Elastin degradation products in acute lung injury induced by gastric contents aspiration.

BACKGROUND: Gastric contents aspiration is a high-risk condition for acute lung injury (ALI). Consequences range from subclinical pneumonitis to respiratory failure, depending on the volume of aspirate. A large increment in inflammatory cells, an important source of elastase, potentially capable of damaging lung tissue, has been described in experimental models of aspiration. We hypothesized that in early stages of aspiration-induced ALI, there is proteolytic degradation of elastin, preceding collagen deposition. Our aim was to evaluate whether after a single orotracheal instillation of gastric fluid, there is evidence of elastin degradation. METHODS: Anesthesized Sprague-Dawley rats received a single orotracheal instillation of gastric fluid and were euthanized 4, 12 and 24 h and at day 4 after instillation (n = 6/group). We used immunodetection of soluble elastin in lung tissue and BALF and correlated BALF levels of elastin degradation products with markers of ALI. We investigated possible factors involved in elastin degradation and evaluated whether a similar pattern of elastin degradation can be found in BALF samples of patients with interstitial lung diseases known to have aspirated. Non-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used. RESULTS: We found evidence of early proteolytic degradation of lung elastin. Elastin degradation products are detected both in lung tissue and BALF in the first 24 h and are significantly reduced at day 4. They correlate significantly with ALI markers, particularly PMN cell count, are independent of acidity and have a similar molecular weight as those obtained using pancreatic elastase. Evaluation of BALF from patients revealed the presence of elastin degradation products not present in controls that are similar to those found in BALF of rats treated with gastric fluid. CONCLUSIONS: A single instillation of gastric fluid into the lungs induces early proteolytic degradation of elastin, in relation to the magnitude of alveolar-capillary barrier derangement. PMN-derived proteases released during ALI are mostly responsible for this damage. BALF from patients showed elastin degradation products similar to those found in rats treated with gastric fluid. Long-lasting effects on lung elastic properties could be expected under conditions of repeated instillations of gastric fluid in experimental animals or repeated aspiration events in humans.

Acute lung injury induced by whole gastric fluid: hepatic acute phase response contributes to increase lung antiprotease protection.

BACKGROUND: Gastric contents aspiration in humans is a risk factor for severe respiratory failure with elevated mortality. Although aspiration-induced local lung inflammation has been studied in animal models, little is known about extrapulmonary effects of aspiration. We investigated whether a single orotracheal instillation of whole gastric fluid elicits a liver acute phase response and if this response contributes to enrich the alveolar spaces with proteins having antiprotease activity. METHODS: In anesthetized Sprague-Dawley rats receiving whole gastric fluid, we studied at different times after instillation (4 h -7 days): changes in blood cytokines and acute phase proteins (fibrinogen and the antiproteases alpha1-antitrypsin and alpha2-macroglobulin) as well as liver mRNA expression of the two antiproteases. The impact of the systemic changes on lung antiprotease defense was evaluated by measuring levels and bioactivity of antiproteases in broncho-alveolar lavage fluid (BALF). Markers of alveolar-capillary barrier derangement were also studied. Non-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used. RESULTS: Severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage and PMNn cell infiltration was seen in the first 24 h and later resolved. Despite a large increase in several lung cytokines, only IL-6 was found elevated in blood, preceding increased liver expression and blood concentration of both antiproteases. These changes, with an acute phase response profile, were significantly larger for alpha2-macroglobulin (40-fold increment in expression with 12-fold elevation in blood protein concentration) than for alpha1-antitrypsin (2-3 fold increment in expression with 0.5-fold elevation in blood protein concentration). Both the increment in capillary-alveolar antiprotease concentration gradient due to increased antiprotease liver synthesis and a timely-associated derangement of the alveolar-capillary barrier induced by aspiration, contributed a 58-fold and a 190-fold increase in BALF alpha1-antitrypsin and alpha2-macroglobulin levels respectively (p < 0.001). CONCLUSIONS: Gastric contents-induced acute lung injury elicits a liver acute phase response characterized by increased mRNA expression of antiproteases and elevation of blood antiprotease concentrations. Hepatic changes act in concert with derangement of the alveolar capillary barrier to enrich alveolar spaces with antiproteases. These findings may have significant implications decreasing protease burden, limiting injury in this and other models of acute lung injury and likely, in recurrent aspiration.

Resolution of lung injury after a single event of aspiration: a model of bilateral instillation of whole gastric fluid.

Gastric aspiration is a high-risk condition for lung injury. Consequences range from subclinical pneumonitis to respiratory failure, with fibrosis development in some patients. Little is known about how the lung repairs aspiration-induced injury. By using a rat model of single orotracheal instillation of whole gastric contents, we studied the time course of morphological and biochemical changes during injury and resolution, and evaluated whether repair involved long-term fibrosis. Anesthetized rats received one gastric fluid instillation. At 4, 12, and 24 hours and 4 and 7 days, we performed lung histological studies and biochemical measurements in bronchoalveolar lavage fluid and lung tissue. Physiological measurements were performed at 12 to 24 hours. Long-term outcome was studied histologically at day 60. During the first 24 hours, severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage, increased neutrophils and cytokines, and physiological dysfunction were observed. At days 4 and 7, an organizing pneumonia (OP) pattern developed, with foreign-body giant cells and granulomas. Lung matrix metalloproteinase 9 and 2 activities increased, with metalloproteinase-9 linked to early inflammation and metalloproteinase-2 to OP. At day 60, lung architecture was normal. In conclusion, a continuum of alterations starting with severe injury, evolving toward OP and later resolving, characterizes the rat single aspiration event. In addition to identifying markers of staging and severity, this model reveals that OP participates in the repair of aspiration-induced injury.

[Antitransglutaminase antibodies determination for the diagnosis of celiac disease]. / Determinación de anticuerpos anti-transglutaminasa en el diagnóstico de enfermedad celíaca.

BACKGROUND: The diagnosis of celiac disease is based in clinical features, serology and intestinal biopsy. There are recent reports that antiglutaminase antibodies have a good correlation with anti endomisial antibodies. AIM: To assess the sensitivity and specificity of antitransglutaminase antibodies in the diagnosis of celiac disease and their correlation with antiendomisial antibodies. MATERIAL AND METHODS: Forty nine patients with celiac disease (mean age 30 years, 12 male) were studied. Thirty were symptomatic and 19, asymptomatic. As controls, 34 subjects (mean age 27 years, seven male), with normal duodenal biopsies, were studied. Sera was processed for the determination of antigliadin IgA by ELISA, antiendomisium IgA by indirect immunofluorescence, and antitransglutaminase IgA by ELISA. RESULTS: Antigliadin antibodies had a sensitivity of 73%, a specificity of 96%, a positive predictive value of 93% and a negative predictive value of 82% for the diagnosis of celiac disease. Antiendomisium and antitransglutaminase antibodies had a specificity and positive predictive value of 100%, sensitivities of 89 and 92% respectively and negative predictive values of 92 and 94% respectively. No significant differences in the diagnostic yield of antiendomisium and antitransglutaminase antibodies, were observed. CONCLUSIONS: In this group of patients, antitransglutaminase antibodies had a high concordance with antiendomisium antibodies, for the diagnosis of celiac disease. Considering that the determination of antitransglutaminase antibodies is of lower cost and less complicated than antiendomisium antibodies, it is a useful tool for the diagnosis and follow up of patients with celiac disease.

Algunos aspectos epidemiológicos y clínicos de la litiasis biliar y de la pancreatitis crónica en Chile / Some epidemiologic and clinic aspects of biliary lithiasis and chronic pancreatitis in Chile

La litiasis biliar alcanza, en Chile, una prevalencia mayor que en todos los demás países; afecta alrededor de 12 a 13% de la población; es más común en la mujer que en el hombre; su frecuencia aumenta con la edad y en los mayores de 15 años tiene una prevalencia promedio de 45%. En éste hecho hay concordancia entre la radiología; la ecotomografía y los estudios necrópsicos. Entre los factores que condicionan la elevada prevalencia de litiasis biliar entre nosotros deben mencionarse los raciales; los constitucionales, los nutricionales, los iatrogénicos y algunas patologías concomitantes. Desde el punto de vista de salud pública, la litiasis biliar es causa de 10 a 13% de las consultas; del 5% de las hospitalizaciones; del 40% de las operaciones electivas y del 25% de las de urgencia. El 30 a 40% de las litiasis biliares asintomáticas se complican con el tiempo. La litiasis biliar es un importante factor predisponente al cáncer vesicular. Las operaciones electivas tienen una mortalidad de 0,3% y las de urgencia de 1,5%. La mortalidad global de la litiasis biliar es de 6,2% por 100.000 pero asciende a 50 por 100.000 en los mayores de 65 años. Se destacan la elevada prevalencia del alcoholismo que afecta al 15% de la población chilena adulta y su importancia en la etiopatogenia de la pancreatitis crónica. Se analizan comparativamente dos series necrópsicas: una de 101 casos de cirrosis hepática alcohólica y otra de 103 casos sin cirrosis. En la primera se detecta compromiso histológico pancreático en el 56,4% (alteraciones severas propias de pancreatitis crónica en 29,0%) mientras que en la segunda el compromiso pancreático sólo se pesquisó en el 15,0% siendo severo sólo en el 3,2%