Improvement of gas exchange, pulmonary function, and lung injury with partial liquid ventilation. A study model in a setting of severe respiratory failure.

STUDY OBJECTIVE: To evaluate gas exchange, pulmonary function, and lung histology during gas ventilation of the perfluorocarbon-filled lung compared with gas ventilation of the gas-filled lung in severe respiratory failure. STUDY DESIGN: Application of gas (GV) or partial liquid (PLV) ventilation in lung-injured sheep. SETTING: A research laboratory at a university medical center. SUBJECTS: Eleven sheep 17.1 +/- 1.8 kg in weight. INTERVENTIONS: Lung injury was induced by intravenous administration of 0.07 mL/kg oleic acid followed by saline pulmonary lavage. When alveolar-arterial oxygen pressure difference (P[A-a]O2) was 600 mm Hg or more and PaO2 was 50 mm Hg or less with fraction of inspired oxygen of 1.0, bijugular venovenous extracorporeal life support (ECLS) was instituted. For the first 30 min on ECLS, all animals were ventilated with gas. Over the ensuing 2.5 h, ventilation with 15 mL/kg gas was continued without intervention in the control group (GV, n = 6) or with the addition of 35 mL/kg of perflubron (PLV, n = 5). MEASUREMENTS AND RESULTS: At 3 h after initiation of ECLS, Qps/Qt was significantly reduced in the PLV animals when compared with the GV animals (PLV = 41 +/- 13%; GV = 93 +/- 4%; p < 0.005). At the same time point, pulmonary compliance was increased in the PLV when compared with the GV group (PLV = 0.61 +/- 0.14 mL/cm H2O/kg; GV = 0.41 +/- 0.02 mL/cm H2O/kg; p < 0.005). The ECLS flow rate required to maintain the PaO2 in the 50 to 80 mm Hg range was substantially and significantly lower in the PLV group when compared with that of the GV group (PLV = 25 +/- 20 mL/kg/min; GV = 87 +/- 15 mL/kg/min; p < 0.001). Light microscopy performed on lung biopsy specimens demonstrated a marked reduction in lung injury in the liquid ventilated (LV) when compared with the GV animals. CONCLUSION: In a model of severe respiratory failure, PLV improves pulmonary gas exchange and pulmonary function and is associated with a reduction in pulmonary pathology.

Calcium regulation of antigen expression on normal and malignant human squamous cells in vitro.

In vitro, normal keratinocytes exhibit undifferentiated morphologic features and proliferate for multiple passages in low-calcium medium (less than or equal to 0.3 mmol/L) whereas, in high-calcium medium (greater than or equal to 1.0 mmol/L), these cells assume differentiation characteristics, begin to stratify, and eventually cease proliferating. In contrast, malignant keratinocytes grow well in high-calcium medium. Expression of pemphigus vulgaris antigen, a squamous cell marker, is altered on cultured normal keratinocytes by calcium. In this study we compared the effects of calcium levels on expression of cell surface antigens by UM-SCC-38, a human squamous carcinoma cell line, and normal keratinocytes cultured from newborn foreskin. Pemphigus, pemphigoid, beta 2-microglobulin antigens, as well as the epidermal growth factor receptor and the A9 germinal epithelial cell basement membrane squamous carcinoma antigen were examined. Pemphigus antigen was strongly expressed on normal and malignant cells in high-calcium but not low-calcium medium. Calcium concentration did not affect the expression of any of the other antigens tested. Thus, although calcium induces differentiation and eventual loss of proliferative capacity in normal but not malignant keratinocytes in vitro, we were unable to demonstrate differences in pemphigus vulgaris antigen expression that might be linked to the growth inhibitory effects induced by high calcium levels in nontransformed epithelial cells in culture.

Lung management with perfluorocarbon liquid ventilation improves pulmonary function and gas exchange during extracorporeal membrane oxygenation (ECMO).

We investigated whether pulmonary function and gas exchange would improve with liquid perfluorocarbon ventilation (LV) during ECMO for severe respiratory failure. Lung injury was induced in 11 young sheep 15.1 +/- 3.7 kg in weight utilizing right atrial injection of 0.07 cc/kg oleic acid followed by saline pulmonary lavage. When (A-a)DO2 > or = 600 mmHg and PaO2 < or = 50 mmHg with FiO2 = 1.0, ECMO was instituted. Animals were then ventilated with either standard ECMO "lung rest" gas ventilator settings (ECMO, n = 5) or with "total" liquid ventilation at standard ventilator device settings (LIQ-ECMO, n = 6) utilizing perflubron (perfluooctyl bromide, Liquivent; Alliance Pharmaceutical Corp.). After 3 hours on ECMO, pulmonary physiologic shunt decreased (ECMO = 88 +/- 11% vs LIQ-ECMO = 31 +/- 1%; p < .001) and pulmonary compliance increased (ECMO = 0.50 +/- 0.06 cc/cmH2O/kg vs. LIQ-ECMO = 1.04 +/- 0.19 cc/cmH2O/kg; p < .001). The ECMO flow rate required to maintain the PaO2 in the 50-80 mmHg range was decreased significantly (ECMO = 116 +/- 14 ml/kg/min vs. LIQ-ECMO = 14 +/- 5 ml/kg/min; p < .001). In this model requiring extracorporeal support for severe respiratory failure, lung management with liquid ventilation improves pulmonary function and gas exchange.

Evaluation of gas exchange, pulmonary compliance, and lung injury during total and partial liquid ventilation in the acute respiratory distress syndrome.

OBJECTIVE: To investigate whether pulmonary compliance and gas exchange will be sustained during "total" perfluorocarbon liquid ventilation followed by "partial" perfluorocarbon liquid ventilation when compared with gas ventilation in the setting of the acute respiratory distress syndrome (ARDS). STUDY DESIGN: A prospective, controlled, laboratory study. SETTING: A university research laboratory. SUBJECTS: Ten sheep, weighing 12.7 to 25.0 kg. INTERVENTIONS: Lung injury was induced in ten young sheep, utilizing a right atrial injection of 0.07 mL/kg of oleic acid followed by saline pulmonary lavage. Bijugular venovenous extracorporeal life support access, a pulmonary artery catheter, and a carotid artery catheter were placed. When the alveolar-arterial O2 gradient was >/= 600 torr and PaO2

Total liquid ventilation with perfluorocarbons increases pulmonary end-expiratory volume and compliance in the setting of lung atelectasis.

OBJECTIVE: To compare compliance and end-expiratory lung volume during reexpansion of normal and surfactant-deficient ex vivo atelectatic lungs with either gas or total liquid ventilation. DESIGN: Controlled, animal study using an ex vivo lung preparation. SETTING: A research laboratory at a university medical center. SUBJECTS: Thirty-six adult cats, weighing 2.5 to 4.0 kg. INTERVENTIONS: Heparin (300 U/kg) was administered, cats were killed, and lungs were excised en bloc. Normal lungs and saline-lavaged, surfactant-deficient lungs were allowed to passively collapse and remain atelectatic for 1 hr. Lungs then were placed in a plethysmograph and ventilated for 2 hrs with standardized volumes of either room air or perfluorocarbon. Static pulmonary compliance and end-expiratory lung volume were measured every 30 mins. MEASUREMENTS AND MAIN RESULTS: Reexpansion of normal atelectatic lungs with total liquid ventilation was associated with an 11-fold increase in end-expiratory lung volume when compared with the increase in end-expiratory lung volume observed with gas ventilation (total liquid ventilation 50 +/- 14 mL, gas ventilation 4 +/- 9 mL, p < .0001). The difference was even more pronounced in the surfactant-deficient lungs with an approximately 19-fold increase in end-expiratory lung volume observed in the total liquid ventilated group, compared with the gas ventilated group (total liquid ventilation 44 +/- 17 mL, gas ventilation 2 +/- 8 mL, p = .0001). Total liquid ventilation was associated with an increase in pulmonary compliance when compared with gas ventilation in both normal and surfactant-deficient lungs (normal: gas ventilation 6 +/- 1 mL/cm H2O, total liquid ventilation 14 +/- 4 mL/cm H2O, p < .0001; surfactant-deficient: gas ventilation 4 +/- 1 mL/cm H2O, total liquid ventilation 9 +/- 3 mL/cm H2O, p < .01). CONCLUSIONS: End-expiratory lung volume and static compliance are increased significantly following attempted reexpansion with total liquid ventilation when compared with gas ventilation in normal and surfactant-deficient, atelectatic lungs. The ability of total liquid ventilation to enhance recruitment of atelectatic lung regions may be an important means by which gas exchange is improved during total liquid ventilation when compared with gas ventilation in the setting of respiratory failure.

Liquid ventilation improves pulmonary function, gas exchange, and lung injury in a model of respiratory failure.

OBJECTIVE: The authors evaluated gas exchange, pulmonary function, and lung histology during perfluorocarbon liquid ventilation (LV) when compared with gas ventilation (GV) in the setting of severe respiratory failure. BACKGROUND: The efficacy of LV in the setting of respiratory failure has been evaluated in premature animals with surfactant deficiency. However, very little work has been performed in evaluating the efficacy of LV in older animal models of the adult respiratory distress syndrome (ARDS). METHODS: A stable model of lung injury was induced in 12 young sheep weighing 16.4 +/- 3.0 kg using right atrial injection of 0.07 mL/kg of oleic acid followed by saline pulmonary lavage and bijugular venovenous extracorporeal life support (ECLS). For the first 30 minutes on ECLS, all animals were ventilated with gas. Animals were then ventilated with either 15 mL/kg gas (GV, n = 6) or perflubron ([PFC], LV, n = 6) over the ensuing 2.5 hours. Subsequently, ECLS was discontinued in five of the GV animals and five of the LV animals, and GV or LV continued for 1 hour or until death. MAIN FINDINGS: Physiologic shunt (Qps/Qt) was significantly reduced in the LV animals when compared with the GV animals (LV = 31 +/- 10%; GV = 93 +/- 4%; p < 0.001) after 3 hours of ECLS. At the same time point, pulmonary compliance (CT) was significantly increased in the LV group when compared with the GV group (LV = 1.04 +/- 0.19 mL/cm H2O/kg; GV = 0.41 +/- 0.02 mL/cm H2O/kg; p < 0.001). In addition, the ECLS flow rate required to maintain the PaO2 in the 50- to 80-mm Hg range was substantially and significantly lower in the LV group when compared with that of the GV group (LV = 14 +/- 5 mL/kg/min; GV = 87 +/- 15 mL/kg/min; p < 0.001). All of the GV animals died after discontinuation of ECLS, whereas all the LV animals demonstrated effective gas exchange without extracorporeal support for 1 hour (p < 0.01). Lung biopsy light microscopy demonstrated a marked reduction in alveolar hemorrhage, lung fluid accumulation, and inflammatory infiltration in the LV group when compared with the GV animals. CONCLUSION: In a model of severe respiratory failure, LV improves pulmonary gas exchange and compliance with an associated reduction in alveolar hemorrhage, edema, and inflammatory infiltrate.

11p deletions and breakpoints in squamous cell carcinoma: association with altered reactivity with the UM-E7 antibody.

The UM-E7 monoclonal antibody raised against the UM-SCC-I human squamous cell carcinoma (SCC) cell line identifies a cell surface antigen that is strongly expressed in normal tissues. The locus (MICI) controlling the expression of E7 and related cell surface antigens has been mapped to chromosome band 11p13. This band has been identified as a region of cancer-associated aberrations and as the probable locus of a tumor suppressor gene. Although E7 antigen expression is strong in normal keratinocytes, it varies among squamous carcinoma cell lines. Some SCC lines (12/26) exhibit weak expression of the E7 antigen, whereas other SCC cell lines (14/26) and 21 cell lines from other tumor types express the antigen strongly. On the basis of these observations and of mapping data, we postulated that low E7 antigen expression in a subset of SCC cell lines might be associated with chromosomal rearrangement or deletion involving the E7 locus on 11p. Fully evaluable karyotypes were prepared from 19 SCC cell lines, including 11 with weak and eight with strong E7 expression. Eight of the 11 lines with weak E7 expression had 11p abnormalities. Four of these contained 11p deletions, and four others had a breakpoint in 11p. In contrast, none of the cell lines in the group with strong E7 expression had an 11p deletion, although one had a rearrangement with an 11p breakpoint. In the four tumors with visible 11p deletions, the smallest region of overlap corresponded to the 11p13-p14 region. The mean log10 50% endpoint E7 titer in the group with 11p deletions or breakpoints was nearly two orders of magnitude lower than that of the lines with no 11p abnormality (1.95 +/- 0.53) (P less than 0.02). Our results indicate that the UM-E7 antibody identifies tumors with 11p13-p14 deletions and other 11p rearrangements and that the 11p region is a site of nonrandom chromosome rearrangement in a subset of human squamous cancers. The strong association of loss of antigen expression with visible 11p deletion or rearrangement in some tumors suggests that other tumors with this phenotype may contain submicroscopic lesions of 11p13-p14.