Selective serotonin reuptake inhibitors and tricyclic antidepressants : novel immunomodulating agents

• Main Author: Gordon, Sevelanne
• Published: University of Brighton 2012
• Subjects: 616.24; B000 Health Professions
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590050

Acute respiratory distress syndrome (ARDS) is an inflammatory disease in humans where no satisfactory therapeutic options exist. Regulation of the immune system by neurotransmitters has been identified as a possible exploitable strategy to treat inflammatory conditions. Antidepressant drugs have been found to have secondary actions including anti-inflammatory activity in a wide range of disease states in vivo. The cellular effects of these drugs that contribute to this effect have yet to be elucidated. The aim was to examine whether anti-depressants have a direct effect on the immune system or an effect on the target tissue such as lung cells. This thesis utilised both primary lung epithelium cells along with the cell lines A549, 16HBE14o- and BETIY02. The macrophage cell line RAW 264.7 was used to determine effects of anti-depressants on immune cells. Mitochondrial function was used as a measure of cell viability while morphological techniques were used to determine levels of apoptosis and necrosis. Cellular cytokine release was used as a determination of inflammation. Nitric oxide production by activated immune cells was measured using the nitrite assay and the expression of inducible nitric oxide synthase measured by Western blot. The BETIY02 cell line was found to have the most similar characteristics to primary lung epithelium cells and could be used as an effective substitute for large-scale screening and mechanistic studies especially in inflammation. Fluoxetine and desipramine reduced the inflammatory signals coming from lung cells exposed to lipopolysaccharide (LPS). In addition to this they proved effective in reducing immune cell activation as evidenced by reduced NO release following LPS exposure via a mechanism of inhibiting iN OS protein expression. Fluoxetine and desipramine exhibited anti-inflammatory effects on both the lung cells and the immune cells, identifying possible therapeutic potential for ARDS.