1-2-oleoylphosphatidylcholine and Disease-Models--Animal

Inflammation, the major hallmark of all chronic respiratory diseases is generally managed by inhaled corticosteroids. However, long term high dose treatment can result in significant side effects. Hence, there is a medical need for non-steroidal anti-inflammatory therapies to address airway inflammation. Phospholipids have been shown to reduce inflammation in several inflammatory conditions; however, their clinical translation has been limited to liposomal formulations traditionally used as drug carriers and their biological activity has not been investigated. Here we report the first application of empty liposomes as an anti-inflammatory treatment in airway inflammation. In the current study, liposomes (UTS-001) were prepared from cholesterol and a synthetic phospholipid (DOPC). The formulation was characterised in terms of size, charge, polydispersity index, morphology and stability as colloidal suspension and freeze-dried nanoparticles. Time-dependant uptake of UTS-001 in airway epithelial cells was observed which was inhibited by nystatin demonstrating that the uptake is via the caveolae pathway. In-vitro, in primary nasal epithelial cells, UTS-001 treatment successfully attenuated IL-6 levels following TNF-α stimulation. Consistent with the in-vitro findings, in-vivo, in the ovalbumin model of allergic airway inflammation, UTS-001 significantly reduced total immune cell counts in bronchoalveolar lavage fluid and reduced airway hyperresponsiveness in response to increasing doses of methacholine challenge. Therefore, our results establish UTS-001 as a potential anti-inflammatory treatment that may be useful as a therapeutic for lung inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cholesterol; Colloids; Disease Models, Animal; Drug Compounding; Female; Humans; Interleukin-6; Liposomes; Mice, Inbred C57BL; Nanoparticles; Nasal Mucosa; Ovalbumin; Phosphatidylcholines; Pneumonia; Respiratory Hypersensitivity; Tumor Necrosis Factor-alpha

Impairment of surfactant is involved in development of acute respiratory distress syndrome. To develop artificial surfactant substitute for clinical use, we prepared synthetically reconstituted surfactant (SRS) by adding porcine surfactant-associated protein B and C (SP-B and SP-C) to synthetic phospholipids, and compared its effect with that of modified natural surfactant (MNS) in rats with acute lung injury caused by endotoxin.. Escherichia coli endotoxin (71+18 mg x kg(-1), mean+/-SD) was injected into the tracheas of 27 anesthetized and mechanically ventilated rats (FI(O2) of 1.0). When the PaO2 had decreased to below 26.7 kPa, the rats were randomly assigned to three groups. The MNS and SRS groups (n=9, each) were given 100 mg x kg(-1) of MNS and SRS through the airway, respectively. The control group (n=9) was given air in the same volume.. The PaO2 of the control group remained below 13.3 kPa until the end of the experiment (6 h after the assignment). The PaO2 of the MNS group increased to 45.3+/-9.5 kPa and that of the SRS group to 45.5+/-3.7 kPa 0.5 h after the assignment (P<0.05 vs. control group). The PaO2 of both groups remained above 40 kPa throughout the experiment.. In this acute lung injury model, the effects of replacement therapy with surfactant consisting of synthetic phospholipids, SP-B and SP-C, were the same as those observed with MNS. These results warrant development of surfactant substitutes based on natural SP-B and SP-C, and synthetic phospholipids.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Animals; Disease Models, Animal; Endotoxins; Escherichia coli; Follow-Up Studies; Male; Oxygen; Partial Pressure; Phosphatidylcholines; Phosphatidylglycerols; Positive-Pressure Respiration; Proteolipids; Pulmonary Surfactants; Random Allocation; Rats; Rats, Wistar; Respiratory Distress Syndrome