Edward P. Ingenito

Life-support system benefits from noise

Mechanical ventilators are used to provide life support for patients with respiratory failure. But over the long term, these machines can damage the lungs, causing them to collapse and the partial pressure of oxygen in the arteries to drop to abnormally low values. In conventional mechanical ventilation, the respiratory rate and volume of air inspired per breath are fixed, although during natural breathing these parameters vary appreciably. A computer-controlled ventilator has now been introduced that can use noise to mimic this variability. We describe a conceptual model of lung injury in which the partial pressure of arterial oxygen is improved significantly by computer-controlled rather than conventional mechanical ventilation, in agreement with recent experimental data.

Relation between Preoperative Inspiratory Lung Resistance and the Outcome of Lung-Volume–Reduction Surgery for Emphysema

BACKGROUND Surgery to reduce lung volume has recently been reintroduced to alleviate dyspnea and improve exercise tolerance in selected patients with emphysema. A reliable means of identifying patients who are likely to benefit from this surgery is needed. METHODS We measured lung resistance during inspiration, static recoil pressure at total lung capacity, static lung compliance, expiratory flow rates, and lung volumes in 29 patients with chronic obstructive lung disease before lung-volume-reduction surgery. The changes in the forced expiratory volume in one second (FEV1) six months after surgery were related to the preoperatively determined physiologic measures. A response to surgery was defined as an increase in the FEV1 of at least 0.2 liter and of at least 12 percent above base-line values. RESULTS Of the 29 patients, 23 had some improvement in FEV1 including 15 who met the criteria for a response to surgery. Among the variables considered, only preoperative lung resistance during inspiration predicted changes in expiratory flow rates after surgery. Inspiratory lung resistance correlated significantly and inversely with improvement in FEV1 after surgery (r=-0.63, P<0.001). A preoperative criterion of an inspiratory resistance of 10 cm of water per liter per second had a sensitivity of 88 percent (14 of 16 patients) and a specificity of 92 percent (12 of 13 patients) in identifying patients who were likely to have a response to surgery. CONCLUSIONS Preoperative lung resistance during inspiration appears to be a useful measure for selecting patients with emphysema for lung-volume-reduction surgery.

Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration.

Organ regeneration in mammals is hypothesized to require a functional pool of stem or progenitor cells, but the role of these cells in lung regeneration is unknown. Whereas postnatal regeneration of alveolar tissue has been attributed to type II alveolar epithelial cells (AECII), we reasoned that bronchioalveolar stem cells (BASCs) have the potential to contribute substantially to this process. To test this hypothesis, unilateral pneumonectomy (PNX) was performed on adult female C57/BL6 mice to stimulate compensatory lung regrowth. The density of BASCs and AECII, and morphometric and physiological measurements, were recorded on days 1, 3, 7, 14, 28, and 45 after surgery. Vital capacity was restored by day 7 after PNX. BASC numbers increased by day 3, peaked to 220% of controls (P<0.05) by day 14, and then returned to baseline after active lung regrowth was complete, whereas AECII cell densities increased to 124% of baseline (N/S). Proliferation studies revealed significant BrdU uptake in BASCs and AECII within the first 7 days after PNX. Quantitative analysis using a systems biology model was used to evaluate the potential contribution of BASCs and AECII. The model demonstrated that BASC proliferation and differentiation contributes between 0 and 25% of compensatory alveolar epithelial (type I and II cell) regrowth, demonstrating that regeneration requires a substantial contribution from AECII. The observed cell kinetic profiles can be reconciled using a dual-compartment (BASC and AECII) proliferation model assuming a linear hierarchy of BASCs, AECII, and AECI cells to achieve lung regrowth.

Epithelial cell PPARγ contributes to normal lung maturation

Peroxisome proliferator‐activated receptor (PPAR)‐γ is a member of the nuclear hormone receptor superfamily that can promote cellular differentiation and organ development. PPARγ expression has been reported in a number of pulmonary cell types, including inflammatory, mesenchymal, and epithelial cells. We find that PPARγ is prominently expressed in the airway epithelium in the mouse lung. In an effort to define the physiological role of PPARγ within the lung, we have ablated PPARγ using a novel line of mice capable of specifically targeting the airway epithelium. Airway epithelial cell PPARγ‐targeted mice display enlarged airspaces resulting from insufficient postnatal lung maturation. The increase in airspace size is accompanied by alterations in lung physiology, including increased lung volumes and decreased tissue resistance. Genome‐wide expression profiling reveals a reduction in structural extracellular matrix (ECM) gene expression in conditionally targeted mice, suggesting a disruption in epithelial‐mesenchymal interactions necessary for the establishment of normal lung structure. Expression profiling of airway epithelial cells isolated from conditionally targeted mice indicates PPARγ regulates genes encoding known PPARγ targets, additional lipid metabolism enzymes, and markers of cellular differentiation. These data reveal airway epithelial cell PPARγ is necessary for normal lung structure and function.—Simon, D. M., Arikan, M. C., Srisuma, S., Bhattacharya, S., Tsai, L. W., Ingenito, E. P., Gonzalez, F., Shapiro, S. D., and Mariani, T. J. Epithelial cell PPARγ contributes to normal lung maturation. FASEB J. 20, E710–E720 (2006)

Bronchoscopic Lung Volume Reduction in Severe Emphysema

Lung volume reduction surgery (LVRS) produces physiological, symptomatic, and survival benefits in selected patients with advanced emphysema. Because it is associated with significant morbidity, mortality, and cost, nonsurgical alternatives for achieving volume reduction have been developed. Three bronchoscopic lung volume reduction (BLVR) approaches have shown promise and reached later-stage clinical trials. These include the following: (1) placement of endobronchial one-way valves designed to promote atelectasis by blocking inspiratory flow; (2) formation of airway bypass tracts using a radiofrequency catheter designed to facilitate emptying of damaged lung regions with long expiratory times; and (3) instillation of biological adhesives designed to collapse and remodel hyperinflated lung. The limited clinical data currently available suggest that all three techniques are reasonably safe. However, efficacy signals have been substantially smaller and less durable than those observed after LVRS. Studies to optimize patient selection, refine treatment strategies, characterize procedural safety, elucidate mechanisms of action, and characterize short- and longer-term effectiveness of these approaches are ongoing. Results will be available over the next few years and will determine whether BLVR represents a safe and effective alternative to LVRS.

Technique to determine inspiratory impedance during mechanical ventilation : Implications for flow limited patients

AbstractWe present the design of an enhanced ventilator waveform (EVW) for routine measurement of inspiratory resistance (R) and elastance (E) spectra in ventilator-dependent and/or severely obstructed flow-limited patients. The EVW delivers an inspiratory tidal volume of fresh gas with a flow pattern consisting of multiple sinusoids from 0.156 to 8.1 Hz and permits a patient-driven exhalation to the atmosphere or positive end-expiratory pressure. Weighted least-squares estimates of the coefficients in a sinusoidal series approximation of the EVW inspirations yielded inspiratory R and E spectra. We first validated the EVW approach using simulated pressure and flow data under different physiological conditions, noise levels, and harmonic distortions. We then applied the EVW in four intubated patients during anesthesia and paralysis: two with mild airway obstruction and two with severe emphysema and flow limitation. While the level of inspiratory R was similar in both groups of patients, the inspiratory E of the emphysematous patients demonstrated a pronounced frequency-dependent increase consistent with severe peripheral airway obstruction. We conclude that the EVW offers a potentially practical and efficient approach to monitor lung function in ventilator-dependent patients, especially those with expiratory flow limitation.

No-cut thoracoscopic lung plication: a new technique for lung volume reduction surgery

BACKGROUND Lung volume reduction surgery (LVRS) using a linear cutting stapler or laser ablation via median sternotomy or thoracoscopy is a current therapy for symptomatic emphysema. The primary causes of morbidity and mortality (as high as 20%) are existing comorbidities and prolonged air leaks secondary to visceral pleural division. We report a novel technique using minimally invasive techniques designed to achieve volume reduction while preserving the visceral pleura. A novel lung grasper and a knifeless stapler are used to permanently plicate lung tissue without cutting visceral pleura. STUDY DESIGN This prospective analysis involves a consecutive series of patients who had LVRS using this method. Between May 1995 and September 1996, 32 patients underwent 50 unilateral, staged bilateral, or bilateral thoracoscopic lung plication procedures. The indications for LVRS were standard; they included severe limiting dyspnea (forced expiratory volume in one second [FEV1] = 0.68 +/- 0.05), hyperinflated lungs with flattened diaphragms on chest x-ray, and diffuse emphysema seen on chest computed tomography scan. Ventilation and perfusion scanning was used to identify potential ventilation and perfusion mismatch target areas of lung for plication. RESULTS The right lung was plicated first in 25 of 32 patients (78%), and upper lobe plications predominated (77%). A mean of 9.3 +/- 0.8 staple firings were used for each unilateral plication procedure. There were no perioperative deaths. Two patients (4%) required axillary thoracotomies to repair air leaks. Mean chest tube duration was 6.3 +/- 0.5 days. Median hospital stay was 7 days (range 3-15). An Intensive Care Unit stay was required following 8 procedures (17%). Postoperative morbidity occurred in 18 (39%) of 46 procedures, including 5 cases of atrial fibrillation and 4 persistent (> 7 days) air leaks. A minimum 2 month followup was available for 22 patients (32 of 46 procedures), demonstrating a clear chest x-ray with significant improvement in ipsilateral diaphragmatic contour. Twelve patients had unilateral reduction, and 10 patients had bilateral reduction in either a staged (n = 7) or sequential at one operation (n = 3) fashion. Twenty-five (78%) of 32 procedures were associated with improved pulmonary function, with a mean increase in FEV1, in patients in this subgroup of procedures, of 43 +/- 7% for each ipsilateral plication at a mean followup of 3.8 +/- 0.5 months. For the entire group of 32 procedures, the mean improvement in measured FEV1 was 29 +/- 7%. Supplemental oxygen requirement was significantly reduced in 9 of 16 patients following plication. CONCLUSION These data suggest that minimally invasive surgical techniques coupled with a no-cut lung plication can achieve significant lung volume reduction with favorable postoperative morbidity and mortality. Lung plication appears to hold promise as an alternative technique of LVRS.

Lung-Derived Mesenchymal Stromal Cell Post-Transplantation Survival, Persistence, Paracrine Expression, and Repair of Elastase-Injured Lung

While multipotent mesenchymal stromal cells have been recently isolated from adult lung (L-MSCs), there is very limited data on their biological properties and therapeutic potential in vivo. How L-MSCs compare with bone marrow-derived MSCs (BM-MSCs) is also unclear. In this study, we characterized L-MSC phenotype, clonogenicity, and differentiation potential, and compared L-MSCs to BM-MSCs in vivo survival, retention, paracrine gene expression, and repair or elastase injury after transplantation. L-MSCs were highly clonogenic, frequently expressed aldehyde dehydrogenase activity, and differentiated into osteocytes, chondrocytes, adipocytes, myofibroblasts, and smooth muscle cells. After intravenous injection (2 h), L-MSCs showed greater survival than BM-MSCs; similarly, L-MSCs were significantly more resistant than BM-MSCs to anchorage independent culture (4 h) in vitro. Long after transplantation (4 or 32 days), a significantly higher number of CD45(neg) L-MSCs were retained than BM-MSCs. By flow cytometry, L-MSCs expressed more intercellular adhesion molecule-1 (ICAM-1), platelet derived growth factor receptor alpha (PDGFRα), and integrin α2 than BM-MSCs; these proteins were found to modulate endothelial adherence, directional migration, and migration across Matrigel in L-MSCs. Further, L-MSCs with low ICAM-1 showed poorer lung retention and higher phagocytosis in vivo. Compared with BM-MSCs, L-MSCs expressed higher levels of several transcripts (e.g., Ccl2, Cxcl2, Cxcl10, IL-6, IL-11, Hgf, and Igf2) in vitro, although gene expression in vivo was increased by L-MSCs and BM-MSCs equivalently. Accordingly, both L-MSCs and BM-MSCs reduced elastase injury to the same extent. This study demonstrates that tissue-specific L-MSCs possess mechanisms that enhance their lung retention after intravenous transplantation, and produce substantial healing of elastase injury comparable to BM-MSCs.

Comparison of variable and conventional ventilation in a sheep saline lavage lung injury model.

Objective:There has recently been considerable interest in alternative lung-protective ventilation strategies such as variable ventilation (VV). We aimed at testing VV in a large animal lung injury model and exploring the mechanism of improvement in gas exchange seen with VV. Design:Randomized, controlled comparative ventilation study. Setting:Research laboratory at a veterinary hospital. Subjects:Female sheep weighing 59.8 ± 10.57 kg and excised calf lungs. Interventions:In a sheep saline lavage model of lung injury, we applied VV, whereby tidal volume (VT) and frequency (f) varied on each breath. Sheep were randomized into one of two groups (VV, n = 7; or control, n = 6) and ventilated for 4 hrs with all mean ventilation settings matched. Measurements and Main Results:Gas exchange, lung mechanics, and hemodynamic measures were recorded over the 4 hrs. VV sheep showed improvement in gas exchange (i.e., oxygenation and carbon dioxide elimination) and ventilation pressures (i.e., reduced mean and peak airway pressures) but control sheep did not. VV sheep also displayed lower-lung elastance and mechanical heterogeneity in comparison with control sheep from 2 to 4 hrs of ventilation. To study the mechanism behind improvements seen with VV, we examined the time course associated with the enhanced recruitment occurring during VV in eight saline-lavaged excised calf lungs. We found that the recruitment associated with a larger VT during VV lasted over 200 secs, nearly an order of magnitude greater than the average time interval between large VT deliveries during VV. Conclusions:The application of VV in a large animal model of lung injury results in improved gas exchange and superior lung mechanics in comparison with CV that can be explained at least partially by the long-lasting effects of the recruitments occurring during VV.

Epithelial Cell Apoptosis Causes Acute Lung Injury Masquerading as Emphysema

Theories of emphysema traditionally revolved around proteolytic destruction of extracellular matrix. Models have recently been developed that show airspace enlargement with the induction of pulmonary cell apoptosis. The purpose of this study was to determine the mechanism by which a model of epithelial cell apoptosis caused airspace enlargement. Mice were treated with either intratracheal microcystin (MC) to induce apoptosis, intratracheal porcine pancreatic elastase (PPE), or their respective vehicles. Mice from all groups were inflated and morphometry was measured at various time points. Physiology measurements were performed for airway resistance, tissue elastance, and lung volumes. The groups were further analyzed by air-saline quasistatic measurements, surfactant staining, and surfactant functional studies. Mice treated with MC showed evidence of reversible airspace enlargement. In contrast, PPE-treated mice showed irreversible airspace enlargement. The airspace enlargement in MC-treated mice was associated with an increase in elastic recoil due to an increase in alveolar surface tension. PPE-treated mice showed a loss of lung elastic recoil and normal alveolar surface tension, a pattern more consistent with human emphysema. Airspace enlargement that occurs with the MC model of pulmonary epithelial cell apoptosis displays physiology distinct from human emphysema. Reversibility, restrictive physiology due to changes in surface tension, and alveolar enlargement associated with heterogeneous alveolar collapse are most consistent with a mild acute lung injury. Inflation near total lung capacity gives the appearance of enlarged alveoli as neighboring collapsed alveoli exert tethering forces.