Dry powder aerosolization of a recombinant surfactant protein-C-based surfactant for inhalative treatment of the acutely inflamed lung.
OBJECTIVE
Inhalative application of substantial amounts of pulmonary surfactant to the acutely inflamed lung represents a desirable therapeutic approach but was impossible under clinical conditions because of the technical limitations of currently available devices. We developed a new dry powder aerosolizer for administration of a recombinant surfactant protein-C-based surfactant, determined aerosol characteristics, and evaluated its use in animal models of acute lung injury.


METHODS
Laboratory experiment.


METHODS
University laboratory.


METHODS
Rabbits and mice.


METHODS
The efficacy of an aerosol application of recombinant surfactant protein-C surfactant was assessed in three animal models of acute lung injury: in rabbits with acute lung injury caused by repetitive lavage with prolonged and injurious ventilation; in rabbits at day 4 after inhalative application of bleomycin; and in bleomycin-challenged, spontaneously breathing mice.


RESULTS
Analysis of aerosolizer characteristics revealed favorable properties making inhalative surfactant treatment in acute lung injury/acute respiratory distress syndrome possible. The generated aerosol had a mass median aerodynamic diameter of 1.6 microm, with 85% of all particles being smaller than 5 microm. The average mass of surfactant being aerosolized was approximately 800 mg/min, thus allowing delivery of large amounts of surfactant. Biochemical and biophysical surfactant properties remained unaltered after aerosolization. In both rabbit models aerosolization of approximately 500 mg recombinant surfactant protein-C surfactant resulted in a far-reaching restoration of gas exchange and compliance, with Pao2/Fio2 values approaching control values. In bleomycin-challenged, spontaneously breathing mice, surfactant aerosolization resulted in a restoration of compliance.


CONCLUSIONS
The described dry powder aerosolizer may be applicable to surfactant therapy of acute lung injury/acute respiratory distress syndrome. This conclusion is based on four main factors. High doses comparable to those used for intratracheal instillation in humans can be generated within a relatively short time period, the device can be connected to the inspiratory limb of the ventilator circuit, the aerosolized surfactant material is biophysically fully active, and therapeutic efficacy was proven in three different animal models of acute lung injury/acute respiratory distress syndrome.
Ruppert
Clemens
C
University of Giessen Lung Center, Justus-Liebig University, Department of Internal Medicine, Medical Clinic II, Giessen, Germany.
Kuchenbuch
Tim
T
Boensch
Marc
M
Schmidt
Sebastian
S
Mathes
Uwe
U
Hillebrand
Vera
V
Henneke
Ingrid
I
Markart
Philipp
P
Reiss
Irwin
I
Schermuly
Ralph T
RT
Seeger
Werner
W
Günther
Andreas
A
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000503:physiopathology; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011208:Powders; D037721:Pulmonary Surfactant-Associated Protein C / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D013045:Species Specificity
D000336:Aerosols; D011208:Powders; D037721:Pulmonary Surfactant-Associated Protein C; D011994:Recombinant Proteins