Maria Amigoni

Lung injury and recovery in a murine model of unilateral acid aspiration: functional, biochemical, and morphologic characterization.

Background:Acid aspiration is a complication of general anesthesia. Most animal models developed to define its pathophysiology have focused on the acute (≤24 h) phase of the injury. The authors describe a model of acid aspiration allowing the study of this type of lung injury over time. Methods:The authors instilled hydrochloric acid (0.1 m, 1.5 ml/kg) or normal saline in the right bronchus of mice. Lung injury was evaluated at 6 h, 12 h, 24 h, and 2 weeks by assessing arterial blood gases, respiratory system compliance, lung wet weight normalized by body weight, lung myeloperoxidase activity, and histology. Twelve hours and 2 weeks after injury, a computed tomography scan was obtained. Results:In the hydrochloric acid group, arterial oxygen tension decreased (P < 0.05) at 12 and 24 h, whereas it recovered at 2 weeks; respiratory system compliance was lower both at 24 h and 2 weeks (P < 0.05). Lung weight increased at 12 and 24 h (P < 0.05). Myeloperoxidase activity peaked between 6 and 12 h. Computed tomography at 12 h showed that almost 30% of the injured lung was abnormally aerated. Although reduced, the abnormalities were still present at 2 weeks as confirmed by a fibrotic scar well evident at histologic examination. Conclusion:The authors characterized a murine model of regional acid aspiration allowing long-term survival. Despite a partial recovery, at 2 weeks the injury persisted, with evidence of fibrosis and lung compliance reduction. This long-term, low-mortality model seems suitable for assessment of the effects of different therapies on lung injury and repair.

Simultaneous Measurement of Beat-to-Beat Carotid Diameter and Pressure Changes to Assess Arterial Mechanical Properties

Use of local arterial distensibility measurements by change in carotid artery diameter divided by pulse pressure has limitations because blood pressure is often taken in a vessel distant or at a time different from where and when change in diameter is taken. In 92 subjects (23 to 91 years of age), carotid artery diameter was continuously measured ecographically, whereas blood pressure was continuously measured simultaneously tonometrically on the contralateral artery, the 2 signals being synchronized via 2 EKGs. Within each cardiac cycle, there was a linear relationship between the changes in vessel diameter and the changes in blood pressure during either the protomesosystole or the diastole after the dicrotic notch. The diastolic slope was displaced upward and steeper than the systolic slope, the pressure–diameter loop showing a hysteresis. Both slopes showed a high reproducibility when data were averaged over a several-second period. There were small differences between consecutive cardiac cycles, suggesting that modulation of arterial mechanical response to continuous changes in intravascular pressure may undergo physiological variations. In the 92 subjects, systolic and diastolic slopes correlated significantly with distensibility values obtained by Reneman formula and exhibited a close inverse relationship with each subject’s age and systolic blood pressure, thereby showing the ability to reflect age- and pressure-dependent large artery stiffening. This method may allow precise assessment of man’s arterial mechanical properties within each cardiac cycle. This highly dynamic assessment may help to collect information on properties of normal and altered large elastic arteries and the mechanisms involved in disease.

Increased Arterial Stiffness in Normoglycemic Normotensive Offspring of Type 2 Diabetic Parents

Diabetes is associated with a reduction of arterial distensibility. Limited information exists regarding whether or how early this appears in the course of the disease. We studied 54 normoglycemic, normotensive, healthy offspring of 2 parents with type 2 diabetes mellitus and 55 age- and sex-matched healthy control subjects. Carotid diastolic diameter and systodiastolic change were measured by echo tracking (Wall Track System) and wall thickness by echocolor Doppler (Sonos 5500, Philips). Pulse pressure was measured by a semiautomatic device positioned on the brachial artery and arterial distensibility calculated by Reneman formula. Blood pressure, blood glucose, glycohemoglobin, and insulin sensitivity (homeostasis model assessment index) were normal or only slightly elevated and by and large similar in the 2 groups. Compared with control subjects, offspring of diabetic parents showed similar carotid diameters at diastole and a reduced increase in carotid diameter at systole (−16%), a reduced carotid artery distensibility (−30%), and an increased pulse pressure (+21.8%), all differences being statistically significant (P<0.05) and persisting in subgroups with elevated or normal body mass index values (<25 and ≥25 kg/m2). Carotid artery wall thickness was not different between the 2 groups. Thus, subjects with predisposition to diabetes show carotid artery stiffening even in the absence of blood pressure alterations, as well as substantial alterations of glucose metabolism, body mass index, and changes in carotid wall thickness. This suggests that, in diabetes, alterations in arterial mechanical properties represent an early phenomenon, which may occur in the absence of metabolic and blood pressure alterations.

Low anthracyclines doses-induced cardiotoxicity in acute lymphoblastic leukemia long-term female survivors†

High dosage anthracyclines in pediatric patients with acute lymphoblastic leukemia (ALL) is associated with cardiotoxicity. However, data on the cardiac effects of lower cumulative doses of these drugs are not conclusive. The aim of this study was to assess the cardiac effects of low cumulative anthracycline doses in long‐term survivors of ALL.

Unilateral Acid Aspiration Augments the Effects of Ventilator Lung Injury in the Contralateral Lung

Background:Mechanical ventilation is necessary during acute respiratory distress syndrome, but it promotes lung injury because of the excessive stretch applied to the aerated parenchyma. The authors’ hypothesis was that after a regional lung injury, the noxious effect of mechanical ventilation on the remaining aerated parenchyma would be more pronounced. Methods:Mice, instilled with hydrochloric acid (HCl) in the right lung, was assigned to one of the following groups: mechanical ventilation with tidal volumes (VT) 25 ml/kg (HCl-VILI25, n = 12), or VT 15 ml/kg (HCl-VILI15, n = 9), or spontaneous breathing (HCl-SB, n = 14). Healthy mice were ventilated with VT 25 ml/kg (VILI25, n = 11). Arterial oxygenation, lung compliance, bronchoalveolar lavage inflammatory cells, albumin, and cytokines concentration were measured. Results:After 7 h, oxygenation and lung compliance resulted lower in HCl-VILI25 than in VILI25 (P < 0.05, 210 ± 54 vs. 479 ± 83 mmHg, and 32 ± 3.5 vs. 45 ± 4.1 µl/cm H2O, mean ± SD, respectively). After right lung injury, the left lung of HCl-VILI25 group received a greater fraction of the VT than the VILI25 group, despite an identical global VT. The number of total and polymorphonuclear cells in bronchoalveolar lavage resulted significantly higher in HCl-VILI25, compared with the other groups, in not only the right lung, but also in the left lung. The albumin content in the left lung resulted higher in HCl-VILI25 than in VILI25 (224 ± 85 vs. 33 ± 6 µg/ml; P < 0.05). Cytokines levels did not differ between groups. Conclusion:Aggressive mechanical ventilation aggravates the preexisting lung injury, which is noxious for the contralateral, not previously injured lung, possibly because of a regional redistribution of VT.

Pulmonary surfactant synthesis after unilateral lung injury in mice

Aspiration pneumonitis can lead to alveolar surfactant dysfunction. We employed a murine model of unilateral aspiration to compare surfactant synthesis in the injured (I) and noninjured (NI) contralateral lung. Mice were instilled with hydrochloric acid in the right bronchus and, after 18 h, an intraperitoneal dose of deuterated water was administered as precursor of disaturated phosphatidylcholine (DSPC)-palmitate. Selected bronchoalveolar lavage fluid (BALF) was collected at scheduled time points and lungs were removed. We measured DSPC-palmitate synthesis in lung tissue and secretion in BALF by gas chromatography-isotope ratio mass spectrometry, together with total proteins and myeloperoxidase activity (MPO) by spectrophotometry. BALF total proteins and MPO were significantly increased in the I lungs compared with NI and naïve control lungs. The DSPC pool size was significantly lower in the BALF of the I lungs compared with naïve controls. DSPC synthesis was accelerated in the I and NI lungs. DSPC secretion of the I lungs was similar to their respective naïve controls, and it was markedly lower compared with their respective NI contralateral lungs. DSPC synthesis and secretion were faster, especially in the NI lungs, compared with naïve control lungs, as a possible compensatory mechanism due to a cross-talk between the lungs triggered by inflammation, hyperventilation, and/or undetermined type II cell reaction to the injury.

The effects of exogenous surfactant treatment in a murine model of two-hit lung injury.

BACKGROUND:Because pulmonary endogenous surfactant is altered during acute respiratory distress syndrome, surfactant replacement may improve clinical outcomes. However, trials of surfactant use have had mixed results. We designed this animal model of unilateral (right) lung injury to explore the effect of exogenous surfactant administered to the injured lung on inflammation in the injured and noninjured lung. METHODS:Mice underwent hydrochloric acid instillation (1.5 mL/kg) into the right bronchus and prolonged (7 hours) mechanical ventilation (25 mL/kg). After 3 hours, mice were treated with 1 mL/kg exogenous surfactant (Curosurf®) (surf group) or sterile saline (NaCl 0.9%) (vehicle group) in the injured (right) lung or did not receive any treatment (hydrochloric acid, ventilator-induced lung injury). Gas exchange, lung compliance, and bronchoalveolar inflammation (cells, albumin, and cytokines) were evaluated. After a significant analysis of variance (ANOVA) test, Tukey post hoc test was used for statistical analysis. RESULTS:At least 8 to 10 mice in each group were analyzed for each evaluated variable. Surfactant treatment significantly increased both the arterial oxygen tension to fraction of inspired oxygen ratio and respiratory system static compliance (P = 0.027 and P = 0.007, respectively, for surf group versus vehicle). Surfactant therapy increased indices of inflammation in the acid-injured lung compared with vehicle: inflammatory cells (685 [602–773] and 216 [125–305] × 1000/mL, respectively; P < 0.001) and albumin in bronchoalveolar lavage (BAL) (1442 ± 588 and 743 ± 647 &mgr;g/mL, respectively; P = 0.027). These differences were not found (P = 0.96 and P = 0.54) in the contralateral (uninjured) lung (inflammatory cells 131 [78–195] and 119 [87–149] × 1000/mL and albumin 135 ± 100 and 173 ± 115 &mgr;g/mL). CONCLUSIONS:Exogenous surfactant administration to an acid-injured right lung improved gas exchange and whole respiratory system compliance. However, markers of inflammation increased in the right (injured) lung, although this result was not found in the left (uninjured) lung. These data suggest that the mechanism by which surfactant improves lung function may involve both uninjured and injured alveoli.

Heart Function and Myocardial Tissue Characterization in Patients with HCV Related Cirrhosis: Diastolic Dysfunction and Cardiac Hypertrophy

Evidence of diastolic dysfunction in cirrhosis contributed to the definition of cirrhotic cardiomyopathy. In 109 patients with chronic HCV infection with or without cirrhosis E/A ratio, a Doppler marker of diastolic dysfunction, was decreased in cirrhotics (0.89 ± 0.03 vs controls 1.21 ± 0.07, p < 0.01) and to a lesser extent in patients with advanced liver fibrosis (1.17 ± 0.07, p < 0.01). Left ventricular parietal wall thickness was increased. The nature of this abnormality in human cirrhosis has not been clarified, animal studies reporting cardiac hypertrophy. To this aim we employed the echo- cardiographic integrated backscatter (IBS) technique to obtain an indirect estimate of tissue density (decreased when a higher percentage of muscle fibres is present and increased when fibrosis prevails) to provide myocardial tissue charac- terization in a subset of patients with compensated HCV cirrhosis. The average IBS signal was reduced in cirrhotics at the level of the posterior wall (21.72 ± 1.46 dB versus 30.85 ± 1.40 dB in controls, p < 0.01). Our results confirm diastolic dysfunction in postviral cirrhosis pointing to cardiac hypertrophy as the anatomopathological background in the compen- sated stage of disease.