(1) Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, USA
(2) Regions Hospital, St. Paul, USA
(3) University of Lisbon, Lisbon, Portugal
(4) Departments of Medicine and Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, USA
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Apoptosis has been implicated in the process of lung injury. A drug that inhibits apoptosis could be very helpful to understand the role of programmed cell death in ventilator-induced lung injury (VILI). We examined whether tauroursodeoxycholic acid (TUDCA), an anti-apoptotic bile acid prevents ventilator-induced apoptosis in rabbit model of VILI.
Materials and methods
Following median thoracotomy (open chest model), rabbits (n=15) were randomly assigned. Controls were ventilated for 4 h with Pressure Control Ventilation (PCV) using a low peak pressure of 10 cm H2O (group 1). Experimental animals received PCV using a high peak pressure of 25 cm H2O (groups 2 and 3). Group 3 also received TUDCA via a 100mg/kg bolus followed by 50 mg/kg/h maintenance dose. At the end of the protocol, the animals were euthanized, the left lung was removed for wet weight to dry weight (WW/DW) determinations and kidney/right lung samples were stored for TUNEL assay of apoptosis. Primary endpoints included apoptosis. How TUDCA affected WW/DW, PaO2/FIO2 ratios and the haemodynamics were secondary end-points.
High levels of apoptosis were seen in the lungs of group 2 but not in the kidneys of any group. The addition of TUDCA in group 3 reduced apoptosis in the lung to a level similar to controls. There were significant differences in WW/DW and PaO2/FIO2 between the control and the 2 experimental groups but not between groups 2 and 3. TUDCA appears to reduce the rise in pulmonary vascular resistance associated with VILI and help maintain cardiac output.
Ventilation with high pressure induced cellular apoptosis in lung but not kidneys. TUDCA significantly reduced ventilator-induced apoptosis in the lungs. This study is the first to demonstrate that the reduced cardiac output, increased pulmonary vascular resistance and apoptosis in the lungs associated with VILI is reduced by TUDCA.