Background: Alterations to pulmonary surfactant composition have been encountered in the Acute Respiratory Distress Syndrome (ARDS). However, only few data are available regarding the time-course and duration of surfactant changes in ARDS patients, although this information may largely influence the optimum design of clinical trials addressing surfactant replacement therapy. We therefore examined the time-course of surfactant changes in 15 patients with direct ARDS (pneumonia, aspiration) over the first 8 days after onset of mechanical ventilation.

Intraalveolar and intravascular fibrin formation are typical hallmarks of acute inflammatory lung diseases, and may foster subsequent fibroproliferative events. We investigated the regulation and cellular sources of key coagulation and fibrinolysis factors in lungs undergoing compartmentalized challenge with endotoxin (LPS). BALB/c mice received 15 ng LPS either by intravenous injection or by inhalation. Quantitative gene expression analysis (real-time RT-PCR) was performed for tissue factor (TF), TF pathway inhibitor (TFPI), tissue-type plasminogen activator (t-PA), urokinase-type-PA (u-PA), PA inhibitor-1 (PAI-1), and PAI-2 in peripheral white blood cells (PBC) as well as in alveolar macrophages (AM), type-II pneumocytes (ATII), endothelial cells (EC) and smooth muscle cells (SMC), all obtained by laser microdissection. Neither route of LPS administration caused substantial protein leakage or leukocyte recruitment into the alveolar space. Compartmentalized upregulation of procoagulant and downregulation of fibrinolytic activities was, however, observed in response to both modes of LPS challenge. Intraalveolar endotoxin, in particular, caused strong upregulation of TF ( approximately 20-fold increase in gene expression) and PAI-2 (225-fold increase) in microdissected AM, upregulation of PAI-1 in microdissected ATII (300-fold increase) and EC (180-fold increase), upregulation of t-PA in EC (40-fold), and downregulation of u-PA in vascular smooth muscle cells. TFPI was largely unchanged in all cell types, and PBC showed no major gene regulatory response to inhaled endotoxin. We conclude that the lung possesses a cell-specific alveolar coagulation and fibrinolysis system, being independent of the vascular coagulation cascade and responding readily with enhanced procoagulant and anti-fibrinolytic activities to LPS challenge.

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.