RESUMEN
Ketorolac tromethamine, a new nonsteroidal anti-inflammatory agent of the pyrrolo-pyrrole group, was assayed for inhibitory effects on polymorphonuclear leukocytes (PMN) in a variety of systems. Ketorolac inhibited PMN superoxide anion generation, lysozyme release, myeloperoxidase release, adherence to plastic surfaces, and chemotaxis in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) in a dose-dependent manner. Ketorolac also inhibited phorbol myristate acetate-stimulated adherence of PMN to bovine pulmonary artery endothelial cells. The drug inhibited lysozyme and myeloperoxidase release by PMN in response to C5a but failed to inhibit C5a stimulation of PMN in any of the other assays. Levels of ketorolac required to inhibit PMN function in most systems were in the range of 0.2 to 1.0 mg/ml, but chemotaxis to fMLP was inhibited by concentrations of ketorolac as low as 1 microgram/ml. Ketorolac, currently the only nonsteroidal anti-inflammatory drug available in a parenteral form may have therapeutic usefulness in a variety of conditions thought to be mediated in part by PMN, including sepsis.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Neutrófilos/efectos de los fármacos , Tolmetina/análogos & derivados , Trometamina/farmacología , Adhesión Celular/efectos de los fármacos , Quimiotaxis de Leucocito/efectos de los fármacos , Complemento C5a/farmacología , Combinación de Medicamentos , Humanos , Ketorolaco Trometamina , Cinética , Leucotrieno B4/biosíntesis , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/metabolismo , Neutrófilos/fisiología , Estimulación Química , Superóxidos/metabolismo , Tolmetina/farmacologíaRESUMEN
Amiodarone-induced interstitial pneumonitis is a serious, frequently fatal untoward effect of a commonly used antiarrhythmic agent. Recent reports suggest that bronchoalveolar lavage (BAL) fluid cellular analysis might be used to diagnose amiodarone-induced pneumonitis. The purpose of this study was to determine if the diagnosis of amiodarone-induced pneumonitis could be made by patient history, pulmonary function evaluation, and examination of BAL fluid. We studied five groups of patients. Three of the five groups received amiodarone: patients receiving amiodarone without evident lung toxic reaction, patients with amiodarone-induced pneumonitis, and amiodarone-treated patients diagnosed as having other pathologic processes involving the lung. The two other groups examined were healthy volunteers and patients with interstitial lung disease from causes other than amiodarone. Pulmonary function tests included vital capacity (FVC), first second forced exhaled volume (FEV1), total lung capacity (TLC), and diffusing capacity for carbon monoxide (DCO). BAL fluid analysis included total and differential cell counts. We found that amiodarone-induced interstitial pneumonitis was not associated with an alteration in pulmonary function or BAL cellular composition which could permit its distinction from amiodarone-treated patients diagnosed as having an unrelated pulmonary process or patients with interstitial lung disease from other causes. The most frequent abnormality encountered in patients with amiodarone toxicity was a reduction in the percentage of macrophages in the differential cell count. The sensitivity, specificity, and predictive value of this finding was 82 percent, 69 percent, and 69 percent, respectively. The sensitivity, specificity, and predictive value of a > or = 15 percent reduction in DCO was 44 percent, 50 percent, and 36 percent, respectively. We conclude that amiodarone-induced interstitial pneumonitis remains a diagnosis of exclusion, and the role of BAL fluid analysis is to narrow the differential diagnosis through microbiologic culture and cytologic examination.
Asunto(s)
Amiodarona/efectos adversos , Líquido del Lavado Bronquioalveolar , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/diagnóstico , Anciano , Líquido del Lavado Bronquioalveolar/patología , Broncoscopía , Recuento de Células , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Fibrosis Pulmonar/patología , Pruebas de Función Respiratoria , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To determine if the plasma levels of three endothelial-specific proteins, von Willebrand factor (vWF), tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) may be useful in predicting the development of acute respiratory distress syndrome (ARDS). DESIGN: Blood samples were obtained from normal healthy volunteers and on the first day from patients at risk for ARDS and those with ARDS. Daily sequential measurements of vWF and TFPI were performed in two patients. SETTING: Normal subjects were employees at Saint Louis University Hospital, St. Louis, Missouri. Patients at risk and those with ARDS were patients admitted to the medical and surgical floors and the intensive care units at St. Louis University Hospital. PATIENTS AND PARTICIPANTS: Plasma levels of vWF, TFPI and TM were measured in 27 normals, and on day 1 in 15 patients at risk for ARDS and 18 patients with ARDS from different etiologic factors. MEASUREMENTS AND RESULTS: Plasma levels of vWF were significantly elevated in the at-risk (p < 0.01) and ARDS group (p < 0.001) as compared to normals but did not differ significantly between the two groups (p > 0.05). Plasma levels of TFPI were not significantly different between the normal and the at-risk group (p > 0.05); however, they were significantly elevated in ARDS as compared with at-risk and normal groups (p < 0.001). Levels of TM were significantly increased in the at-risk group as compared to normals (p < 0.01) but were not significantly different from the ARDS group (p > 0.05). Eight patients at risk progressed to develop ARDS. A vWF level of > 300% in patients at risk was 62% sensitive and 71% specific for predicting the development of ARDS with a positive predictive value of only 34%. TFPI levels were normal in 7 of the 8 patients who developed ARDS. A TM level of > 100 ng/ml in patients at risk was 50% sensitive and 57% specific with a positive predictive value of merely 8% for development of ARDS. There was no significant difference in the mean plasma levels of the three proteins on day 1 in patients at risk who developed ARDS as compared with those who did not develop ARDS. There was also no difference in mean plasma levels of the three proteins in patients with ARDS from sepsis as compared with ARDS from other etiologies. Plasma levels of vWF and TFPI correlated significantly. CONCLUSION: Plasma levels of vWF, TFPI and TM did not appear to serve as useful markers for predicting ARDS in patients at risk.
Asunto(s)
Endotelio Vascular/patología , Lipoproteínas/sangre , Síndrome de Dificultad Respiratoria/etiología , Trombomodulina/sangre , Factor de von Willebrand/metabolismo , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Humanos , Valor Predictivo de las Pruebas , Síndrome de Dificultad Respiratoria/sangreRESUMEN
Tumor necrosis factor (TNF) was measured antigenically and functionally in serum and bronchoalveolar lavage fluid (BAL) of patients with ARDS and those at high risk for ARDS. Of 22 patients with ARDS, 14 had sepsis or serious infection as the major clinical predisposition, and 10 of 20 high-risk patients had sepsis or serious infection. Mean levels of TNF in serum of patients with ARDS and high risk showed a trend toward elevation but were not significantly higher than mean serum levels in normal subjects. Mean levels of TNF in BAL of ARDS patients (242 +/- 126 pg/ml) were significantly higher than in normal subjects (9 +/- 5 pg/ml), p less than 0.05. Antigenic levels of TNF were undetectable in approximately half the patients with ARDS or the high-risk state. Levels of TNF in BAL appeared to be highest in the first day of ARDS. There appeared to be no relationship between levels of TNF in serum or BAL and subsequent mortality. However, serum levels of TNF were significantly higher in septic patients than in nonseptic patients, whereas this difference was not apparent in BAL. These results show that functional and antigenic elevations of TNF are present in BAL and perhaps in serum of patients with ARDS or with the high-risk state.
Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Síndrome de Dificultad Respiratoria/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioinmunoensayo , Síndrome de Dificultad Respiratoria/epidemiología , Factores de Riesgo , Factores de TiempoRESUMEN
Serum levels of the acute-phase reactant, C-reactive protein (CRP), increase dramatically during acute inflammatory episodes. CRP inhibits migration of neutrophils toward the chemoattractant, f-Met-Leu-Phe (fMLP) and therefore acts as an anti-inflammatory agent. Since tyrosine kinases are involved in neutrophil migration and CRP has been shown to decrease phosphorylation of some neutrophil proteins, we hypothesized that CRP inhibits neutrophil chemotaxis via inhibition of MAP kinase activity. The importance of p38 MAP kinase in neutrophil movement was determined by use of the specific p38 MAP kinase inhibitor, SB203580. CRP and SB203580 both blocked random and fMLP-directed neutrophil movement in a concentration-dependent manner. Additionally, extracellular signal-regulated MAP kinase (ERK) was not involved in fMLP-induced neutrophil movement as determined by use of the MEK-specific inhibitor, PD98059. Blockade of ERK with PD98059 did not inhibit chemotaxis nor did it alter the ability of CRP or SB203580 to inhibit fMLP-induced chemotaxis. More importantly, CRP inhibited fMLP-induced p38 MAP kinase activity in a concentration-dependent manner as measured by an in vitro kinase assay. Impressively, CRP-mediated inhibition of p38 MAP kinase activity correlated with CRP-mediated inhibition of fMLP-induced chemotaxis (r = -0.7144). These data show that signal transduction through p38 MAP kinase is necessary for neutrophil chemotaxis and that CRP intercedes through this pathway in inhibiting neutrophil movement.
Asunto(s)
Proteína C-Reactiva/farmacología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas Quinasas Activadas por Mitógenos , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Movimiento Celular/efectos de los fármacos , Quimiotaxis/efectos de los fármacos , Flavonoides , Humanos , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular , N-Formilmetionina Leucil-Fenilalanina/antagonistas & inhibidores , Neutrófilos/efectos de los fármacos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Piridinas/farmacología , Transducción de Señal , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein primarily synthesized by the endothelium. A major fraction (approximately 85%) of TFPI remains associated with the endothelium, whereas a small fraction (approximately 15%) is secreted into the blood. In our attempts to search for a marker(s) of endothelial injury in the setting of adult respiratory distress syndrome (ARDS), we retrospectively measured plasma TFPI levels in patients at risk for and with ARDS caused by several etiologic factors. Plasma von Willebrand factor antigen (vWF-Ag), another endothelial-specific protein, was also measured in these patients. The mean plasma TFPI levels were slightly elevated (approximately 1.3-fold), whereas vWF-Ag levels were significantly elevated (approximately 3-fold) in the at-risk group as compared with those in the normal subjects. Both the TFPI (approximately 1.8-fold) and the vWF-Ag (approximately 4-fold) levels were further elevated in the ARDS group. Moreover, the sequential plasma samples from patients with ARDS had progressively increased levels of vWF-Ag and TFPI up to Days 4 and 8, respectively. Neither plasma vWF-Ag nor TFPI levels correlated with mortality in the at-risk group or the ARDS group. TFPI levels were also measured in bronchoalveolar lavage fluids (BALF). The levels (ng/ml) were: normal subjects, 0.05 +/- 0.02 SE; at-risk group, 0.35 +/- 0.16 SE; ARDS group, 0.99 +/- 0.28 SE. Thus, the BALF TFPI levels were increased approximately 7-fold in the at-risk group and approximately 20-fold in the ARDS group relative to the value in the normal subjects. These findings indicate increased local synthesis of TFPI in the alveolar space both in the at-risk patients and in those with ARDS. In additional studies in a primate model of sepsis, lethal doses (LD100) of E. coli administered to baboons resulted in a progressive increase in TFPI levels (approximately 2-fold at 6 h), whereas sublethal doses caused only minimal increase (approximately 1.2-fold). The vWF-Ag levels were elevated approximately 5-fold after infusion of LD100 concentrations of E. coli at 6 h and 4-fold after infusion of sublethal concentrations of E. coli at 24 h. Autopsies on animals in the LD100 group revealed pulmonary congestion, leukocyte infiltration, edema, and hemorrhage, all suggestive of acute lung injury. Thus, in the setting of acute lung injury plasma vWF-Ag appears to be considerably increased prior to significant damage to the endothelium, whereas increased plasma TFPI occurs only after severe injury.(ABSTRACT TRUNCATED AT 400 WORDS)