged↗
PubMed1987

The influence of tissue heterogeneity on results of fitting nonlinear model equations to regional tracer uptake curves: with an application to compartmental models used in positron emission tomography.

An analytical method based on Taylor expansions was developed to analyze errors caused by tissue heterogeneity in dynamic positron emission tomography (PET) measurements. Some general rules concerning the effect of parameter variances and covariances were derived. The method was further applied to various compartmental models currently used for measurement of blood flow, capillary permeability, glucose metabolism, and tracer binding. Blood flow and capillary permeability are shown to be generally underestimated in heterogeneous tissue, the underestimation being more severe for slowly decaying, constant or increasing input functions rather than for bolus input, and increasing with measurement time. Typical errors caused by the heterogeneity due to insufficient separation between gray and white matter by a PET scanner with full width at half-maximum (FWHM) = 5 to 10 mm resolution range between -0.9 and -6% in dynamic CBF measurements with intravenous (i.v.) bolus injection of 15O-water or inhalation of 18F-fluoromethane and total measurement times of 6 or 10 min, respectively. Binding or metabolic rates determined with tracers that are essentially trapped in tissue (e.g., FDG for measurement of cerebral glucose metabolism) are only slightly overestimated (0.5-3.0%) at typical measurement times and are essentially independent of the shape of the input function. The error increase considerably if tracer accumulation is very slow, however, or if short measurement times [less than 5/(k2 + k3)] are used. Some rate constants are also subject to larger errors.

Blood-Brain Barrier↗
PubMed2006

In vivo determination of diffusive transport parameters in a superfused tissue.

To address the hypothesis that functional changes in tissue transport can be related to structural alterations, we combined mathematical modeling with in vivo experimentation. The model concept includes interstitial diffusion and removal by a distributed microvasculature. Transport of solute and water across the peritoneum is measured via a plastic chamber affixed to the abdominal wall of anesthetized Sprague-Dawley rats. Solutions containing [(14)C]mannitol, with or without vasoactive compounds [control (C; n = 10), C + nitroprusside (NP; n = 10), C + norepinephrine (NE; n = 10)], were infused into the chamber, and the volume and tracer concentrations were determined over 60 min to calculate the mass transfer coefficient (MTC) and the water flux. At 60 min, FITC-dextran (500 kDa) was given to mark the perfused vasculature. After euthanasia, the tissue under the chamber was frozen, dried, sliced with a cryomicrotome, and examined with fluorescent microscopy and quantitative autoradiography. The microvessel density (x10(3)/cm(2): NE, 50 +/- 10; C, 180 +/- 7.0; NP, 225 +/- 15) resulted in marked differences (P < 0.05) in water flux (mul.min(-1).cm(-2): NE, 0.1 +/- 0.1; C, 1.6 +/- 0.4; NP, 1.0 +/- 0.2) and in mannitol MTC (x10(3) cm/min: NE, 0.9 +/- 0.3; C, 3.8 +/- 0.3; NP, 3.6 +/- 0.6). Concentration profiles and calculated capillary permeability and tissue diffusivity were significantly different among the groups. These results demonstrate a direct correlation of mass transfer, diffusion, capillary permeability, and water flux with peritoneal vascular density and validate a method by which mechanistic changes in transport may be measured.

Animals↗
PubMed1975

Pathogenesis of neurogenic pulmonary oedema.

Evidence suggests that the initial phase of neurogenic pulmonary oedema results from a centrally mediated, massive, sympathetic discharge. It is postulated that this produces intense, generlised, but transient, vasoconstriction with a resultant shift of blood from the high-resistance systemic circulation to the low-resistance pulmonary circulation. Pronounced increases in pulmonary vascular pressures and blood-volume then produce pulmonary oedema because of the hydrostatic effect of increased pulmonary capillary pressure. In addition, pulmonary hypertension and hypervolaemia injure pulmonary blood-vessels, altering pulmonary capillary permeability and producing lung haemorrhage. After the transient systemic and pulmonary vascular hypertension subside, the patient is left with abnormal pulmonary capillary permeability, so that pulmonary oedema persists in the face of normal haemodynamic and cardiac function.

Blood Pressure↗
PubMed2006

Alveolar-capillary membrane permeability for early prediction of response of inhaled steroid on patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Glucocorticosteroid reversibility-testing is undertaken over a period of 3 months to identify whether patients with chronic obstructive pulmonary disease (COPD) would benefit from long-term inhaled corticosteroids. This study assessed whether alveolar-capillary membrane (a/c) permeability testing can be used as an early alternative test method for the same purpose. METHODS: Fourteen patients with severe and symptomatic moderate COPD (group S) were prescribed inhaled steroid 800 microg/day for 3 months. Before inhalation and 4 weeks after inhalation therapy, forced expiratory volume in 1 s (FEV(1)) and a/c permeability using (99m)Tc-DTPA were performed. FEV(1) was recorded again at the end of the third month. Another 10 patients with COPD of comparable severity (group B) prescribed with inhaled bronchodilators were examined and studied as controls. RESULTS: In group S, the permeability decreased in eight patients (group D) and increased in six patients (group I). No significant change was noted in FEV(1) at the end of the first month. However, seven patients in group D showed significant improvement in FEV(1) at the end of the third month, whereas in patients in group I no significant changes were observed. In group B, no significant change in a/c permeability was observed, although the FEV(1) increased by 12-17%. CONCLUSION: With steroid inhalation, the a/c permeability at 4 weeks predicts future changes in lung functions. Long-term inhaled corticosteroids are likely to be useful if permeability decreases. This test, which needs further validation, appears to provide much earlier prediction of response than glucocorticoid reversibility testing.

Administration, Inhalation↗
PubMed1976

Speculations on neurogenic pulmonary edema (NPE).

Evidence suggests the following pathogenesis for neurogenic pulmonary edema. The initial phase results from a centrally mediated, massive, sympathetic discharge. This produces intense, generalized, but transient, vasoconstriction with a resultant shift of blood from the high-resistance systemic circulation to the lowresistance pulmonary circulation. Marked increases in pulmonary vascular pressures and marked increases in pulmonary blood volume then produce pulmonary edema because of the hydrostatic effect of increased pulmonary capillary pressure. In addition, pulmonary hypertension and hypervolemia injure pulmonary blood vessels, altering pulmonary capillary permeability and producing lung hemorrhage. After the transient systemic and pulmonary vascular hypertension subside, the patient is left with abnormal pulmonary capillary permeability, so that pulmonary edema persists in the face of normal hemodynamics and normal cardia function.

Animals↗
PubMed2006

Effects of tumor necrosis factor alpha antagonist, platelet activating factor antagonist, and nitric oxide synthase inhibitor on experimental otitis media with effusion.

OBJECTIVES: We studied the inflammatory responses in otitis media with effusion induced by lipopolysaccharide (LPS) in rats, and compared the preventive effects of tumor necrosis factor (TNF) soluble receptor type I (sTNFRI, a TNF-alpha antagonist), platelet activating factor antagonist, and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). METHODS: We used 2 control groups of Sprague Dawley rats (untreated and saline-treated) and 4 experimental groups, which all received an intratympanic injection of LPS, followed in 3 groups by experimental treatment of the same ear. The LPS group had no additional treatment. The L-NAME group received intraperitoneal injection of L-NAME and was reinjected after 12 hours. The A-85783 group was first given an intraperitoneal injection of A-85783. The sTNFRI group was first given an intratympanic injection of sTNFRI. Twenty-four hours after the initial intratympanic injection of LPS, temporal bones from each group were examined histopathologically and the vascular permeability of the middle ear mucosa was measured by Evans blue vital dye staining. RESULTS: The L-NAME, A-85783, and sTNFRI groups showed significantly reduced capillary permeability, subepithelial edema, and infiltration of inflammatory cells in comparison with the LPS group. There were no differences in capillary permeability, subepithelial edema, or infiltration of inflammatory cells between the A-85783 and sTNFRI groups. The L-NAME group showed no difference in vascular permeability or subepithelial edema in comparison with the A-85783 and sTNFRI groups, but showed more infiltration of inflammatory cells. CONCLUSIONS: We conclude that sTNFRI, A-85783, and L-NAME can be proposed as alternative future treatments for otitis media with effusion. However, L-NAME may be the least effective of these agents.

Animals↗
PubMed1987

Characteristics of inflammation induced by fusarenon-X, a trichothecene mycotoxin from Fusarium species.

Fusarenon-X (F-X) is one of the trichothecene mycotoxins, which have been suggested to induce Fusarium mycotoxicoses. Administration of F-X to experimental animals causes diarrhea, skin irritation, and foot edema. In the present work the properties of F-X-induced inflammation were examined. F-X increased capillary permeability of the abdominal blood vessels in a dose-dependent manner in mice. The F-X-induced increase of the abdominal capillary permeability was not inhibited by 200 mg/kg po of phenylbutazone, 200 mg/kg po of aspirin, 40 mg/kg po of phentolamine, 50 mg/kg po of diphenhydramine, 100 mg/kg po of dibenzyline, 200 mg/kg of hydrocortisone, and 4 mg/kg sc of reserpine. These results suggest that the permeability increment by F-X may not be mediated by serotonin, histamine, norepinephrine, prostaglandins, leukotrienes, and thromboxanes. The increment by F-X also appears to result from histological changes in the capillary blood vessels which are possibly induced by F-X-induced inhibition of protein synthesis, and/or from unidentified inflammatory chemical mediators.

Abdomen↗
PubMed1995

The immediate environment of cardiomyocytes: substantial concentration differences between the interstitial fluid and plasma water for substrates and transmitters.

Substantial transcapillary concentration differences can be inferred from published data on capillary permeability, and from tissue uptake applying Fick's Law for membrane transfer. Concentration differences caused by the diffusive resistance of the capillary wall will be enhanced additionally, if the permeating substrates are metabolized by the endothelial cells. These concentration differences can be verified by sampling and analysing interstitial fluid/transudate from colloid free perfused hearts. With colloid free perfusion, concentration differences can be even underestimated, since the lack of plasma proteins will increase capillary permeability. The observed concentration differences expressed as percentage of interstitial to vascular values amount--for glucose down to 50% for lactate up to 700%, for glutathion, uric acid, adenosine, and catecholamines up to 200-600% when these substances are released from the myocardium, and down to 10-20%, when e.g. adenosine or catecholamines are taken up. The magnitude of these gradients has to be taken into consideration in many respects. In particular, interstitial accumulation of metabolites and mediators (lactate, adenosine, uric acid, catecholamines) are obviously of physiological and pathophysiological importance.

Animals↗
PubMed2002

Parametric imaging of tumor perfusion using flow- and permeability-limited tracers.

PURPOSE: To quantitatively evaluate the spatial distribution of flow- and permeability-limited perfusion in MCF7 human breast cancer tumors orthotopically implanted in CD1-NU mice. MATERIALS AND METHODS: Flow-limited perfusion was derived from (2)H-MRI recorded before and after infusion of deuterated water. Permeability-limited perfusion was evaluated from GdDTPA-enhanced (1)H-MRI. RESULTS: The dominant processes in tumor perfusion, namely blood flow and capillary permeability, were mapped in orthotopically implanted MCF7 human breast cancer tumors. The dynamic data were processed according to physiological models, yielding parametric maps of intravascular volume fraction, water perfusion rate, GdDTPA permeability rate constant, and extracellular volume fraction accessible to GdDTPA. The maps exhibited the heterogeneous distribution of each perfusion parameter. Most of the tumor tissue (> or =95%) was perfused with HDO, while GdDTPA was perfused in only about 50% of it. In most loci the perfusion rate was limited by capillary permeability to GdDTPA. CONCLUSION: The results demonstrated the instructive value of tracers with different properties used in conjunction to achieve a deeper understanding of tumor perfusion capacity. This study offers tools for the accurate, noninvasive evaluation of drug delivery efficacy.

Animals↗
PubMed1990

U74500A inhibition of oxidant-mediated lung injury.

Toxic oxygen species are thought to play a primary role in the pathophysiological mechanisms responsible for a diverse group of lung diseases. In this study, isolated perfused rat lungs were subjected to oxidant injury induced by ischemia-reperfusion (IR) and t-butyl hydroperoxide (t-buOOH) challenge. Both forms of injury caused large increases in capillary permeability as assessed by the capillary filtration coefficient (Kfc). IR and t-buOOH challenge caused increases in the Kfc of 0.95 +/- 0.22 and 0.30 +/- 0.06 ml.min-1.cmH2O-1.100 g lung tissue-1, respectively. U74500A, a potent inhibitor of iron-mediated lipid peroxidation, significantly attenuated the endothelial damage seen in both forms of injury. In lungs pretreated with U74500A, the Kfc increased 0.01 +/- 0.02 and 0.11 +/- 0.03 ml.min-1.cmH2O-1.100 g lung tissue-1 following IR and t-buOOH challenge, respectively. In lungs pretreated with the iron binding protein transferrin the Kfc increased 0.31 +/- 0.11 and 0.19 +/- 0.03 ml.min-1.cmH2O-1.100 g lung tissue-1 following IR and t-buOOH challenge, respectively. In these studies, transferrin significantly attenuated permeability in the IR group only. However, the attenuation of injury in IR due to U74500A was significantly greater (P less than 0.05) than the attenuation provided by transferrin. Both forms of injury also caused small but statistically significant increases in pulmonary artery pressure. These results suggest that the increase in capillary permeability seen after IR and t-buOOH is in part mediated by iron-dependent mechanisms.

Animals↗