RESUMO
This retrospective study was designed to evaluate the safety and efficacy of a bronchoprotective sputum induction protocol in moderate to severe chronic obstructive pulmonary disease (COPD). Forty-two adults with COPD (FEV1 = 51.7 +/- 3.2% predicted (mean +/- SEM)) under went sputum induction using a protocol designed to minimize hypertonic saline-induced bronchoconstriction. Hypertonic (3%) saline was used for subjects with FEV1 > or = 50%, and normal (0.9%) saline was used for subjects with FEV1 < 50%. Primary outcomes were change in peak flow, FEV1 and oxygen saturation. Mean decline in peak flow during sputum induction was 13.2 +/- 2.1%. FEV1 fell by 11.4 +/- 2.3%, an absolute fall of 0.14 +/- 0.031. Oxygen saturation did not change. A fall in peak flow of > or = 20% reliably predicted a fall in FEV1 of > or = 20%. Thirty-five of 42 subjects (83.3%) produced an acceptable sputum sample. Sputum eosinophil and neutrophil percentages were 2.8 +/- 0.9 and 73.0 +/- 3.0%, respectively, and were not correlated with changes in peak flow, FEV1 or oxygen saturation. A protocol for sputum induction which restricts the use of hypertonic saline based on lung function is both safe and effective in subjects with moderate to severe COPD.
Assuntos
Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Solução Salina Hipertônica/administração & dosagem , Escarro , Adulto , Volume Expiratório Forçado , Humanos , Oximetria , Pico do Fluxo Expiratório , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
STUDY OBJECTIVES: To determine how often serum lidocaine concentrations (SLC) fall into the potentially toxic range (> 5 mg/L) in asthmatics undergoing research bronchoscopy, and to determine whether subject or procedure characteristics are associated with higher SLC. DESIGN: Prospective, observational study. SETTING: Academic research center. PARTICIPANTS: Fifty-one volunteers with mild to moderate asthma enrolled in three separate bronchoscopy protocols to study airway inflammation in asthma. INTERVENTIONS: Lidocaine was administered topically to the upper airway and tracheobronchial tree to achieve local anesthesia for bronchoscopy. Venous blood was sampled during bronchoscopy, 30 min after upper airway anesthesia was completed (time 1), and 30 min after bronchoscopy was completed (time 2). MEASUREMENTS AND RESULTS: The mean total amount of lidocaine administered was 600 +/- 122 mg (8.2 +/- 2.0 mg/kg). No signs or symptoms of lidocaine toxicity were observed in any of the subjects. SLC ranged between 0.10 and 2.90 mg/L at time 1 and 0.50 and 3.20 mg/L at time 2. SLC was significantly correlated with the total amount of lidocaine (milligrams/kilogram) administered at both points (time 1, r = 0.33, p = 0.021; time 2, r = 0.33, p = 0.023). No statistically significant relationship was observed between SLC and subject age, sex, weight, baseline FEV(1), procedure length, or study protocol. No statistically significant relationship was found between subject FEV(1) and either total lidocaine dose or procedure length. CONCLUSIONS: An average total dose of 600 mg (8.2 mg/kg) of lidocaine appears to be safe in mild to moderate asthmatics undergoing research bronchoscopy.
Assuntos
Anestesia Local/métodos , Anestésicos Locais/farmacocinética , Asma/sangue , Broncoscopia/métodos , Lidocaína/farmacocinética , Centros Médicos Acadêmicos , Administração Tópica , Adulto , Anestésicos Locais/administração & dosagem , Asma/diagnóstico , Biópsia/métodos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Lidocaína/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV(1) was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.
Assuntos
Asma/classificação , Asma/patologia , Eosinófilos/patologia , Adulto , Asma/fisiopatologia , Membrana Basal/patologia , Biópsia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Broncoscopia , Contagem de Células , Distribuição de Qui-Quadrado , Feminino , Humanos , Imuno-Histoquímica , Inflamação/patologia , Pulmão/patologia , Masculino , Testes de Função Respiratória , Estatísticas não ParamétricasAssuntos
Ácido Aspártico , Encéfalo/enzimologia , Peptídeos , Proteínas Metiltransferases/metabolismo , Proteína O-Metiltransferase/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Calmodulina/metabolismo , Bovinos , Cinética , Modelos Biológicos , Estereoisomerismo , Especificidade por SubstratoRESUMO
Modification of calmodulin by protein carboxyl methyltransferase requires deamidation of one or more labile asparagine residues (Johnson, B.A., Freitag, N. E., and Aswad, D. W. (1985) J. Biol. Chem. 260, 10913-10916). We now show that deamidation results in the generation of two altered forms of calmodulin, designated A and B, which can be separated by electrophoresis under nondenaturing conditions. The A form is characterized by a larger apparent molecular radius, has only 10% the activity of native calmodulin when assayed for its ability to activate a Ca2+/calmodulin-dependent protein kinase from rat brain, and serves as an excellent substrate for the methyltransferase. The B form more closely resembles native calmodulin: it has an apparent molecular radius more like the native, exhibits about 40% the activity of native calmodulin, and is a relatively poor methyl acceptor. Evidence suggests that the A and B forms probably contain isoaspartate (A) and aspartate (B) in place of Asn-60 and/or Asn-97. Incubation of the A form with methyltransferase and S-adenosyl-L-methionine converts about half of the A form to an electrophoretic band indistinguishable from the B form. The activity of this partly converted calmodulin rises to 30-50% that of native calmodulin. These observations imply that the methyltransferase may have a biological role in restoring activity to proteins which contain abnormal isoaspartyl peptide bonds resulting from asparagine deamidation.