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Biomedical subjects

M A Matthay

Publications and source records attributed to M A Matthay.

At least 127 records · Page 7Linked to original sources
PubMed1996

Transepithelial water permeability in microperfused distal airways. Evidence for channel-mediated water transport.

Water movement across the airway epithelium is important for regulation of the volume and composition of airspace fluid. A novel approach is reported here to measure osmotic and diffusional water permeability in intact airways. Small airways (100-200 microns diameter, 1-2 mm length) from guinea pig lung were microdissected and perfused in vitro using concentric glass holding and perfusion pipettes. For measurement of osmotic water permeability (Pf), the airway lumen was perfused wit PBS (300 mOsM) containing a membrane impermeable fluorophore, fluorescein sulfonate (FS), and the airway was bathed in solutions of specified osmolalities. Pf determination was based on the changes in FS fluorescence at the distal end of the airway resulting from transepithelial water transport. Pf was 4-5 x 10(-3) cm/s at 23 degrees C and independent of lumen flow rate (10-100 nl/min) and the magnitude and direction of the osmotic gradient (bath osmolality 50-600 mOsM). Temperature dependence measurements gave an activation energy of 4.4 kcal/mol (15-37 degrees C). Pf was not altered by 0.3 mM HgCl2 or 50 microM forskolin, but was increased to 31 x 10(-3) cm/s by 100 micrograms/ml amphotericin B, indicating that osmosis is not limited by unstirred layers. Diffusional water permeability (Pd) was measured by H2O/D2O (deuterium oxide) exchange using the H2O/D2O-sensitive fluorescent probe aminonapthelane trisulfonic acid in the lumen. Measured Pd was 3-6 x 10(-6) cm/s at 23 degrees C, indicating significant restriction to water diffusion by unstirred layers. Antibody localization of water channels showed strong expression of the mercurial-insensitive water channel (AQP-4) at the basolateral membrane of airway epithelial cells. These results provide functional evidence that water movement across the distal airway epithelium is mediated by water channels.

Animals↗
PubMed1996

Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity.

Reversible airway hyperreactivity underlies the pathophysiology of asthma, yet the precise mediators of the response remain unclear. Human studies have correlated aberrant activation of T helper (Th) 2-like effector systems in the airways with disease. A murine model of airway hyperreactivity in response to acetylcholine was established using mice immunized with ovalbumin and challenged with aerosolized antigen. No airway hyperractivity occurred in severe combined immunodeficient mice. Identically immunized BALB/c mice developed an influx of cells, with a predominance of eosinophils and CD4+ T cells, into the lungs and bronchoalveolar lavage fluid at the time that substantial changes in airway pressure and resistance were quantitated. Challenged animals developed marked increases in Th2 cytokine production, eosinophil influx, and serum immunoglobulin E levels. Neutralization of interleukin (IL) 4 using monoclonal antibodies administered during the period of systemic immunization abrogated airway hyperractivity but had little effect on the influx of eosinophils. Administration of anti-IL-4 only during the period of the aerosol challenge did not affect the subsequent response to acetylcholine. Finally, administration of anti-IL-5 antibodies at levels that suppressed eosinophils to < 1% of recruited cells had no effect on the subsequent airway responses. BALB/c mice had significantly greater airway responses than C57BL/6 mice, consistent with enhanced IL-4 responses to antigen in BALB/c mice. Taken together, these data implicate IL-4 generated during the period of lymphocyte priming with antigen in establishing the cascade of responses required to generate airway hyperractivity to inhaled antigen. No role for IL-5 or eosinophils could be demonstrated.

Acetylcholine↗
PubMed1996

Transalveolar osmotic and diffusional water permeability in intact mouse lung measured by a novel surface fluorescence method.

A surface fluorescence method was developed to measure transalveolar transport of water, protons, and solutes in intact perfused lungs. Lungs from c57 mice were removed and perfused via the pulmonary artery (approximately 2 ml/min). The airspace was filled via the trachea with physiological saline containing a membrane-impermeant fluorescent indicator (FITC-dextran or aminonapthalene trisulfonic acid, ANTS). Because fluorescence is detected only near the lung surface due to light absorption by lung tissue, the surface fluorescence signal is directly proportional to indicator concentration. Confocal microscopy confirmed that the fluorescence signal arises from fluorophores in alveoli just beneath the pleural surface. Osmotic water permeability (Pf) was measured from the time course of intraalveolar FITC-dextran fluorescence in response to changes in perfusate osmolality. Transalveolar Pf was 0.017 +/- 0.001 cm/s at 23 degrees C, independent of the solute used to induce osmosis (sucrose, NaCl, urea), independent of osmotic gradient size and direction, weakly temperature dependent (Arrhenius activation energy 5.3 kcal/mol) and inhibited by HgCl2. Pf was not affected by cAMP activation but was decreased by 43% in lung exposed to hyperoxia for 5 d. Diffusional water permeability (Pd) and Pf were measured in the same lung from intraalveolar ANTS fluorescence, which increased by 1.8-fold upon addition of 50% D2O to the perfusate, Pd was 1.3 x 10(-5) cm/s at 23 degrees C. Transalveolar proton transport was measured from FITC-dextran fluorescence upon switching perfusate pH between 7.4 and 5.6; alveolar pH half-equilibrated in 1.9 and 1.0 min without and with HCO3-, respectively. These results indicate high transalveolar water permeability in mouse lung, implicating the involvement of molecular water channels, and establish a quantitative surface fluorescence method to measure water and solute permeabilities in intact lung.

Animals↗
PubMed1996

Increased interleukin-8 concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis.

OBJECTIVE: To test the hypothesis that significantly higher concentrations of interleukin-8 (IL-8) are found in the pulmonary edema fluid and plasma of patients with a septic vs. a nonseptic etiology of acute respiratory distress syndrome (ARDS). DESIGN: Prospective measurement of IL-8 concentrations in previously collected edema fluid and plasma. SETTING: Adult intensive care units at a university medical center. PATIENTS: There were 27 patients with ARDS (16 patients with a septic etiology and nine patients with a nonseptic etiology) plus eight control patients with hydrostatic pulmonary edema. MEASUREMENTS AND MAIN RESULTS: IL-8 was present in the pulmonary edema fluid of all patients with ARDS, but the median IL-8 concentration was higher in the edema fluid of patients with ARDS associated with sepsis (84.2 ng/mL, n = 16) compared with the ARDS patients without sepsis (14.8 ng/mL, n = 11) (p < .05). In patients with cardiogenic edema, IL-8 concentration (5.0 ng/mL,n = 8, p < .05) was significantly lower than those values in patients with ARDS. Median plasma concentration of IL-8 was increased in septic individuals (1.3 ng/mL), but these concentrations were not significantly higher than in patients with a nonseptic etiology of ARDS (0.35 ng/mL) (p = .14) or those patients with cardiac failure (0.21 ng/mL). CONCLUSIONS: The high concentrations of IL-8 in pulmonary edema fluid, coupled with the relatively low concentrations of IL-8 in the plasma, suggest that the lung was the primary source of IL-8 in the patients with ARDS. The markedly increased concentrations of IL-8 in the pulmonary edema fluid of patients with ARDS from sepsis suggests that this group of patients may be particularly suitable for potential trials directed at inhibiting the activity of this important chemokine.

Adolescent↗
PubMed1996

Salt and water transport across alveolar and distal airway epithelia in the adult lung.

Substantial progress has been made in understanding the role of the distal airway and alveolar epithelial barriers in regulating lung fluid balance. Molecular, cellular, and whole animal studies have demonstrated that reabsorption of fluid from the distal air spaces of the lung is driven by active sodium transport. Several different in vivo, in situ, and isolated lung preparations have been used to study the mechanisms that regulate fluid transport in the normal and injured lung. Catecholamine-dependent and -independent regulatory mechanisms have been identified that modulate fluid transport, probably by acting on apical sodium channel uptake or the activity of the Na, K-ATPase pumps. Recently, a family of molecular water channels (aquaporins) has been identified that are small (approximately 30 kDa) integral membrane proteins expressed widely in fluid-transporting epithelia and endothelia. At present, four different water channels have been identified in trachea and lung. Measurements of osmotic water permeability in in situ perfused lung and isolated perfused airways suggest a significant contribution of these molecular water channels to measured water permeability. However, further studies are required to determine the role of these water channels in normal pulmonary physiology and disease. Recent studies have provided new insights into the role of the alveolar epithelial barrier in clinical and experimental acute lung injury. Unlike the lung endothelium, the alveolar epithelium is resistant to several clinically relevant types of injury, including endotoxemia and bacteremia as well as aspiration of hyperosmolar solutions. In addition, even when the alveolar barrier has been injured, its capacity to transport edema fluid from the distal air spaces of the lung recovers rapidly. Future studies need to integrate new insights into the molecular mechanisms of alveolar epithelial sodium and water transport with functional studies in the normal and injured lung.

Adult↗
PubMed1996

Transforming growth factor-alpha increases alveolar liquid clearance in anesthetized ventilated rats.

The effect of transforming growth factor-alpha (TGF-alpha) on alveolar liquid clearance was examined in ventilated, anesthetized rats. An isosmolar Ringer lactate solution with 10, 50, or 200 ng/ml TGF-alpha and 125I-labeled albumin as the alveolar protein tracer was instilled into the right lower lung lobe; the rats were studied for 1 and 4 h. Compared with control rats, addition of 50 ng/ml TGF-alpha to the instilled fluid increased alveolar liquid clearance by 47% over 1 h and by 66% over 4 h (P < 0.05). This increase was similar to the 50% increase in alveolar liquid clearance over 1 h in rats instilled with a beta-adrenergic agonist, salmeterol (28). There was a dose-dependent effect of TGF-alpha (10, 50, 200 ng/ml) on alveolar liquid clearance. The combination of both TGF-alpha and salmeterol did not have an additive effect on alveolar liquid clearance. The TGF-alpha-stimulated increase in alveolar liquid clearance was inhibited by amiloride (10(-4) M), indicating that the increase in clearance depended on increased Na+ uptake across the alveolar epithelium. There was only a twofold increase in intracellular cAMP levels in isolated rat alveolar epithelial type II cells after stimulation with TGF-alpha. In contrast, beta-adrenergic agonist treatment increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels more than tenfold. Genistein (10(-6) M), a tyrosine protein kinase inhibitor, inhibited the TGF-alpha-stimulated increase in alveolar liquid clearance. In summary, TGF-alpha can stimulate in vivo alveolar liquid clearance at a rate similar to beta-adrenergic stimulation by increasing Na+ uptake by alveolar epithelial type II cells. However, the effect may be mediated by a non-cAMP dependent mechanism. Because genistein blocked the increase in alveolar fluid clearance, the signal transduction may involve genistein-dependent phosphorylation.

Adrenergic beta-Agonists↗
PubMed1996

Soluble and insoluble fibronectin increases alveolar epithelial wound healing in vitro.

Adhesive interactions between cells and extracellular matrix proteins are important in cell attachment, migration, and proliferation. The present work defines the role of fibronectin (soluble and insoluble) compared with type I and type IV collagen on in vitro alveolar epithelial wound healing. Repeated video microscopy experiments demonstrated that the half-time of wound closure was decreased in the presence of soluble fibronectin (6.6 +/- 2.1 vs. 17.4 +/- 0.8 h in serum-free medium, P < 0.05). Video microscopy, electron microscopy, and vinculin distribution demonstrated the contribution of two main events during the repair process: the migration of epithelial cell sheets and the spreading of the cells. During the wound healing, the internuclear distance between two adjacent cells at the migrating edge of the wound was significantly increased 10 h after wounding in the presence of soluble fibronectin (67 +/- 3.0 vs. 45 +/- 1.5 microns in serum-free medium, P < 0.05), indicating that cell spreading is involved as part of the mechanism for wound closure. Compared with type I and type IV collagen, insoluble fibronectin was the most potent stimulus for alveolar type II cell motility and wound healing in the absence of other serum factors. These results demonstrate that alveolar epithelial wound healing can be modulated in vitro by the composition of the extracellular matrix, an effect that may be mediated by changes in cell shape.

Animals↗
PubMed1996

Alveolar epithelial clearance of protein.

Substantial progress has been made in understanding the rate, the pathways, and the mechanisms regulating alveolar protein removal from the uninjured lung. Whole animal studies and cellular studies have demonstrated that the majority of alveolar epithelial protein clearance occurs by passive nondegradative diffusional pathways. Some evidence, however, has been recently presented that alveolar epithelial cells express an albumin-binding receptor as well as a polymeric immunoglobulin receptor, both of which might be important for alveolar epithelial clearance of protein. However, the contribution of these receptors requires further studies. Little is known about alveolar clearance of protein during pathological conditions; further studies are required to determine the roles of the different cell types in the lung for removal of protein from the alveolar spaces of the lung. Alveolar macrophages are likely to play an important role in the degradation and removal of insoluble protein from the distal air spaces after acute lung injury. In conclusion, the present data suggest that most proteins and peptides deposited on the epithelial surfaces in the distal air spaces are cleared as intact molecules, predominantly via paracellular routes. The contribution of pinocytic processes appear to be of minor importance for translocation of bulk quantities of proteins or peptides across the alveolar epithelium.

Animals↗
PubMed1996

Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe hypothermia.

Although hypothermia abolishes alveolar fluid clearance in the in situ goat lung and in the ex vivo human lung, it is unknown whether alveolar fluid clearance resumes in lungs that are rewarmed after severe hypothermia. An isosmolar albumin solution was instilled into resected human lungs that were rewarmed to 37 degrees C after hypothermia (7 +/- 3 degrees C), and then alveolar fluid clearance was measured by the concentration of albumin in the alveolar fluid sample after 4 h. In control experiments in lungs that had not been cooled and rewarmed, alveolar fluid clearance was 11 +/- 2% over 4 h. In separate experiments, hypothermia completely abolished alveolar fluid clearance. However, alveolar fluid clearance resumed to a normal level of 12 +/- 1% over 4 h in the lungs that were rewarmed after hypothermia. Amiloride decreased alveolar fluid clearance by 47% in the rewarmed lungs. Terbutaline increased alveolar fluid clearance by nearly 300% in 2-h experiments in the rewarmed lungs (P < 0.05). The results of this study indicate that alveolar sodium-channel transport mechanisms are preserved in resected human lungs that are exposed to rewarming after hypothermia.

Aged↗
PubMed1996

Alveolar liquid clearance is increased by endogenous catecholamines in hemorrhagic shock in rats.

The primary objective of this study was to test the hypothesis that hemorrhagic shock would stimulate alveolar liquid clearance by a catecholamine-dependent mechanism. Anesthetized rats were hemorrhaged to a mean arterial pressure of 30 mmHg for 90 min, but they were not resuscitated. Alveolar liquid clearance was measured by the concentration of labeled and unlabeled protein over 2 h in an isosmolar physiological solution of 5% albumin that had been instilled into one lung. Hemorrhaged rats developed a severe metabolic acidosis that was associated with a 5- to 10-fold rise in plasma epinephrine levels. There was a 60% increase in alveolar liquid clearance in the hemorrhaged rats compared with control rats (55 +/- 6 vs. 34 +/- 7%; P < 0.05). Amiloride (10(-4) M) or propranolol (10(-4)M) inhibited the increase in alveolar liquid clearance. Thus the endogenous release of catecholamines associated with hemorrhagic shock markedly stimulates alveolar fluid clearance by a beta-adrenergic-mediated stimulation of active sodium transport. These data suggest a new, previously unrecognized mechanism that may protect against alveolar flooding in the acute phase of hemorrhagic shock.

Amiloride↗
PubMed1996

Sharp increase in rat lung water channel expression in the perinatal period.

Three members of the water channel (aquaporin) family are expressed in adult rat lung: CHIP28 (AQP-1), MIWC (AQP-4), and AQP-5. Because water channels may be important in the clearance of fluid from the newborn lung, the expression of water channels just before and after birth was investigated using the ribonuclease (RNAse) protection assay. RNA was isolated from lungs, brain, and heart of prenatal rats (fetal days F19, F20, and F21) and postnatal rats (days +1, +2, +5, +7, +21, and adult). Transcript expression was measured relative to a beta-actin control by quantitative densitometry. Whereas beta-actin mRNA expression was nearly constant over time, distinct expression patterns were observed for the three water channels. CHIP28 mRNA expression rose slowly from days F19 to +1, then strongly at day +2, and remained elevated over the first week. MIWC mRNA was weakly expressed prenatally, but strongly increased just after birth. AQP-5 mRNA increased slowly and monotonically between days F20 and +7. These patterns contrasted sharply with the developmental expression of CHIP28 in heart, which decreased over time, and MIWC in brain. Immunocytochemistry showed CHIP28 protein expression in capillary endothelia and MIWC in airway epithelia by day +1; quantitative immunoblot analysis showed increased CHIP28 protein expression over time. These findings are consistent with a role of lung water channels in perinatal fluid clearance; however, proof of physiologic significance will require functional measurements of air space-capillary water permeability.

Animals↗
PubMed1996

Pulmonary edema in a woman following fetal surgery.

Most cases of acute lung injury in pregnancy are attributed to hydrostatic pulmonary edema. In this report, however, we describe a 20-year-old pregnant woman who developed a unique case of increased permeability pulmonary edema following surgery for the repair of a fetal congenital diaphragmatic hernia. Two days after surgery, the patient developed acute respiratory failure and diffuse alveolar edema, requiring intubation and positive pressure ventilation for 5 days. The diagnosis of increased permeability pulmonary edema was confirmed by the ratio of pulmonary edema fluid to plasma protein (ratio=0.99). The patient received IV nitroglycerine for tocolysis. As a nitric oxide donor, the nitroglycerine may have combined with exogenous oxygen to form peroxynitrite, a known impediment to alveolar epithelial cell function. Many cases of pulmonary edema in pregnancy are diagnosed as hydrostatic based on clinical parameters, such as positive maternal fluid balance. In this case, these parameters would have been misleading. Measurement of the protein concentration in the pulmonary edema fluid allowed us to accurately determine that the patient had increased permeability pulmonary edema as the cause of her acute respiratory failure. Sampling of pulmonary fluid can differentiate the type of edema formation and in some cases help to identify mechanisms of acute lung injury.

Adult↗
PubMed1995

Death and other complications of emergency airway management in critically ill adults. A prospective investigation of 297 tracheal intubations.

BACKGROUND: Hospitalized patients outside of the operating room frequently require emergency airway management. This study investigates complications of emergency airway management in critically ill adults, including: (1) the incidence of difficult and failed intubation; (2) the frequency of esophageal intubation; (3) the incidence of pneumothorax and pulmonary aspiration; (4) the hemodynamic consequences of emergent intubation, including death, during and immediately following intubation; and (5) the relationship, if any, between the occurrence of complications and supervision of the intubation by an attending physician. METHODS: Data were collected on consecutive tracheal intubations carried out by the intensive care unit team over a 10-month period. Non-anesthesia residents were supervised by anesthesia residents, critical care attending physicians, or anesthesia attending physicians. RESULTS: Two hundred ninety-seven consecutive intubations were carried out in 238 adult patients. Translaryngeal tracheal intubation was accomplished in all patients. Intubation was difficult in 8% of cases (requiring more than two attempts at laryngoscopy by a physician skilled in airway management). Esophageal intubation occurred in 25 (8%) of the attempts but all were recognized before any adverse sequelae resulted. New infiltrates suggestive of pulmonary aspiration were present on chest radiography after 4% of intubations. Seven patients (3%) died during or within 30 min of the procedure. Five of the seven patients had systemic hypotension (systolic blood pressure < or = 90 mmHg), and four of the five were receiving vasopressors to support systolic blood pressure. Patients with systolic hypotension were more likely to die after intubation than were normotensive patients (P < 0.001). There was no relationship between supervision by an attending physician and the occurrence of complications. CONCLUSIONS: In critically ill patients, emergency tracheal intubation is associated with a significant frequency of major complications. In this study, complications were not increased when intubations were accomplished without the supervision of an attending physician as long as the intubation was carried out or supervised by an individual skilled in airway management. Mortality associated with emergent tracheal intubation is highest in patients who are hemodynamically unstable and receiving vasopressor therapy before intubation.

Adult↗
PubMed1995

Frequency and importance of barotrauma in 100 patients with acute lung injury.

OBJECTIVES: To determine the occurrence rate of barotrauma in acute lung injury patients, whether barotrauma is an independent risk factor for mortality, and the role of barotrauma in the outcome of those patients who died. DESIGN: Prospective, cohort study. SETTING: Intensive care units at a university hospital. PATIENTS: Consecutive adult patients (n = 100) meeting the usual criteria for a diagnosis of acute lung injury requiring mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Barotrauma occurred in 13 (13%) of 100 patients. Mortality rates were not different in patients with (76%) and without (64%) barotrauma. Using univariate analysis, barotrauma was not associated with increased mortality (odds ratio 1.85; confidence interval 0.42 to 9.20; p = .53). However, when barotrauma was incorporated into a logistic regression model, along with other potential predictors of mortality, barotrauma was associated with increased mortality (odds ratio 6.15; confidence interval 1.11 to 33.9; p = .017). The presence of nonpulmonary organ dysfunction and sepsis was strongly associated with mortality. In the setting of barotrauma, the mortality rate was 100% if associated with two or more nonpulmonary organ dysfunctions compared with a mortality rate of 40% with one or no nonpulmonary organ failure. Barotrauma contributed directly to the cause of death in only one patient. CONCLUSIONS: Barotrauma occurred in only 13% of patients with acute lung injury. Barotrauma was an independent marker of mortality when adjusted for other predictors of mortality. However, barotrauma directly contributed to < 2% of all deaths. We hypothesize that barotrauma is an indication of severity of acute lung injury rather than a major cause of increased mortality.

Adult↗
PubMed1995

Cellular uptake of albumin from lungs of anesthetized rabbits.

Resolution of alveolar edema depends on clearance of serum protein, as well as liquid from the alveolar space. Protein clearance is slower than liquid clearance and may take days to weeks. Our earlier studies presented evidence for the importance of paracellular removal of soluble protein from the air spaces. However, long-term protein clearance may also depend on uptake by alveolar epithelial cells or macrophages. This study examined cellular uptake of soluble human albumin and insoluble colloidal gold-albumin from the lungs of anesthetized rabbits. Native albumin was endocytosed by both alveolar type I and type II cells and appeared in vesicles and endosomes. Neither cell type took up colloidal gold-albumin over periods as long as 8 h. Alveolar macrophages took up native albumin and colloidal gold-albumin to a greater extent and more rapidly than alveolar epithelial cells. The tracer proteins were found in vesicles, endosomes, and phagolysosomes. Similarly, cultured alveolar macrophages took up native albumin more rapidly than cultured type II cells. Thus macrophages may be important in clearing precipitated protein from the air spaces, and they may have a role in completing the clearance of soluble protein. The potential for transepithelial transport of soluble alveolar protein exists, but based on this work and our prior studies, it appears to be a low-capacity pathway.

Animals↗
PubMed1995

Alveolar endotoxin increases alveolar liquid clearance in rats.

Under some pathological conditions, ion transport across alveolar epithelial cells is downregulated, whereas under other pathological conditions, it may be upregulated. Because endotoxin is a biologically relevant pathological stimulus, we investigated the effect of endotoxin on alveolar epithelial liquid clearance in vivo. Escherichia coli endotoxin (220 micrograms/kg) was instilled into the lungs via the trachea of rats. Then, 24 or 40 h after endotoxin instillation, alveolar and lung liquid clearances were studied over 1 h by instillation of a 5% albumin solution with 1.5 microCi of 125I-labeled albumin (6 ml/kg into both lungs). Alveolar liquid clearance was significantly greater at 24 h (36 +/- 5%) and 40 h (38 +/- 7%) after endotoxin exposure than in saline-instilled controls (27 +/- 6%). Although there was an influx of neutrophils into the air space, there was no increase in lung epithelial permeability to protein at 24 or 40 h. Amiloride (2 x 10(-3) M), a sodium channel inhibitor, significantly reduced alveolar liquid clearance in the rats exposed to endotoxin. However, the increase in alveolar liquid clearance was not inhibited when propranolol (2 x 10(-5) M) was added to the 5% albumin solution. Thus exposure to alveolar endotoxin upregulates net alveolar fluid clearance in vivo for up to 40 h, a potentially important mechanism for accelerating alveolar fluid clearance under some pathological conditions. The increase in alveolar liquid clearance 24 and 40 h after instillation of endotoxin into the air spaces is mediated by an increased uptake of sodium through amiloride-sensitive sodium channels.

Amiloride↗