RESPIRATORY MECHANICS AND SURFACTANT IN THE ACUTE RESPIRATORY DISTRESS SYNDROME

1. Although abnormalities in pulmonary surfactant were initially implicated in the pathogenesis of the acute respiratory distress syndrome (AROS) 30 years ago, most subsequent research has focused on mediators of the parenchymal acute lung injury (ALI) and the associated increase in alveolocapillary permeability . 2. Surfactant is essential for normal breathing and the severity of ALI correlates with surfactant dysfunction and abnormalities in surfactant composition; however, no relationship has been shown with respiratory system compliance. In neonates and most animal models, respiratory system compliance will directly reflect the elastic properties of the lung. However, the greater vertical height of the chest wall in adults, in combination with the increase in lung density due to ALI, results in dependent collapse of alveoli. Because simple, global measurement of compliance is strongly influenced by the volume of aerated lung, alternative measures of respiratory mechanics may reflect surfactant dysfunction . 3. Using a dynamic, volume-dependent model of respiratory mechanics to indirectly reflect this heterogeneous inflation, we have found direct relationships with surfactant composition in patients with ARDS. A failure of surfactant to increase surface tension in large alveoli may also explain why lung overdistension occurs at relatively low pressures. Furthermore, surfactant dysfunction will exaggerate heterogeneous lung inflation, augmenting regional overinflation, and is essential for ALI secondary to repetitive opening and closing of alveoli during tidal ventilation . 4. Ventilation-induced ALI has also been shown to result in massive increases in pro-inflammatory cytokines within the lung. Because ALI itself fails to compartmentalize cytokines, with spillover into the systemic circulation resulting in distant organ dysfunction, surfactant dysfunction may have widespread implications .     

Adriamycin-induced glomerulosclerosis in the rat

To evaluate long-term effect of sustained proteinuria induced by a single injection of adriamycin (ADR) on occurrence of focal segmental glomerulosclerosis (FSG), we treated 50 Sprague-Dawley (SD) rats, weighing 250 g with 5 mg/kg body weight of ADR. After six months of heavy proteinuria, 40% of ADR-treated rats did not develop FSG. In the remaining 60% of animals, a mild FSG was observed associated with the presence of large tubular casts and interstitial inflammation. Glomerulosclerosis was never observed in absence of tubulointerstitial lesions. Nine months after ADR, all rats exhibited FSG with renal insufficiency but the severest changes were restricted to the tubulointerstitial level. Our results indicate that chronic proteinuria induced by ADR is a relatively good model of glomerular sclerosis, however, the cause of glomerular sclerosis is probably different from that operating in other experimental models of FSG. Both sclerotic changes and progression of disease seem to be dependent on formation of tubular casts with consequent interstitial changes. This study raises the question of the relative role of tubulointerstitial changes in the subsequent development of FSG.     

Benznidazole-induced ultrastructural and biochemical alterations in rat esophagus

Benznidazole (Bz) is a drug used in the chemotherapy of the acute and intermediate phases of Chagas' disease (American Trypanosomiasis), an endemic parasitic disease afflicting more than 16 million people in Latin America. Serious toxic side effects of Bz have been reported in treated human beings and in experimental animals. Bz toxicity would be linked to its nitroreductive bioactivation to reactive intermediates and to the corresponding amine known to occur in vivo and mediated by different enzymatic systems. In the present study the presence of Bz nitroreductases in rat esophagus and the occurrence of Bz induced esophageal cell injury are described. Already 1 and 3 h after an intragastric Bz administration to Sprague-Dawley male rats (240-260 g body weight) at a dose of 100 mg/kg esophageal levels of the drug were 66.4+/-4.0 and 149.2+/-14.3 nmol per g tissue, respectively. The esophageal mucosa homogenates exhibited Bz nitroreductase activity attributable to the participation of cytochrome P450 reductase and xanthine oxidoreductase (XOR). The ultrastructural observation of esophageal tissue from Bz treated animals 24 h after its administration evidenced: detachment and conglomeration of polyribosomes, reduction in the presence of desmosomes and of the amount of bacteria on its surface. The potential significance of these alterations is not fully clear at present. However, these deleterious effects might be additive or synergistic with those induced by the evolution of the disease.     

Effect of dietary proteins and lipids in patients with membranous nephropathy and nephrotic syndrome

Twenty-four patients with idiopathic membranous nephropathy, long-lasting nephrotic syndrome and serum creatinine less than 2 mg/dl ate sequentially, in a randomized cross-over design, a normal protein diet containing 1.1 +/- 0.3 g/kg/day of proteins and a low protein diet containing 0.7 +/- 0.1 g/kg/day of protein, each diet for a period of 3 months. Both diets were low in fat (less than 30% of total calories) and cholesterol (less than 200 mg/day) content and rich in polyunsaturated fatty acids and in linoleic acid (10% of energy). Random assignment to one of the two 3 month diet periods was done after a RUN-IN period of at least one month on the hypolipidic normal protein diet. Glomerular filtration rate (inulin clearance), 24 hour urinary protein loss and serum albumin concentration did not significantly differ at the end of the two diet periods, indicating that long-term restriction of protein intake does not modify GFR or urinary protein loss in nephrotic patients. Serum total and LDL-cholesterol and daily proteinuria were significantly lower at the end of both diet periods than at the beginning and at the end of the RUN-IN period. We suggest that these changes were a consequence of the manipulation of dietary fat intake.     

Low-dose flying spot digital radiography of the chest: sensitivity studies

Standard film examinations of the chest were compared with low-dose flying spot digital radiographic examinations obtained with a prototype unit in 174 patients. Analysis of pooled data from a double-blind study of 120 patients showed that film was more sensitive than digital images in the detection of pulmonary parenchymal abnormalities, that is, abnormal opacities, atelectasis, scar, and interstitial lung disease (P less than .05). Analysis of pooled data from a side-by-side study of 54 patients showed that the digital images were more sensitive than film in the detection of normal mediastinal and pleural soft-tissue contours, including the azygoesophageal recess, paraspinal line, and vertebral disk spaces (P less than .05). However, film was more sensitive than digital images in the detection of abnormalities of the lung, including scar, interstitial lung disease, septal lines, and the presence of vascular catheters (P less than .05). These findings suggest that low-dose flying spot digital radiography of the chest, as performed with this specific prototype unit, is not adequate to replace film in the detection of abnormalities of the lung parenchyma.     

Antioxidative stress therapy with dithiothreitol tetraacetate I. Protection against carbon tetrachloride induced liver necrosis

Dithiothreitol (DTT) is kown to prevent or even reverse several deleterious effects of radiation or of chemical agents operating via free radical and oxidative stress. However, its use has been hampered by its chemical instability and toxic properties. In this work, we synthesized and characterized dithiothreitol tetraacetate (DTT-Ac) which is less toxic and chemically stable, and we provided GLC/MS evidence that it is able to rapidly generate fully deacetylated DTT in liver after its administration to rats. Treatment with DTT-Ac simultaneously with CCl₄ or 3 h after the hepatotoxin was able to significantly prevent the CCl₄-induced liver necrosis at 24 h after poisoning. DTT-Ac administration was able to significantly reduce the intensity of the covalent binding of CCl₄ reactive metabolites to microsomal lipids (CB), but it did not prevent the CCl₄-induced initiation of a lipid peroxidation (LP) process as evidenced by diene hyperconjugation of microsomal lipids.Results suggest that DTT-Ac protective effects might be due to its in vivo conversion to DTT which in turn would decrease the intensity of CB via different potential mechanisms to be explored. Protection cannot be attributed to decreases in levels of CC₄ reaching the liver or to chain breaking effects on LP.     

Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma

The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45- CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).