RESUMO
Protein tyrosine phosphatase 1B (PTP1B) has anti-inflammatory potential but PTP1B responses are desensitized in the lung by prolonged cigarette smoke exposure. Here we investigate whether PTP1B expression affects lung disease severity during respiratory syncytial viral (RSV) exacerbations of chronic obstructive pulmonary disease (COPD). Ptp1b(-/-) mice infected with RSV exhibit exaggerated immune cell infiltration, damaged epithelial cell barriers, cytokine production, and increased apoptosis. Elevated expression of S100A9, a damage-associated molecular pattern molecule, was observed in the lungs of Ptp1b(-/-) mice during RSV infection. Utilizing a neutralizing anti-S100A9 IgG antibody, it was determined that extracellular S100A9 signaling significantly affects lung damage during RSV infection. Preexposure to cigarette smoke desensitized PTP1B activity that coincided with enhanced S100A9 secretion and inflammation in wild-type animals during RSV infection. S100A9 levels in human bronchoalveolar lavage fluid had an inverse relationship with lung function in healthy subjects, smokers, and COPD subjects. Fully differentiated human bronchial epithelial cells isolated from COPD donors cultured at the air liquid interface secreted more S100A9 than cells from healthy donors or smokers following RSV infection. Together, these findings show that reduced PTP1B responses contribute to disease symptoms in part by enhancing S100A9 expression during viral-associated COPD exacerbations.
Assuntos
Calgranulina B/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Fumar/imunologia , Animais , Anticorpos Neutralizantes/farmacologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Calgranulina B/genética , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Knockout , Cultura Primária de Células , Proteína Tirosina Fosfatase não Receptora Tipo 1/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/virologia , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/crescimento & desenvolvimento , Vírus Sinciciais Respiratórios/imunologia , Transdução de Sinais , Fumar/genética , Fumar/patologia , Poluição por Fumaça de TabacoRESUMO
OBJECTIVES: To describe the incidence of renal dysfunction, hypokalaemia and hypomagnesaemia in AIDS patients with cryptococcal meningitis and on amphotericin B treatment. Secondary objective was to determine all-cause mortality in the same group. DESIGN: Prospective, observational study. SETTING: Kenyatta National Hospital (KNH), Nairobi, Kenya. SUBJECTS: Seventy consecutive patients with AIDS and cryptococcal meningitis on amphotericin B. RESULTS: About 58.6% of the patients had at least 100% rise in the creatinine level. Thirty eight point six per cent of patients experienced a rise in serum creatinine of at least 50%. Ninty three per cent of the patients developed hypokalaemia and 80% had hypomagnesaemia at trough magnesium level. Only 54.3% of patients completed the intended 14-day treatment. Thirty point five per cent of patients died within the two week follow-up period. CONCLUSION: The incidences of amphotericin B associated nephrotoxicity, hypokalemia and hypomagnesaemia were high in this studied population.
