Fipronil is an insecticide that acts at the gamma-aminobutyric acid receptor and glutamate-gated chloride channels in the central nervous systems of target organisms. The use of fipronil is increasing across the globe. Presently, very little data exist on the potential impact of exposure to fipronil on the lungs. We studied the same by exposing mice to fipronil intranasally (N=8) or orally (N=7) for 7 days followed by collection of blood, broncho-alveolar lavage (BAL) fluid and lung tissues. Control mice were given corn oil (N=15). The oral and intranasal exposure routes were chosen because these are the most common routes of exposure for humans and animals. Hematoxylin-eosin stained lung sections showed normal histology in the control lungs compared to the thickened alveolar septa, disruption of the airways epithelium and damage to vascular endothelium in the intranasal and the oral groups. Lung sections stained for von Willebrand factor showed that mice exposed to fipronil either orally or intranasally had increased staining in the endothelium and septal capillaries. Compared to the control mice, TLR4 expression in lungs from animals treated orally with fipronil was reduced while animals exposed intranasally had increased TLR4 staining in the airway epithelium. Similarly, TLR9 stained lungs showed that orally treated animals had reduced TLR9 reaction in the airway epithelial cells but intranasally exposed animals had intense TLR9 staining in the alveolar septa and airway epithelium. The slides were also scored blindly to gain a quantitative understanding of the staining; there were a significantly higher number of TLR4 positive stained cells in the intranasal fipronil group (P=0.010) but no significant differences between treatments for TLR9 positive stained cells (P=0.226). The U937 cell line was employed to compliment the in vivo work. Cells were exposed to fipronil in DMSO at concentrations of 0.29 µm to 5.72 µm per 1 ml for various times from 3, 9 and 24 hours. Viability was assessed and western blots on Toll-like receptors 4 and 9 were completed in addition to immunofluorescence. Cell death was determined with trypan blue method. A significant increase in cell death was observed when the cell line was exposed to higher concentrations of fipronil (P<0.0001). Western blots on TLR4 and 9 revealed no significant differences (TLR4 {P=0.49}, TLR9 {P = 0.94}) between cells exposed to fipronil and those exposed to the control (DMSO). The data taken together show that fipronil causes cell dealth in vitro, and induces lung inflammation following oral or intranasal exposure but has different effects on the expression of TLR4 and TLR9 in vivo. Because of the central roles of TLR4 and TLR9 in lung inflammation, fipronil-induced changes in the expression of these receptors would alter the pulmonary response to bacterial infections in the host exposed to fipronil. Further studies are needed to examine the mechanisms through which fipronil regulates expression of immune receptors and also the pulmonary response of fipronil-exposed animals to subsequent microbial infections.

published_or_final_version / Anaesthesiology / Doctoral / Doctor of Philosophy

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A spectrum of chronic inflammation is commonly seen in association with advanced human atherosclerosis. This local complication of advanced atherosclerosis is termed '<i>chronic periaortitis</i>'. This may be seen sub-clinically in necropsy samples or may present clinically, in more severe cases, as the conditions previously termed 'idiopathic retroperitoneal fibrosis', 'inflammatory aneurysm' or 'peri-aneurysmal retroperitoneal fibrosis'. The inflammatory cells consist of lymphocytes and plasma cells. Thinning or breaching of the media is common to all forms. A histological survey of necropsy material and surgical material has confirmed the unifying concept of chronic periaortitis. Histochemical, immunohistochemical, immunofluorescence and electron microscopy have been used in this study to examine the nature of the inflammatory response. Locally activated B lymphocytes are stimulated to produce immunoglobulin, predominantly IgG, to oxidised low density lipoprotein (LDL) and ceroid elaborated with human atheroma. T helper lymphocytes and HLA-DR positive cells mediate this response. These findings have been confirmed using <i>in vitro</i> culture of lymphocytes derived from tissue and peripheral blood of patients with chronic periaortitis. Antibodies to oxidized LDL and ceroid have been detected in serum from patients with chronic periaortitis using a modified ELISA technique. This has led to the development of a potential diagnostic test for chronic periaortitis. These results support the hypothesis that chronic periaortitis has an auto-allergic cause and that the allergen is a component of ceroid, likely to be oxidized LDL, elaborated in human atherosclerotic plaques.

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