Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury

Abstract

Background Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke‐induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single‐chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. However, neither aerosolized plasminogen activator (PA) yielded durable improvements in physiologic responses or reduction in cast burden. Here, we hypothesized that perfluorochemical (PFC) liquids would facilitate PA distribution and sustain improvements in physiologic outcomes in ISALI. Methods Spontaneously breathing adult sheep (n = 36) received anesthesia and analgesia and were instrumented, exposed to cotton smoke inhalation, and supported by mechanical ventilation for 48 h. Groups (n = 6/group) were studied without supplemental treatment, or, starting 4 h post injury, they received intratracheal low volume (8 mL) PFC liquid alone or a dose range of tPA/PFC or scuPA/PFC suspensions (4 or 8 mg in 8 mL PFC) every 8 h. Outcomes were evaluated by sequential measurements of cardiopulmonary parameters, lung histomorphology, and biochemical analyses of bronchoalveolar lavage fluid. Results Dose‐response and PA‐type comparisons of outcomes demonstrated sustained superiority with low‐volume PFC suspensions of scuPA over tPA or PFC alone, favoring the highest dose of scuPA/PFC suspension over lower doses, without airway bleeding. Conclusions We propose that this improved profile over previously reported aerosolized delivery is likely related to improved dose distribution. Sustained salutary responses to scuPA/PFC suspension delivery in this translational model are encouraging and support the possibility that the observed outcomes could be of clinical importance.

Perfluorocarbons in Research and Clinical Practice: A Narrative Review

“…Several studies have shown the ability of PFCs to increase drug delivery while reducing the side effects related to their systemic administration. 5,[70][71][72][73][74] Animal models demonstrated that gentamicin and vancomycin administration during PLV with PFCs resulted in higher lung concentration compared with intravenous administration and less systemic side effects. 70,71 Similarly, surfactant delivery with PLV allowed a more uniform distribution in both lungs compared with CMV and was associated with improved lung compliance and systemic oxygenation.…”

“…Several studies have shown the ability of PFCs to increase drug delivery while reducing the side effects related to their systemic administration. 5,70–74…”

Administration of Drugs/Gene Products to the Respiratory System: A Historical Perspective of the Use of Inert Liquids

“…In contrast, PFC-facilitated plasminogen activator delivery resulted in significantly better physiologic and histologic outcomes. PFC-facilitated delivery of plasminogen activator demonstrated improved outcomes than achieved by nebulization of plasminogen activators alone ( Wolfson et al, 2020 ).…”