Intercellular adhesion molecule-I (ICAM-I, CD54) deficiency segregates the unique pathophysiological requirements for generating idiopathic pneumonia syndrome (IPS) versus graft-versus-host disease following allogeneic murine bone marrow transplantation.

Following allogeneic bone marrow transplantation (alloBMT), idiopathic pneumonia syndrome (IPS) and graft-versus-host disease (GVHD) caused by donor cell alloreactivity remain major obstacles to a successful outcome. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is involved in regulating lymphohematopoietic cell migration and facilitating T-cell responses. To determine whether ICAM-1 expression in the host would affect IPS or GVHD tissue injury responses, ICAM-1(-/-) mice were compared with ICAM-1(+/+) controls. ICAM-1(-/-) recipients did not exhibit the manifestations of IPS injury such as an increase in lung weights nor decreased lung function. The influx of T cells, macrophages, and neutrophils was dramatically dampened as was the production of the inflammatory cytokines interferon-gamma and tumor necrosis factor alpha and the chemokines monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and lymphotactin, normally upregulated in the lung during IPS. In contrast, systemic levels of these mediators were unaffected and GVHD-induced lesions in the liver and colon did not differ in severity regardless of ICAM-1 expression. GVHD-mediated mortality was accelerated in ICAM-1(-/-) recipients at doses of allogeneic spleen cells that are otherwise not uniformally lethal. These data implicate ICAM-1 as playing a critical role in the generation of IPS; therefore, ICAM-1 may be a discerning element, segregating IPS from GVHD injury post-alloBMT.

Effect of hypothermic pulmonary artery flushing on capillary filtration coefficient.

BACKGROUND: We previously demonstrated that surfactant dilution and inhibition occur immediately after pulmonary artery flushing with hypothermic modified Euro-Collins solution. Consequently, we speculated that increased capillary permeability contributed to these surfactant changes. To test this hypothesis, we evaluated the effects of hypothermic pulmonary artery flushing on the pulmonary capillary filtration coefficient (Kfc), and additionally performed a biochemical analysis of surfactant. METHODS: We used a murine isolated, perfused lung model to measure the pulmonary capillary filtration coefficient and hemodynamic parameters, to determine the wet to dry weight ratio, and to evaluate surfactant by biochemical analysis of lung lavage fluid. We defined three study groups. In group I (controls), we harvested lungs without hypothermic pulmonary artery flushing, and measured Kfc immediately. In group II (in situ flush), we harvested lungs after hypothermic pulmonary artery flushing with modified Euro-Collins solution, and then measured Kfc. Experiments in groups I and II were designed to evaluate persistent changes in Kfc after pulmonary artery flushing. In group III (ex vivo flush), we flushed lungs ex vivo to evaluate transient changes in Kfc during hypothermic pulmonary artery flushing. RESULTS: Groups I and II did not differ significantly in capillary filtration coefficient and hemodynamics. Group II showed significant alterations on biochemical surfactant analysis and a significant increase in wet-to-dry weight ratio, when compared with group I. In group III, we observed a significant transient increase in capillary filtration coefficient during pulmonary artery flushing. CONCLUSIONS: Hypothermic pulmonary artery flushing transiently increases the capillary filtration coefficient, leads to an increase in the wet to dry weight ratio, and induces biochemical surfactant changes. These findings could be explained by the effects of hypothermic modified Euro-Collins solution on pulmonary capillary permeability.

KGF pretreatment decreases B7 and granzyme B expression and hastens repair in lungs of mice after allogeneic BMT.

We investigated keratinocyte growth factor (KGF) as a pretreatment therapy for idiopathic pneumonia syndrome (IPS) generated as a result of lung damage and allogeneic T cell-dependent inflammatory events occurring in the early peri-bone marrow (BM) transplant (BMT) period. B10.BR (H2(k)) recipient mice were transplanted with C57BL/6 (H2(b)) BM with spleen cells after lethal irradiation with and without cyclophosphamide conditioning with and without subcutaneous KGF pretreatment. KGF-pretreated mice had fewer injured alveolar type II (ATII) cells at the time of BMT and exhibited ATII cell hyperplasia at day 3 post-BMT. The composition of infiltrating cells on day 7 post-BMT was not altered by KGF pretreatment, but the frequencies of cells expressing the T-cell costimulatory molecules B7.1 and B7.2 and mRNA for the cytolysin granzyme B (usually increased in IPS) were decreased by KGF. Sera from KGF-treated mice had increases in the Th2 cytokines interleukin (IL)-4, IL-6, and IL-13 4 days after cessation of KGF administration (i.e., at the time of BMT). These data suggest that KGF hinders IPS by two modes: 1) stimulation of alveolar epithelialization and 2) attenuation of immune-mediated injury as a consequence of failure to upregulate cytolytic molecules and B7 ligand expression and the induction of anti-inflammatory Th2 cytokines in situ.

Effects of decreased respiratory frequency on ventilator-induced lung injury.

To determine if decreased respiratory frequency (ventilatory rate) improves indices of lung damage, 17 sets of isolated, perfused rabbit lungs were ventilated with a peak static airway pressure of 30 cm H(2)O. All lungs were randomized to one of three frequency/peak pulmonary artery pressure combinations: F20P35 (n = 6): ventilatory frequency, 20 breaths/min, and peak pulmonary artery pressure, 35 mm Hg; F3P35 (n = 6), ventilatory frequency, 3 breaths/min, and peak pulmonary artery pressure of 35 mm Hg; or F20P20 (n = 5), ventilatory frequency, 20 breaths/min, and peak pulmonary artery pressure, 20 mm Hg. Mean airway pressure and tidal volume were matched between groups. Mean pulmonary artery pressure and vascular flow were matched between groups F20P35 and F3P35. The F20P35 group showed at least a 4.5-fold greater mean weight gain and a 3-fold greater mean incidence of perivascular hemorrhage than did the comparison groups, all p

Psychological and physiological predictors of response to carbon dioxide challenge in individuals with panic disorder.

Past studies in nonclinical samples have found that suffocation fear, but not a behavioral index of carbon dioxide (CO2) sensitivity (i.e., breath-holding duration), predicts anxious response to CO2 challenge. These associations were examined in individuals with panic disorder while adding more sensitive indices of CO2 sensitivity. Consistent with the earlier studies, the authors found that suffocation fear predicted anxious responding to CO2 challenge but breath-holding duration did not. However, highly precise measures of CO2 sensitivity, not included in earlier studies, did predict anxious challenge responding. These findings support the predictive value and possible etiological relevance of both specific psychological variables and physiological CO2 sensitivity in panic vulnerability. Further work is still needed to determine whether the findings are specific to panic disorder.

Perfusion technique determines alveolar fluid resorption rate in the isolated perfused rat lung.

The isolated perfused lung (IPL) preparation is a well-established model for the study of alveolar epithelial sodium transport. We noted that preparations of normal fluid-filled rat lungs with recirculated perfusate reproducibly lost weight, whereas preparations in which the perfusate was discarded after a single pass through the lungs had a variable and lesser weight change. To confirm this, we performed IPL experiments by using male Sprague-Dawley specific-pathogen-free rats (175-225 g). In 10 IPLs, perfusate initially was discarded after passing through the lungs and then was recirculated continuously. During the single-pass period, the rate of weight change was +0.7 +/- 2.0 mg/min compared with -9.0 +/- 1.3 mg/min for the recirculating period. Adenosine 3',5'-cyclic monophosphate (cAMP) accumulated during recirculation. The weight loss induced by recirculation was reproduced by perfusion with 8-bromoadenosine 3',5'-cyclic monophosphate or terbutaline in single-pass fashion and blocked when the kinase inhibitor H-8 or phosphodiesterase was present in the recirculating perfusate. In summary, perfusate recirculation in the IPL stimulates fluid resorption at least partially via cAMP. This should be factored into the design and interpretation of IPL experiments.

The critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients are due to donor T cell infusion and potentiated by cyclophosphamide.

We have hypothesized that lung damage occurring in the peri-bone marrow transplant (BMT) period is critical for the subsequent generation of idiopathic pneumonia syndrome (IPS), a major complication following human BMT. The proinflammatory events induced by a common pre-BMT conditioning regimen, cyclophosphamide (Cytoxan(R)) (Cy) and total body irradiation, were analyzed in a murine BMT model. Electron microscopy indicated that Cy exacerbated irradiation-induced epithelial cell injury as early as day 3 after BMT. Allogenicity was an important contributing factor to lung injury as measured by lung wet and dry weights and decreased specific lung compliance. The most significant pulmonary dysfunction was seen in mice receiving both allogeneic T cells and Cy conditioning. IPS was associated with an influx of T cells, macrophages, and neutrophils early post-BMT. Hydroxyproline levels were not increased, indicating that the injury was not fibrotic early post-BMT. As early as 2 h after chemoradiation, host macrophages increased in number in the lung parenchyma. Continued increases in macrophages occurred if splenic T cells were administered with the donor graft. The expression of costimulatory B7 molecules correlated with macrophage numbers. Frequencies of cells expressing mRNA for the inflammatory proteins TNF-alpha, IL-1beta, and TGFbeta were increased. Cy accelerated the upregulation of TGFbeta and increase in host macrophages. The exacerbation of macrophage activation and severity of IPS was dependent on allogeneic T cells, implicating immune-mediated mechanisms as critical to the outcome of IPS. This demonstration of early injury after BMT indicates the need for very early therapeutic intervention before lung damage becomes profound and irreversible.

Proteinase-free myeloperoxidase increases airway epithelial permeability in a whole trachea model.

In cystic fibrosis the bronchiectatic conducting airways have large numbers of neutrophils in their walls and in their luminal contents. The neutrophil's primary granule enzyme activities of elastase and peroxidase are increased in the sputum of these patients. It has been postulated that these enzymes--together or individually--act to damage the airway epithelium. However, only peroxidase activity has consistently correlated with the degree of structural and functional airway disease in these patients with leakage of plasma protein into the airway lumen (Regelmann et al., Pediatr Pulmonol, 1995; 19:1-9). The present study was designed to test whether human neutrophil-derived myeloperoxidase can independently produce bronchial epithelial damage without the presence of proteases, as measured by increased permeability of the airway epithelium. Human peripheral blood neutrophils were purified, their primary granules isolated, and their peroxidase purified using affinity and ion exchange column chromatography. Activity of the proteinase-free peroxidase was measured using a chromogenic substrate. The effect of this peroxidase on the permeability of excised rat tracheas was measured using radioactive and fluorescent-labeled non-ionic molecules of varying molecular weight. Rat tracheas exposed to 15 minute treatments with either 130 U of peroxidase or hydrogen peroxide (10(-5) M) did not show a significant increase in the permeability of the epithelium to [3H]inulin, [14C]sucrose, and fluorescein isothiocyanate dextran 20 compared with control tracheas. However, those tracheas exposed to 130 U peroxidase followed by 10(-5) M hydrogen peroxide showed an increased permeability to each of the three test solutes. We conclude that proteinase-free myeloperoxidase, in the presence of non-toxic concentrations of its substrates, hydrogen peroxide and halide, produced increases in permeability to non-ionic molecules in the rat trachea within 15 minutes.

Effects of hyperoxia on type II cell Na-K-ATPase function and expression.

Alveolar fluid is resorbed using active Na+ transport primarily through basolateral sodium-potassium-adenosinetriphosphatase (Na-K-ATPase) and apical Na+ channels that are particularly dense on the alveolar type II (ATII) epithelial cells. During lung injury with pulmonary edema, continued or accelerated Na+ and fluid resorption is critical for a favorable outcome. However, little is known of how ATII cell Na+ transport is affected during injury. These experiments examined the effects of acute lung injury on ATII cell Na-K-ATPase activity and expression using an established model of rats exposed to 100% O(2) for 60 h. Na-K-ATPase activity of ATII cells isolated immediately after exposure was assessed by ouabain-sensitive (86)Rb+ uptake in intact cells and by ouabain-sensitive P(i) production by cell membranes. In the presence of 1 mM ouabain, ouabain-sensitive Rb+ uptake was not different between normoxic and hyperoxic cells, but the apparent Na-K-ATPase maximal velocity (Vmax) of hyperoxic cell membranes was 75 +/- 8% of normoxic membranes (P < 0.05). On Western blots of ATII cell membranes, alpha1-subunit protein significantly decreased with hyperoxia (35 +/- 9% of normoxia; P < 0.05), whereas the amounts of the beta-subunit were unchanged (P > 0.05). On Northern blots of ATII cell total RNA, steady-state levels of both the alpha1- and beta1-subunit mRNA increased after hyperoxia (alpha1 = 2.5 +/- 1.3-fold; beta1 = 4.6 +/- 2.5-fold). Thus despite hyperoxic decreases in Na-K-ATPase Vmax and the amount of alpha1-protein, Rb+ uptake by Na-K-ATPase in intact cells was unchanged. The mRNA levels, protein amounts, and enzyme activity did not respond in parallel to hyperoxic injury, and the activity in intact cells correlated best with the amounts of the beta-subunit, the limiting component in de novo pump assembly in many tissues.

Hyperoxic effects on alveolar sodium resorption and lung Na-K-ATPase.

Active Na+ transport by the alveolar epithelium keeps alveoli relatively dry. Hyperoxia increases epithelial permeability, resulting in pulmonary edema. We sought to determine whether active Na+ resorption from the air spaces and Na-K-ATPase activity increased in rats exposed to > 95% O2 for 60 h. The permeability x surface area products for unidirectional resorption of alveolar [14C]sucrose (PSsucrose) and 22Na+ (PSNa+) were measured in isolated, perfused rat lungs immediately after hyperoxia and after 3 and 7 days of recovery in room air. At 60 h of hyperoxia, the mean PSsucrose and PSNa+ increased from 6.71 +/- 0.8 x 10(-5) to 12.6 +/- 1.6 x 10(-5) cm3/s (P = 0.029) and from 23.6 +/- 1.1 x 10(-5) to 31.0 +/- 1.6 x 10(-5) cm3/s (P < 0.008), respectively. However, the values in individual rats ranged widely from no change to nearly a fourfold increase. Subgroup analysis revealed that benzamil- or amiloride-sensitive (transcellular) PSNa+ was significantly reduced in the exposed lungs with normal PSsucrose but was maintained in the lungs with high PSsucrose. By day 3 of recovery, mean Na+ and sucrose fluxes returned to values similar to control. Na-K-ATPase membrane hydrolytic maximal velocity (Vmax) activity fell significantly immediately after hyperoxic exposure but recovered to normal values by day 3 of recovery. The Na-K-ATPase beta 1-subunit antigenic signal did not significantly change, whereas the alpha 1-subunit levels increased during recovery. In summary, there was a heterogeneous response of different rats to acute hyperoxia. Hyperoxia led to complex, nonparallel changes in Na+ pump antigenic protein, hydrolytic activity, and unidirectional active Na+ resorption. Active Na+ transport was differentially affected, depending on degree of injury, but permeability and transport normalized by day 3 of recovery.

Riboflavin-enhanced transport of serum albumin across the distal pulmonary epithelium.

PURPOSE: Conjugation of bovine serum albumin (BSA) with riboflavin (BSA-riboflavin) increases its uptake into cultured epithelial cells. Our purpose was to determine whether transport of BSA-riboflavin across the intact distal pulmonary epithelium is also increased, and whether transcytosis plays a role. METHODS: In anesthetized rats, we instilled 3H-BSA-riboflavin or 3H-BSA into the trachea and measured their appearance in blood. In isolated, perfused rat lungs we measured the distal pulmonary epithelium permeability-surface area product (PS) for FITC-BSA or FITC-BSA-riboflavin. RESULTS: In intact rats we found 2.1 times more 3H-BSA-riboflavin than 3H-BSA appeared in blood 60 min after intratracheal instillation of the protein. In isolated, perfused rat lungs we found that BSA-riboflavin had double the PS of BSA (2.63 vs. 1.46 x 10(-5) cm3/sec). The addition of transcytosis inhibitors monensin or nocodazole (both 3 x 10(-5) M) reduced the BSA-riboflavin PS to that of BSA and had no effect on the PS of unconjugated BSA. Simultaneous measurements of 3H-sucrose PS showed no differences in paracellular transport among any of the experimental groups. CONCLUSIONS: Conjugation with riboflavin increases the flux of BSA across the distal pulmonary epithelium. The increased transport appears to be due to transcytosis, which apparently does not play a significant role in the movement of unconjugated BSA across the distal pulmonary epithelium.

Terbutaline stimulates alveolar fluid resorption in hyperoxic lung injury.

Alveolar fluid resorption occurs by active epithelial sodium transport and is accelerated by terbutaline in healthy lungs. We investigated the effect of terbutaline on the rate of alveolar fluid resorption from rat lungs injured by hyperoxia. Rats exposed to > 95% O2 for 60 h, sufficient to increase wet-to-dry lung weight and cause alveolar edema, were compared with air-breathing control rats. After anesthesia, the animals breathed 100% O2 for 10 min through a tracheostomy. Ringer solution was instilled into the alveoli, and the steady-state rate of volume resorbed at 6 cmH2O pressure was measured via a pipette attached to the tracheostomy tubing. Ringer solution in some animals contained terbutaline (10(-3) M), ouabain (10(-3) M), or both. Normoxic animals resorbed 49 +/- 6 microliters.kg-1.min-1; ouabain reduced this by 39%, whereas terbutaline increased the rate by 75%. The effect of terbutaline was blocked by ouabain. Hyperoxic animals absorbed 78 +/- 9 microliters.kg-1.min-1; ouabain reduced this by 44%. Terbutaline increased the rate by a mean of 39 microliters.kg-1.min-1, similar to the absolute effect seen in the normoxic group, and this was blocked by ouabain. Terbutaline accelerates fluid resorption from both normal and injured rat lungs via its effects on active sodium transport.

Effect of eosinophil peroxidase on airway epithelial permeability in the guinea pig.

Increased numbers of eosinophils and increased concentrations of plasma proteins have been found in the airways of patients with mild asthma. We used an intact guinea pig trachea model to investigate the role of eosinophil peroxidase (EPO) in altering the function of the airway epithelial barrier. EPO in the presence of hydrogen peroxide (H(2)O(2)) and bromide (Br(-)) catalyzes the production of hypobromous acid (HOBr), which is felt to have a toxic effect on airway epithelial cells. An intact guinea pig trachea was mounted on an apparatus in a way that would allow the tracheal epithelium to be exposed to different solutions. Following these exposures, a test solution containing (14)C-sucrose (S), (3)H-inulin (I), and FITC-dextran-20 (D) was placed in the tracheal lumen and positioned in the center of the segment for 90 minutes. Flux of these molecules across the epithelial barrier into a bath was measured, and the permeability (P) was calculated for each molecule to quantify epithelial barrier function. Light and electron micrographic studies were performed to assess cellular damage. We found that there was a dose response to EPO (in the presence of fixed amounts of H(2)(O)(2) and Br(-)). EPO at 7.3 x 10(-7) M caused no increase in P over controls (Ringer's solution alone) for S, I, or D (P> 0.05), whereas EPO at 2.7 x 10(-6) M caused a significant increase in P over controls (P = 0.008) for all test molecules. Light and electron micrographs of the latter tracheas showed no evidence of microscopic changes despite the increased P. Further testing verified that the increase in permeability was caused by the EPO catalyzed reaction and not the individual substrates themselves, and that the reaction was inhibited by a peroxidase inhibitor. We conclude that EPO can alter the barrier function of the airway epithelium before gross cellular damage becomes visible. We hypothesize that changes in the tight junctions are responsible for the alteration in the barrier function of the airway epithelium and that this may play an important role in the pathophysiology of mild asthma.

HOCl effects on the tight junctions of rabbit tracheal epithelium.

We previously found that HOCl, produced from neutrophil products in infected airways, decreases electrical resistance (R) of rabbit tracheal epithelium. Interestingly, HOCl at 6 mM, a reasonable concentration in diseased airways, decreased R without apparent cell damage. This study sought to determine whether this noncytotoxic dose of HOCl causes morphological changes that correlate with the decrease in R. Excised rabbit tracheas were treated with 6 mM HOCl for 15 min, before and after which epithelial R was determined. Epithelial tissue was then fixed and prepared for transmission electron microscopy, immunofluorescent labeling of F-actin or the tight junction protein ZO-1, or freeze fracture to examine tight junction strands. HOCl treatment caused a 50% decrease in R. Electron micrographs showed no cell, cell membrane, or tight junction changes. By laser confocal microscopy, 6 mM HOCl did not affect the distribution of F-actin or ZO-1. However, morphometric analysis of freeze-fracture replicas showed that tight junction strand number was significantly decreased from 7.06 +/- 0.09 to 4.79 +/- 0.11 and junctional width was significantly decreased from 0.306 +/- 0.007 to 0.214 +/- 0.006 microns. These latter changes may have contributed to the observed decrease in epithelial R.

Surfactant dysfunction in lung preservation.

We studied the effect of lung preservation on the surfactant system in rats. Lung surfactant is necessary to maintain normal lung mechanics, and hence normal lung function. We evaluated lung mechanics with pressure-volume (P-V) curves, and analyzed biochemical changes of surfactant in bronchoalveolar lavage (BAL) fluid. Additionally, we determined wet to dry weight ratios (W/D). We defined five study groups. In group I (controls) we harvested lungs without pulmonary artery flushing, then evaluated them immediately. In group II we flushed lungs through the pulmonary artery (PA) with hypothermic modified Euro-Collins solution (mECS), then removed and studied them immediately to determine the consequences of PA flushing alone. In groups III, IV, and V we flushed lungs with mECS, then stored them in normal saline (NS) for 6 hr (group III); in NS for 12 hr (group IV); or in mECS for 12 hr (group V). In groups III, IV, and V we evaluated lungs after storage. All four experimental groups showed significant changes in lung mechanics and surfactant biochemistry, compared with controls. Lungs in groups III, IV, and V showed additional changes in lung mechanics and surfactant biochemistry compared with group II. The W/D in stored lungs (groups III, IV, and V) was significantly higher than in controls and group II. We conclude that lung preservation induces deleterious changes in the surfactant system. Surfactant alterations are evident immediately after pulmonary artery flushing, and increase in severity with storage.

HOCl effects on tracheal epithelium: conductance and permeability measurements.

It is speculated that hypochlorous acid (HOCl), produced by neutrophils, can disrupt the tracheal epithelial barrier without damage to epithelial cells. This was investigated with solute permeability (P) and electrical conductance (G) measurements on tracheae from 4-wk-old rabbits. A new system for epithelial bioelectric measurements on intact tracheae was developed and validated. Control values of G, short-circuit current, and spontaneous potential difference were 4.9 +/- 0.5 (SE) mS/cm2, 42.6 +/- 4.7 microA/cm2, and 8.9 +/- 1.0 mV (lumen negative), respectively (n = 5). Control P values for sucrose, inulin, and Dextran-20 were 5.14 +/- 0.48, 0.63 +/- 0.10, and 0.057 +/- 0.007 x 10(-7) cm/s, respectively (n = 6). Tracheae treated with HOCl had no effect; 6 mM HOCl, a concentration that could exist in infected airways, significantly increased both P and G (about two- to fourfold) without damage to epithelial cells; and 12 and 30 mM HOCl caused more than 10-fold increases for both P and G with cell disruption. Vitamin C blocked epithelial damage caused by 30 mM HOCl. Tracheae from 1-wk-old rabbits were significantly more sensitive to HOCl than those from 4-wk-old or adult rabbits. This study validated a new bioelectric measurement system and showed that HOCl has both dose- and age-dependent effects on the tracheal epithelium.

Tracheal epithelial permeability to nonelectrolytes: species differences.

We developed a new excised tracheal preparation to measure the epithelial permeability of large lipid-insoluble nonelectrolytes and macromolecules. Tracheae were suspended vertically in a Ringer solution bath, and a solution containing labeled test solutes was positioned in the center of the tracheal segment, away from damaged ends. Permeability coefficients, calculated from solute fluxes into the bath, were constant for > or = 2 h at 37 degrees C, and no histological changes were observed. Measurements after epithelial removal with detergent indicate that in the intact trachea the epithelium represents > 90% of the resistance to transport. For the rat trachea, permeability coefficients for sucrose, inulin, and Dextran 20 were 9.22, 2.20, and 0.214 x 10(-7) cm/s, respectively. Values for cat tracheae were similar, those for rabbit tracheae were lower, and those for guinea pig tracheae were markedly greater. With the assumption of transport by diffusion through thin rectangular slits between epithelial cells, the rat and guinea pig data fit a slit width of 7-8 nm, whereas the rabbit and cat data cannot be explained by a model with slits of a single size.

Alterations in feline tracheal permeability after mechanical ventilation.

OBJECTIVES: Previous investigations of ventilator-induced airway injury focused on histopathologic changes associated with various ventilators and strategies for their use. We hypothesized that mechanical ventilation is associated with alterations in tracheal epithelial permeability, and designed a study using an animal model to evaluate changes in tracheal epithelial permeability after administering different types of mechanical ventilation to test this hypothesis. DESIGN: Prospective, multiple-group, controlled trial. Five groups of animals were studied and compared. Eight animals were studied without intubation or mechanical ventilation. A total of 28 animals (seven in each group) were studied after conventional mechanical ventilation, high-frequency positive-pressure ventilation, high-frequency jet ventilation, or high-frequency flow interruption at respiratory rates of 20, 150, 400, and 900 breaths/min, respectively. Comparison of data for each group was done using the Kruskall-Wallis analysis of variance. Between-group comparisons were made using standard error of the mean comparisons. For airway pressures and other physiologic data, one-way analysis of variance was performed. Between-group comparisons were made using the Student-Newman-Keuls' test. SETTING: Small animal physiology laboratory. SUBJECTS: Thirty-six adult cats. INTERVENTIONS: Mechanically ventilated animals were treated for 8 hrs and then killed. Inspired oxygen concentration, BP, and mean airway pressures were comparable in mechanically ventilated animals. Spontaneously breathing control animals were killed without endotracheal intubation or exposure to mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Permeability values in isolated tracheal segments were calculated for 14C-sucrose, 3H-inulin, and fluorescein isothiocyanate-dextran-20. Tracheal epithelial permeability to all studied molecules increased after exposure to mechanical ventilators. These different mechanical ventilators increased epithelial permeability in a progressive manner that paralleled ventilatory frequency. The changes were greatest after ventilation at the highest frequency. These observed changes in tracheal permeability are consistent with previously observed alterations in tracheal histopathology after exposure to mechanical ventilation. CONCLUSIONS: Mechanical ventilation was associated with increases in tracheal permeability to large and small nonionic molecules. These changes occurred with all studied ventilators, used as they are clinically. Permeability changes paralleled ventilatory rate changes.