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Biomedical subjects

Edward P Ingenito

Publications and source records attributed to Edward P Ingenito.

16 recordsLinked to original sources
PubMed2004

Mechanics, nonlinearity, and failure strength of lung tissue in a mouse model of emphysema: possible role of collagen remodeling.

Enlargement of the respiratory air spaces is associated with the breakdown and reorganization of the connective tissue fiber network during the development of pulmonary emphysema. In this study, a mouse (C57BL/6) model of emphysema was developed by direct instillation of 1.2 IU of porcine pancreatic elastase (PPE) and compared with control mice treated with saline. The PPE treatment caused 95% alveolar enlargement (P = 0.001) associated with a 29% lower elastance along the quasi-static pressure-volume curves (P < 0.001). Respiratory mechanics were measured at several positive end-expiratory pressures in the closed-chest condition. The dynamic tissue elastance was 19% lower (P < 0.001), hysteresivity was 9% higher (P < 0.05), and harmonic distortion, a measure of collagen-related dynamic nonlinearity, was 33% higher in the PPE-treated group (P < 0.001). Whole lung hydroxyproline content, which represents the total collagen content, was 48% higher (P < 0.01), and alpha-elastin content was 13% lower (P = 0.16) in the PPE-treated group. There was no significant difference in airway resistance (P = 0.7). The failure stress at which isolated parenchymal tissues break during stretching was 40% lower in the PPE-treated mice (P = 0.002). These findings suggest that, after elastolytic injury, abnormal collagen remodeling may play a significant role in all aspects of lung functional changes and mechanical forces, leading to progressive emphysema.

Animals↗
PubMed2004

Mechanical interactions between collagen and proteoglycans: implications for the stability of lung tissue.

Collagen and elastin are thought to dominate the elasticity of the connective tissue including lung parenchyma. The glycosaminoglycans on the proteoglycans may also play a role because osmolarity of interstitial fluid can alter the repulsive forces on the negatively charged glycosaminoglycans, allowing them to collapse or inflate, which can affect the stretching and folding pattern of the fibers. Hence, we hypothesized that the elasticity of lung tissue arises primarily from 1) the topology of the collagen-elastin network and 2) the mechanical interaction between proteoglycans and fibers. We measured the quasi-static, uniaxial stress-strain curves of lung tissue sheets in hypotonic, normal, and hypertonic solutions. We found that the stress-strain curve was sensitive to osmolarity, but this sensitivity decreased after proteoglycan digestion. Images of immunofluorescently labeled collagen networks showed that the fibers follow the alveolar walls that form a hexagonal-like structure. Despite the large heterogeneity, the aspect ratio of the hexagons at 30% uniaxial strain increased linearly with osmolarity. We developed a two-dimensional hexagonal network model of the alveolar structure incorporating the mechanical properties of the collagen-elastin fibers and their interaction with proteoglycans. The model accounted for the stress-strain curves observed under all experimental conditions. The model also predicted how aspect ratio changed with osmolarity and strain, which allowed us to estimate the Young's modulus of a single alveolar wall and a collagen fiber. We therefore identify a novel and important role for the proteoglycans: they stabilize the collagen-elastin network of connective tissues and contribute to lung elasticity and alveolar stability at low to medium lung volumes.

Animals↗
PubMed2004

Nitric oxide synthase-2 down-regulates surfactant protein-B expression and enhances endotoxin-induced lung injury in mice.

Acute respiratory distress syndrome (ARDS) is a life-threatening ailment characterized by severe lung injury involving inflammatory cell recruitment to the lung, cytokine production, surfactant dysfunction, and up-regulation of nitric oxide synthase 2 (NOS2) resulting in nitric oxide (NO) production. We hypothesized that NO production from NOS2 expressed in lung parenchymal cells in a murine model of ARDS would correlate with abnormal surfactant function and reduced surfactant protein-B (SP-B) expression. Pulmonary responses to nebulized endotoxin (lipopolysaccharide, LPS) were evaluated in wild-type (WT) mice, NOS2 null (-/-) mice, and NOS2-chimeric animals derived from bone marrow transplantation. NOS2-/- animals exhibited significantly less physiologic lung dysfunction and loss of SP-B expression than did WT animals. However, lung neutrophil recruitment and bronchoalveolar lavage cytokine levels did not significantly differ between NOS2-/- and WT animals. Chimeric animals for NOS2 exhibited the phenotype of the recipient and therefore demonstrated that parenchymal production of NOS2 is critical for the development of LPS-induced lung injury. Furthermore, administration of NO donors, independent of cytokine stimulation, decreased SP-B promoter activity and mRNA expression in mouse lung epithelial cells. This study demonstrates that expression of NOS2 in lung epithelial cells is critical for the development of lung injury and mediates surfactant dysfunction independent of NOS2 inflammatory cell expression and cytokine production.

Aerosols↗
PubMed2004

Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma.

PURPOSE: Computed tomography studies demonstrate thickening of the asthmatic airway wall and its relation to disease severity. We evaluated the effect of inhaled corticosteroid on this phenomenon. METHODS: Cross-sectional images of the right upper lobe apical segmental bronchus were obtained by helical computed tomography in 45 corticosteroid-naïve patients with persistent asthma and 28 healthy controls. Airway wall thickness was measured as airway wall area normalized to body surface area. Computed tomography, pulmonary function, and serum levels of eosinophil cationic protein were examined before and after treatment with beclomethasone (800 microg/d for 12 weeks). RESULTS: Before treatment, airway wall thickness was greater in asthma patients than in controls (P <0.0001). After treatment, it decreased by 11% (P <0.001) but remained high (P <0.0001 vs. control); the serum level of eosinophil cationic protein decreased, and airflow obstruction was reduced, but not to the level in controls. The decrease in wall thickness was associated with a decrease in the serum level of eosinophil cationic protein (r = 0.39, P = 0.009) and an increase in the forced expiratory volume in 1 second (r = 0.45, P = 0.003) and was inversely related to disease duration at entry (r = -0.38, P = 0.009). Post-treatment wall thickness was related to disease duration (r = 0.45, P = 0.003) and remaining airflow obstruction. CONCLUSION: Wall thickening of asthmatic central airways responds partially to inhaled corticosteroid therapy and may reflect an overall reduction in airway inflammation. "Unresponsive components," possibly involving structural changes, may increase in the absence of inhaled corticosteroid treatment, potentially leading to chronic airflow obstruction.

Administration, Inhalation↗
PubMed2004

Tissue heterogeneity in the mouse lung: effects of elastase treatment.

We developed a network model in an attempt to characterize heterogeneity of tissue elasticity of the lung. The model includes a parallel set of pathways, each consisting of an airway resistance, an airway inertance, and a tissue element connected in series. The airway resistance, airway inertance, and the hysteresivity of the tissue elements were the same in each pathway, whereas the tissue elastance (H) followed a hyperbolic distribution between a minimum and maximum. To test the model, we measured the input impedance of the respiratory system of ventilated normal and emphysematous C57BL/6 mice in closed chest condition at four levels of positive end-expiratory pressures. Mild emphysema was developed by nebulized porcine pancreatic elastase (PPE) (30 IU/day x 6 days). Respiratory mechanics were studied 3 wk following the initial treatment. The model significantly improved the fitting error compared with a single-compartment model. The PPE treatment was associated with an increase in mean alveolar diameter and a decrease in minimum, maximum, and mean H. The coefficient of variation of H was significantly larger in emphysema (40%) than that in control (32%). These results indicate that PPE treatment resulted in increased time-constant inequalities associated with a wider distribution of H. The heterogeneity of alveolar size (diameters and area) was also larger in emphysema, suggesting that the model-based tissue elastance heterogeneity may reflect the underlying heterogeneity of the alveolar structure.

Airway Resistance↗
PubMed2004

Relating maximum airway dilation and subsequent reconstriction to reactivity in human lungs.

Measures of airway resistance (Raw) during deep inspiration (DI) suggest that asthmatic subjects possess stiffer, more reactive airway smooth muscle. There is evidence that one can enhance airway reactivity in healthy lungs by prohibiting DI for an extended period. The present study had two goals. First, we determined whether the maximum dilation capacity of asthmatic subjects depended on the rate of the DI. Second, we investigated whether the enhanced reactivity in healthy humans might derive from additional mechanisms not present in asthmatic subjects. For the first goal, we tracked Raw in seven healthy and seven asthmatic subjects during a noncoached DI, a DI with a 5- to 10-s breath hold at total lung capacity, and a rapid DI. We found that the minimum resistance achieved at total lung capacity was independent of the manner in which the DI was performed. For the second goal, we tracked the rate of return of Raw after a DI as well as dynamic lung elastance before and after the DI, at baseline and after bronchial challenge. A drop in lung elastance post-DI would indicate reopening of lung regions and/or reduced heterogeneities. The data show that constricted healthy but not asthmatic subjects produce longer lasting residual dilation. Hence, a portion of the enhanced reactivity in a healthy subject's response to prohibition of DIs is likely due to airway closure and/or atelectasis that can be ablated with a DI. We conclude that preventing DIs does not ensure that healthy subjects will transition entirely to an asthmatic-like hyperreactive lung state.

Adult↗
PubMed2004

Evaluation of head-out constant volume body plethysmography for measurement of specific airway resistance in conscious, sedated sheep.

OBJECTIVE: To evaluate the use of a modified whole body plethysmograph in awake sheep. ANIMALS: 10 healthy adult sheep. PROCEDURE: Concurrent measurements of specific airway resistance (sR(aw)) and pulmonary resistance (R(L)) were obtained using a novel noninvasive head-out constant-volume plethysmograph and esophageal balloon-pneumotachography, respectively. All data were collected before and after external resistive loading with 1 and 5.6 cm H2O/L/s. Functional residual capacity (FRC) was measured by helium dilution for computation of airway resistance (R(aw)) preloading (R(aw) = sR(aw)/FRC). RESULTS: The sR(aw) and R(L) were closely correlated in 10 adult sheep. Additionally, sR(aw), and R(L) accurately reflected the magnitude of added resistance. The mean FRC was 52 mL/kg and used to calculate R(aw). At baseline, the values for R(aw) were significantly correlated with sR(aw) and R(L). CONCLUSIONS AND CLINICAL RELEVANCE: Precise measurements of sR(aw) and R(aw) at baseline and sR(aw) after external resistive loading were obtained by use of this novel noninvasive plethysmographic technology. This method should have application to veterinary patients or animals used in research in which noninvasive rapid or serial measurements of sR(aw) in the conscious state are required.

Airway Resistance↗
PubMed2003

Lung and alveolar wall elastic and hysteretic behavior in rats: effects of in vivo elastase treatment.

We investigated the relationship between the microscopic elastic and hysteretic behavior of the alveolar walls and the macroscopic mechanical properties of the whole lung in an in vivo elastase-treated rat model of emphysema. We measured the input impedance of isolated lungs at three levels of transpulmonary pressure (Ptp) and used a linear model to estimate the dynamic elastance and hysteresivity of the lungs. The elastance of the normal lungs increased steeply with Ptp, whereas this dependence diminished in the treated lungs. Hysteresivity decreased significantly with Ptp in the normal lungs, but this dependence disappeared in the treated lungs. To investigate the microscopic origins of these changes, the alveolar walls were immunofluorescently labeled in small tissue strips. By using a fluorescent microscope, the lengths and angular orientations of individual alveolar walls were followed during cyclic uniaxial stretching of the tissue strips. The microstrains (relative change in segment length) and changes in angle of the alveolar walls showed considerable heterogeneity, which was interpreted in terms of a network model. In the normal strips, the alveolar walls showed larger angular changes compared with the treated tissue, whereas the alveolar walls of the treated tissue tended to be more extensible. Hysteresis in the average angle change was also larger in the treated tissue than in the normal tissue. We conclude that the decreased Ptp dependence of elastance and the constant hysteresivity in the treated lungs are related to microstructural remodeling and network phenomena at the level of the alveolar walls.

Animals↗
PubMed2003

Variable ventilation induces endogenous surfactant release in normal guinea pigs.

Variable or noisy ventilation, which includes random breath-to-breath variations in tidal volume (Vt) and frequency, has been shown to consistently improve blood oxygenation during mechanical ventilation in various models of acute lung injury. To further understand the effects of variable ventilation on lung physiology and biology, we mechanically ventilated 11 normal guinea pigs for 3 h using constant-Vt ventilation (n = 6) or variable ventilation (n = 5). After 3 h of ventilation, each animal underwent whole lung lavage for determination of alveolar surfactant content and composition, while protein content was assayed as a possible marker of injury. Another group of animals underwent whole lung lavage in the absence of mechanical ventilation to serve as an unventilated control group (n = 5). Although lung mechanics did not vary significantly between groups, we found that variable ventilation improved oxygenation, increased surfactant levels nearly twofold, and attenuated alveolar protein content compared with animals ventilated with constant Vt. These data demonstrate that random variations in Vt promote endogenous release of biochemically intact surfactant, which improves alveolar stability, apparently reducing lung injury.

Animals↗
PubMed2002

Bronchoscopic lung volume reduction using tissue engineering principles.

Bronchoscopic lung volume reduction (BLVR), a minimally invasive procedure based on tissue engineering principles, was performed in six sheep with papain-induced experimental emphysema (EMPH). Physiologic measurements, at baseline, after generation of EMPH, and at 3 and 9 weeks after BLVR, included lung volumes, diffusing capacity (DL(CO)), pressure-volume relationships for the lung and chest wall, pleural pressures generated during active respiratory muscle contraction, lung resistance and dynamic elastance. The animal model displayed hyperinflation (change in total lung capacity +8%; change in residual volume +66%), reduced DL(CO) (-21%), and elevated airway resistance (+76%) that resembled advanced human EMPH. BLVR was well tolerated without complications, and it reduced lung volumes (change in total lung capacity -16%; change in residual volume -55%) in a pattern that resulted in significant improvements in vital capacity (10%). At autopsy, well-organized, peripheral scars associated with tissue contraction were observed at 33 of the 36 (91%) treated sites. There was no evidence of infection, abscess, or granuloma formation, or allergic reaction. Scar tissue, generated by BLVR, replaced hyperinflated lung, reduced overall lung volume, and improved respiratory function safely and consistently. The BLVR technology employed in this study addresses the limitations identified in our prior attempt at BLVR therapy and appears safe and effective enough to justify a trial in humans.

Airway Resistance↗
PubMed2002

Physiological characterization of variability in response to lung volume reduction surgery.

This paper examines potential physiological mechanisms responsible for improvement after lung volume reduction surgery (LVRS). In 25 patients (63 +/- 9 yr; 11 men, 14 women), spirometry [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], lung volumes [residual volume (RV) and total lung capacity (TLC)], small airway resistance, recoil pressures, and respiratory muscle contractility (RMC) were measured before and 4-6 mo after LVRS. Data were interpreted to assess how changes in each component of lung mechanics affect overall function. Among responders (DeltaFEV(1) > or = 12%; 150 ml), improvement was primarily due to an increase in FVC, not to FEV(1)-to-FVC ratio. Among nonresponders, FEV(1), FVC, and RV/TLC did not change after surgery, although recoil pressure increased in both groups. Both groups experienced a reduction in RMC after LVRS. In conclusion, LVRS improves function in emphysema by resizing the lung relative to the chest wall by reducing RV. LVRS does not change airway resistance but decreases RMC, which attenuates the potential benefits of LVRS that are generated by reducing RV/TLC. Among nonresponders, recoil pressure increased out of proportion to reduced volume, such that no increase in vital capacity or improvement in FEV(1) occurred.

Adult↗
PubMed2002

Variable tidal volume ventilation improves lung mechanics and gas exchange in a rodent model of acute lung injury.

Random variations in breath rate and tidal volume during mechanical ventilation in the setting of acute lung injury have been shown to improve arterial oxygen tension. To test whether this improvement occurs over a specific range of variability, we examined several ventilation protocols in guinea pigs with endotoxin-induced lung injury. In Group I (n = 10), after 30 min of conventional volume-cycled ventilation, animals were ventilated with variable ventilation for 30-min intervals, during which time tidal volume was randomly varied by 10, 20, 40, and 60% of the mean, while simultaneously adjusting the frequency to maintain constant minute ventilation. In a second group of animals (Group II, n = 4), conventional volume-cycled ventilation was administered for 3 h. Variable ventilation significantly improved lung function over conventional volume-cycled ventilation. In Group I, lung elastance decreased, and blood oxygenation increased significantly during periods of 40 and 60% variable ventilation (p < 0.05) compared with conventional ventilation. These data indicate that variable ventilation is effective in improving lung function and gas exchange during acute lung injury.

Animals↗
PubMed2002

Effects of simultaneous exposure of surfactant to serum proteins and free radicals.

Free radicals (FRs) and serum proteins have both been implicated in the pathophysiology of surfactant dysfunction during acute lung injury (ALI). This study examines how these 2 distinct mechanisms interact to contribute to altered surfactant function in this setting. Calf lung surfactant (2 mg/mL) was incubated with no additives (C = control), and with low = (LD = 125 microM FeCl2; 250 microM H2O2) and high-dose (HD = 250 microM FeCl2, 500 microM H2O2) Fenton reaction reagents to generate hydroxyl radical. Each condition was studied with (1) no protein (N); and with 25%, 200%, and 800% (weight protein/weight phospholipid) protein added as (2) bovine albumin, (3) bovine fibrinogen, (4) hemoglobin, or (5) calf serum. Lipid (LFR) and protein (PFR) free-radical products, and modifications in the tertiary structure of Surfactant Protein A (SPA) on Western blot, were observed in N LD and N HD samples. Added proteins reduced LFR and PFR changes as well as SPA structural changes. Protection was greatest for fibrinogen, hemoglobin, and serum, and least for albumin. Minimal to no dysfunction, assayed by pulsating surfactometry, was observed in all samples. These findings indicate that addition of serum proteins to surfactant at 2 mg/mL protects against, rather than promotes, FR-mediated chemical changes in surfactant lipid and protein constituents.

Animals↗
PubMed2002

Lung volume reduction surgery for emphysema: correlation of CT and V/Q imaging with physiologic mechanisms of improvement in lung function.

PURPOSE: To compare the relationship between computer-derived and visually assessed ventilation-perfusion (V/Q) scintigraphy and computed tomographic (CT) scores in evaluating disease severity and distribution in identifying optimal candidates for lung volume reduction surgery (LVRS) and to correlate these radiologic indices with physiologic measures of outcome. MATERIALS AND METHODS: In 39 patients, preoperative V/Q and CT scans were visually scored by two radiologists for disease severity and distribution. Results were compared with computer-derived scores for the same cohort. These indices were correlated with clinical improvement measured with forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), and ratio of FEV(1) to FVC. RESULTS: The disease distribution scores measured with the different methods correlated closely: computer-based and visually assessed CT scores (r = 0.89, P <.001), computer-based and visually assessed V/Q scores (r = 0.83, P <.001), visually assessed CT and V/Q scores (r = -0.50, P <.001), and computer-derived CT and V/Q scores (r = -0.57, P =.015). Similarly, a statistically significant correlation was noted between each of the radiologic methods and clinical outcome measurements (P <.001). CONCLUSION: CT and V/Q preoperative assessment, with either visual scoring or computer-based algorithms, are nearly equivalent in their utility in predicting improvement in FEV(1) measures.

Emphysema↗
PubMed2002

Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury.

Capillary leakage and alveolar edema are hallmarks of acute lung injury (ALI). Neutrophils and serum macromolecules enter alveoli, promoting inflammation. Vascular endothelial growth factor (VEGF) causes plasma leakage in extrapulmonary vessels. Angiopoietin (Ang)-1 and -4 stabilize vessels, attenuating capillary leakage. We hypothesized that VEGF and Ang-1 and -4 modulate vessel leakage in the lung, contributing to the pathogenesis of ALI. We examined a murine model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 and 129/J mice were studied at baseline and 24, 48, and 96 h after single or multiple doses of aerosolized LPS. Both strains exhibited time- and dose-dependent increases in inflammation and a deterioration of lung mechanics. Bronchoalveolar lavage (BAL) protein levels increased significantly, suggesting capillary leakage. Increased BAL neutrophil and total protein content correlated with time-dependent increased tissue VEGF and decreased Ang-1 and -4 levels, with peak VEGF and minimum Ang-1 and -4 expression after 96 h of LPS challenge. These data suggest that changes in the balance between VEGF and Ang-1 and -4 after LPS exposure may modulate neutrophil influx, protein leakage, and alveolar flooding during early ALI.

Acute Disease↗