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Alveolar Type 1 Cells Express the α2 Na,K-ATPase, Which Contributes to Lung Liquid Clearance

Abstract— The alveolar epithelium is composed of alveolar type 1 (AT1) and alveolar type 2 (AT2) cells, which represent ≈95% and ≈5% of the alveolar surface area, respectively. Lung liquid clearance is driven by the osmotic gradient generated by the Na,K-ATPase. AT2 cells have been shown to express the &agr;1 Na,K-ATPase. We postulated that AT1 cells, because of their larger surface area, should be important in the regulation of active Na+ transport. By immunofluorescence and electron microscopy, we determined that AT1 cells express both the &agr;1 and &agr;2 Na,K-ATPase isoforms. In isolated, ouabain-perfused rat lungs, the &agr;2 Na,K-ATPase in AT1 cells mediated 60% of the basal lung liquid clearance. The &bgr;-adrenergic agonist isoproterenol increased lung liquid clearance by preferentially upregulating the &agr;2 Na,K-ATPase protein abundance in the plasma membrane and activity in alveolar epithelial cells (AECs). Rat AECs and human A549 cells were infected with an adenovirus containing the rat Na,K-ATPase &agr;2 gene (Ad&agr;2), which resulted in the overexpression of the &agr;2 Na,K-ATPase protein and caused a 2-fold increase in Na,K-ATPase activity. Spontaneously breathing rats were also infected with Ad&agr;2, which increased &agr;2 protein abundance and resulted in a ≈250% increase in lung liquid clearance. These studies provide the first evidence that &agr;2 Na,K-ATPase in AT1 cells contributes to most of the active Na+ transport and lung liquid clearance, which can be further increased by stimulation of the &bgr;-adrenergic receptor or by adenovirus-mediated overexpression of the &agr;2 Na,K-ATPase.

Etiology of Community-Acquired Pneumonia in Hospitalized Patients in Chile* The Increasing Prevalence of Respiratory Viruses Among Classic Pathogens

BACKGROUND AND STUDY OBJECTIVES The range and relative impact of microbial pathogens, particularly viral pathogens, as a cause of community-acquired pneumonia (CAP) in hospitalized adults has not received much attention. The aim of this study was to determine the microbial etiology of CAP in adults and to identify the risk factors for various specific pathogens. METHODS We prospectively studied 176 patients (mean [+/- SD] age, 65.8 +/- 18.5 years) who had hospitalized for CAP to identify the microbial etiology. For each patient, sputum and blood cultures were obtained as well as serology testing for Mycoplasma pneumoniae and Chlamydophila pneumoniae, urinary antigen testing for Legionella pneumophila and Streptococcus pneumoniae, and a nasopharyngeal swab for seven respiratory viruses. RESULTS Microbial etiology was determined in 98 patients (55%). S pneumoniae (49 of 98 patients; 50%) and respiratory viruses (32%) were the most frequently isolated pathogen groups. Pneumococcal pneumonia was associated with tobacco smoking of > 10 pack-years (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2 to 5.4; p = 0.01). Respiratory viruses were isolated more often in fall or winter (28%; p = 0.011), and as an exclusive etiology tended to be isolated in patients >/= 65 years of age (20%; p = 0.07). Viral CAP was associated with antimicrobial therapy prior to hospital admission (OR, 4.5; 95% CI, 1.4 to 14.6). CONCLUSIONS S pneumoniae remains the most frequent pathogen in adults with CAP and should be covered with empirical antimicrobial treatment. Viruses were the second most common etiologic agent and should be tested for, especially in fall or winter, both in young and elderly patients who are hospitalized with CAP.

Adenovirus-mediated transfer of an Na+/K+ -ATPase β1 subunit gene improves alveolar fluid clearance and survival in hyperoxic rats

Pulmonary edema is cleared via active Na(+) transport by alveolar epithelial Na(+)/K(+)-ATPases and Na(+) channels. Rats exposed to acute hyperoxia have a high mortality rate, decreased Na(+)/K(+)-ATPase function, and decreased alveolar fluid clearance (AFC). We hypothesized that Na(+)/K(+)-ATPase subunit gene overexpression could improve AFC in rats exposed to hyperoxia. We delivered 4 x 10(9) PFU of recombinant adenoviruses containing rat alpha(1) and beta(1) Na(+)/K(+)-ATPase subunit cDNAs (adalpha(1) and adbeta(1), respectively) to rat lungs 7 days prior to exposure to 100% O(2) for 64 hr. As compared with controls and ad alpha(1), AFC in the adbeta(1) rats was increased by >300%. Permeability for large solutes was less in the ad beta(1) than in the other hyperoxia groups. Glutathione oxidation, but not superoxide dismutase activity, was increased only in the adbeta(1) group. Survival through 14 days of hyperoxia was 100% in the adbeta(1) group but was not different from hyperoxic controls in animals given adalpha(1). Our data show that overexpression of a beta(1) Na(+)/K(+)-ATPase subunit augments AFC and improves survival in this model of acute lung injury via antioxidant-independent mechanisms. Conceivably, restoration of AFC via gene transfer of Na(+)/K(+)-ATPase subunit genes may prove useful for the treatment of acute lung injury and pulmonary edema.

Modulation of lung liquid clearance by isoproterenol in rat lungs

beta-Adrenergic agonists have been reported to increase lung liquid clearance by stimulating active Na+ transport across the alveolar epithelium. We studied mechanisms by which beta-adrenergic isoproterenol (Iso) increases lung liquid clearance in isolated perfused fluid-filled rat lungs. Iso perfused through the pulmonary circulation at concentrations of 10(-4) to 10(-8) M increased lung liquid clearance compared with that of control lungs (P < 0.01). The increase in lung liquid clearance was inhibited by the beta-antagonist propranolol (10(-5) M), the Na(+)-channel blocker amiloride (10(-4) M), and the antagonist of Na-K-ATPase, ouabain (5 x 10(-4) M). Colchicine, which inhibits cell microtubular transport of ion-transporting proteins to the plasma membrane, blocked the stimulatory effects of Iso on active Na+ transport, whereas the isomer lumicolchicine, which does not affect cell microtubular transport, did not inhibit Na+ transport. In parallel with these changes, the Na-K-ATPase alpha 1-subunit protein abundance and activity increased in alveolar type II cells stimulated by 10(-6) M Iso. Colchicine blocked the stimulatory effect of Iso and the recruitment of Na-K-ATPase alpha 1-protein to the basolateral membrane of alveolar type II cells. Accordingly, Iso increased active Na+ transport and lung liquid clearance by stimulation of beta-adrenergic receptors and probably by upregulation of apical Na+ channels and basolateral Na-K-ATPase mechanisms. Recruitment from intracellular pools and microtubular transport of Na+ pumps to the plasma membrane participate in beta-adrenergic stimulation of lung liquid clearance in rat lungs.β-Adrenergic agonists have been reported to increase lung liquid clearance by stimulating active Na+ transport across the alveolar epithelium. We studied mechanisms by which β-adrenergic isoproterenol (Iso) increases lung liquid clearance in isolated perfused fluid-filled rat lungs. Iso perfused through the pulmonary circulation at concentrations of 10-4 to 10-8 M increased lung liquid clearance compared with that of control lungs ( P < 0.01). The increase in lung liquid clearance was inhibited by the β-antagonist propranolol (10-5 M), the Na+-channel blocker amiloride (10-4 M), and the antagonist of Na-K-ATPase, ouabain (5 × 10-4 M). Colchicine, which inhibits cell microtubular transport of ion-transporting proteins to the plasma membrane, blocked the stimulatory effects of Iso on active Na+ transport, whereas the isomer lumicolchicine, which does not affect cell microtubular transport, did not inhibit Na+ transport. In parallel with these changes, the Na-K-ATPase α1-subunit protein abundance and activity increased in alveolar type II cells stimulated by 10-6 M Iso. Colchicine blocked the stimulatory effect of Iso and the recruitment of Na-K-ATPase α1-protein to the basolateral membrane of alveolar type II cells. Accordingly, Iso increased active Na+ transport and lung liquid clearance by stimulation of β-adrenergic receptors and probably by upregulation of apical Na+ channels and basolateral Na-K-ATPase mechanisms. Recruitment from intracellular pools and microtubular transport of Na+pumps to the plasma membrane participate in β-adrenergic stimulation of lung liquid clearance in rat lungs.

Six-Minute Walk Test and Maximum Exercise Test in Cycloergometer in Chronic Obstructive Pulmonary Disease. Are the Physiological Demands Equivalent?

a b s t r a c t Background and objectives: The physiological load imposed by the six minute walk test (SMWT) in chronic obstructive pulmonary disease (COPD) patients come from small studies where the influence of disease severity has not been assessed. The aim of the present study was to compare the SMWT with an incremental cardiopulmonary exercise test (CPET) in patients classified by disease severity according to FEV1 (cutoff 50% predicted). Patients and methods: Eighty-one COPD patients (53 with FEV1 ≥50%) performed both tests on two consecutive days. Oxygen consumption (V. O2), carbon dioxide production (V. O2), minute ventilation (V. E), heart rate (HR) and pulse oximetry (SpO2) were measured during SMWT and CPET using portable equipment. Dyspnea and leg fatigue were measured with the Borg scale. Results: In both groups, walking speed was constant during the SMWT and V. O2 showed a plateau after the 3rd minute. When comparing SMWT (6th min) and peak CPET, patients with FEV1 ≥50% showed a greater V. O2, but lower values of V. O2,VE, HR, dyspnea, leg fatigue, and SpO2 during walking. In contrast, in those with FEV1 <50% predicted values were similar. Distance walked during the SMWT strongly correlated with V. O2 at peak CPET (r=0.78; P=0.0001). Conclusion: The SMWT is a constant load exercise in COPD patients, regardless of disease severity. It imposes high metabolic, ventilatory and cardiovascular requirements, which were closer to those of CPET in severe COPD. These findings may explain the close correlation between distance walked and peak CPET V. O2.

Cuadro clínico y factores pronósticos de la neumonía adquirida en la comunidad grave en adultos hospitalizados en la unidad de cuidados intensivos

Objetivo: En Chile existe escasa informacion acerca de la neumonia adquirida en la comunidad de caracter grave manejada en las unidades de cuidados intensivos. En este trabajo se describen el cuadro clinico, los factores pronosticos y el tratamiento de pacientes adultos hospitalizados en la unidad de cuidados intensivos por neumonia adquirida en la comunidad grave. Pacientes y metodos: Se ha realizado un estudio clinico prospectivo y descriptivo que ha incluido a 113 pacientes consecutivos. Resultados: De los 113 pacientes incluidos (edad media ± desviacion estandar: 73 ± 15 anos), el 95% tenia comorbilidad asociada y un 81% pertenecia a las categorias de alto riesgo del indice de gravedad de la neumonia (Pneumonia Severity Index). Se demostro la etiologia en el 31% y los patogenos mas frecuentes fueron Streptococcus pneumoniae (40%), bacilos gramnegativos (17%) y Mycoplasma pneumoniae (6%). Las principales complicaciones fueron necesidad de ventilacion mecanica (45%), shock septico (26%), insuficiencia cardiaca (24%) y arritmias (15%). La mortalidad a los 30 dias fue del 16,8% y mediante un analisis multivariado se identificaron los siguientes factores asociados a mayor riesgo de muerte: insuficiencia renal aguda (odds ratio = 5,1) y glucemia mayor de 300 mg/dl (odds ratio = 7,2). Conclusiones: Los pacientes con neumonia grave ingresados en la unidad de cuidados intensivos son de edad avanzada, con una alta tasa de comorbilidad y complicaciones, pero la mayoria sobrevive.

Prueba de marcha de 6 min y ejercicio máximo en cicloergómetro en la enfermedad pulmonar obstructiva crónica, ¿son sus demandas fisiológicas equivalentes?

BACKGROUND AND OBJECTIVES The physiological load imposed by the six minute walk test (SMWT) in chronic obstructive pulmonary disease (COPD) patients come from small studies where the influence of disease severity has not been assessed. The aim of the present study was to compare the SMWT with an incremental cardiopulmonary exercise test (CPET) in patients classified by disease severity according to FEV(1) (cutoff 50% predicted). PATIENTS AND METHODS Eighty-one COPD patients (53 with FEV(1) > or =50%) performed both tests on two consecutive days. Oxygen consumption (VO(2)), carbon dioxide production (VCO(2)), minute ventilation (V(E)), heart rate (HR) and pulse oximetry (SpO(2)) were measured during SMWT and CPET using portable equipment. Dyspnea and leg fatigue were measured with the Borg scale. RESULTS In both groups, walking speed was constant during the SMWT and VO(2) showed a plateau after the 3rd minute. When comparing SMWT (6th min) and peak CPET, patients with FEV(1) > or =50% showed a greater VO(2), but lower values of VCO(2),V(E), HR, dyspnea, leg fatigue, and SpO(2) during walking. In contrast, in those with FEV(1) <50% predicted values were similar. Distance walked during the SMWT strongly correlated with VO(2) at peak CPET (r=0.78; P=0.0001). CONCLUSION The SMWT is a constant load exercise in COPD patients, regardless of disease severity. It imposes high metabolic, ventilatory and cardiovascular requirements, which were closer to those of CPET in severe COPD. These findings may explain the close correlation between distance walked and peak CPET VO(2).

Clinical Picture and Prognostic Factors for Severe Community-Acquired Pneumonia in Adults Admitted to the Intensive Care Unit

OBJECTIVE In Chile very little information is available on severe community-acquired pneumonia treated in intensive care units. This study describes the clinical picture, prognostic factors, and treatment of adult patients admitted to the intensive care unit for severe community-acquired pneumonia. PATIENTS AND METHODS A total of 113 consecutive patients were included in this prospective, descriptive study. RESULTS The mean (SD) age of the 113 patients was 73 (15). Of these, 95% had associated comorbidity, and 81% were in the high-risk classes of the Pneumonia Severity Index. Etiology was identified in 31%, and the most common pathogens were Streptococcus pneumoniae (40%), gram negative bacilli (17%), and Mycoplasma pneumoniae (6%). The main complications were the need for mechanical ventilation (45%), septic shock (26%), heart failure (24%), and arrhythmias (15%). Mortality at 30 days was 16.8%, and multivariate analysis revealed the following factors to be associated with a greater risk of death: acute renal failure (odds ratio: 5.1), and glycemia above 300 mg/dL (odds ratio: 7.2). CONCLUSIONS The patients with severe pneumonia admitted to the intensive care unit are elderly, with a high level of comorbidity and complications, but most survive.

Hierbas medicinales y graves efectos adversos: angioedema de úvula causado por uso de Ecballium elaterium

Herbal medicine is a growing alternative for established medicine. Many plants and herbs are currently in use for a myriad of diseases and symptoms. However, there are many reports in the literature of life-threatening adverse effects of these drugs. We report a 39 years old male, that consulted for pain in the nostrils and severe nasal obstruction, that appeared two hours after instilling Ecballium elaterirum in the nostrils. On physical examination, uvular edema was observed. The patient was successfully managed with intravenous betametasone and chlorphenamine.

Reducción de la actividad física en pacientes con enfermedad pulmonar obstructiva crónica

BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) decrease their physical activity. However, it is unknown at which stage of the disease the reduction occurs and whether dyspnea is a limiting factor. AIM To compare physical activity between patients with COPD and controls of similar age and to assess its association with disease severity. MATERIAL AND METHODS We studied 112 patients with mild to very severe COPD and 55 controls. Lung function, six-minutes walking test (SMWT), and physical activity through the International Physical Activity Questionnaire (IPAQ) were measured. RESULTS Compared to controls, physical activity was significantly reduced in COPD patients (1823 ± 2598 vs. 2920 ± 3040 METs min/week; p = 0.001). Patients were more frequently sedentary (38 vs. 11%), while controls were more often very active (31 vs. 19%) or moderately active (58 vs. 43%). Physical activity was reduced from Global Initiative for Obstructive Chronic Lung Disease (GOLD) stage 2 and from Modified Medical Research Council (MMRC) dyspnea grade 1. Weak relationships were observed between lung function, SMWT and physical activity. CONCLUSIONS Physical activity decreases early in the course of the disease and when dyspnea is still mild, among patients with COPD.