RESUMO
The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac-/-) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.
Assuntos
Mucina-5AC , Doença Pulmonar Obstrutiva Crônica , Trifosfato de Adenosina/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Camundongos , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucina-5B/genética , Mucina-5B/metabolismo , Muco/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/virologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologiaAssuntos
Líquidos Corporais/fisiologia , Fibroblastos/fisiologia , Expressão Gênica , Interleucina-1/fisiologia , Mitógenos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Edema Pulmonar/genética , Síndrome do Desconforto Respiratório/complicações , Adesão Celular , Divisão Celular , Fibroblastos/metabolismo , Humanos , Inflamação , Pulmão/patologia , Mitógenos/metabolismo , Alvéolos Pulmonares/metabolismo , Edema Pulmonar/etiologia , Edema Pulmonar/patologia , Edema Pulmonar/fisiopatologiaRESUMO
The alveolar fibrinolytic system is altered in acute lung injury (ALI). Levels of the fibrinolytic protease inhibitor, plasminogen activator inhibitor-1 (PAI-1), are too low in bronchoalveolar lavage to address its prognostic significance. This study was performed to assess whether PAI-1 antigen in undiluted pulmonary edema fluid levels can identify patients with ALI and predict their outcome. PAI-1 antigen levels in both plasma and edema fluid were higher in ALI compared with hydrostatic edema, and edema fluid PAI-1 values identified those with ALI with high sensitivity and specificity. Both the high plasma and edema fluid PAI-1 antigen values were associated with a higher mortality rate and fewer days of unassisted ventilation in patients with ALI. Differences in PAI-1 activity were concordant with levels of PAI-1 antigen. Although the fibrin-derived alveolar D-dimer levels were strikingly similar in both groups, ALI patients had a higher relative proportion of D-monomer. In conclusion, PAI-1 levels in edema fluid and plasma identify those with ALI that have a poor prognosis. The data indicate that fibrin turnover in early ALI is a consequence of a rapid fibrinogen influx and fractional fibrinolytic inhibition.