Lack of durable protection against cotton smoke-induced acute lung injury in sheep by nebulized single chain urokinase plasminogen activator or tissue plasminogen activator

摘要

Background Airway fibrin casts are clinically important complications of severe inhalational smoke-induced acute lung injury (ISIALI) for which reliable evidence-based therapy is lacking. Nebulized anticoagulants or a tissue plasminogen activator; tPA, has been advocated, but airway bleeding is a known and lethal potential complication. We posited that nebulized delivery of single chain urokinase plasminogen activator, scuPA, is well-tolerated and improves physiologic outcomes in ISIALI. To test this hypothesis, we nebulized scuPA or tPA and delivered these agents every 4?h to sheep with cotton smoke induced ISIALI that were ventilated by either adaptive pressure ventilation/controlled mandatory ventilation (APVcmv; Group 1, n?=?14) or synchronized controlled mandatory ventilation (SCMV)/limited suctioning; Group 2, n?=?32). Physiologic readouts of acute lung injury included arterial blood gas analyses, PaO~(2)/FiO~(2)ratios, peak and plateau airway pressures, lung resistance and static lung compliance. Lung injury was further assessed by histologic scoring. Biochemical analyses included determination of antigenic and enzymographic uPA and tPA levels, plasminogen activator and plasminogen activator inhibitor-1 activities and d -dimer in bronchoalveolar lavage (BAL). Plasma levels of uPA, tPA antigens, d -dimers and α-macroglobulin-uPA complex levels were also assessed. Results In Group 1, tPA at the 2?mg dose was ineffective, but at 4?mg tPA or scuPA, the PaO~(2)/FiO~(2)ratios, peak/plateau pressures improved during evolving injury (p?