PROTEASE ACTIVATED RECEPTORS PRESENT ON TYPE II PNEUMOCYTES PLAY AN IMPORTANT ROLE IN PULMONARY SURFACTANT PRODUCTION
Funder
National Health and Medical Research Council
Funding Amount
$562,427.00
Summary
Lung surfactant comprises both lipids and proteins and is secreted by alveolar type II cells into the liquid lining the air-tissue interface. These monolayers stabilise the alveoli, decrease the work of breathing, prevent oedema, and assist in the clearance of foreign particles from the epithelial lining. In addition to this homeostatic role in respiration, there is evidence linking surfactant with removal of harmful microbes and allergy and asthma. Various stimuli are known to control surfactan ....Lung surfactant comprises both lipids and proteins and is secreted by alveolar type II cells into the liquid lining the air-tissue interface. These monolayers stabilise the alveoli, decrease the work of breathing, prevent oedema, and assist in the clearance of foreign particles from the epithelial lining. In addition to this homeostatic role in respiration, there is evidence linking surfactant with removal of harmful microbes and allergy and asthma. Various stimuli are known to control surfactant production to maintain normal, healthy lung function but with microbes and allergen, where inflammation is common, the role of pro-inflammatory proteases and protease activated receptors (PAR) in their biology has not been investigated. Our preliminary findings now show, however, that they are involved. In this proposal, we will determine their importance in surfactant production both in vitro and in vivo. The possibility that proteases and their receptors play a role in surfactant production has not been previously described but if shown to play a role in production, we will have identified a novel pathway that will aid our understanding of the mechanisms of surfactant release and, possibly, lung development. Thus, it is anticipated that results from this study may contribute to a significant reduction in morbidity associated with the above mentioned diseases, resulting in reduction in the cost of health care. Social benefits obtained from study this would be improved health as a result of the application of the findings to patients who currently lead a life heavy dependant on medical interventions.Read moreRead less
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune diseases. An agent that could block the effects of C5a could be very useful clinically. There is no such drug available as yet. We have developed powerful agents which specifically block C5a in laboratory tests on isolated cells and tissues, and now propose to test their effectiveness in rats in which the above human disease conditions are mimicked. Our preliminary results are very promising, and we will conduct further testing to determine the scope of the actions of the new drugs. One of our new agents is orally active in rats, and we will determine how the blood levels of the drug relate to its beneficial effects. We are also planning to develop agents that are more effective when given by mouth. The results could lead to a new type of anti-inflammatory drug for humans suffering from a variety of diseases that are poorly treatable at present.Read moreRead less