CATHELICIDINS AND SURFACTANT PROTEINS IN CHRONIC RHINOSINUSITIS: A CLINICAL AND EXPERIMENTAL STUDY ENG HOOI OOI Department of Surgery, Faculty of Health Sciences, The Queen Elizabeth Hospital, University of Adelaide, South Australia, Australia A thesis submitted in fulfilments of the requirement for the Degree of Doctor of Philosophy on 7th June 2007 TABLE OF CONTENTS CATHELICIDINS AND SURFACTANT PROTEINS IN CHRONIC RHINOSINUSITIS: A CLINICAL AND EXPERIMENTAL STUDY..............................1 Acknowledgement..............................................................................................................4 Abstract..............................................................................................................................5 Declaration ........................................................................................................................7 Chapter 1 ...........................................................................................................................8 Literature review ..................................................................................................................... 8 Chronic rhinosinusitis..........................................................................................................................8 Clinical features of chronic rhinosinusitis ........................................................................................8 Table 1 .......................................................................................................................................9 Treatment for chronic rhinosinusitis.................................................................................................9 Factors associated with chronic rhinosinusitis................................................................................10 Allergic Fungal Sinusitis (AFS) .........................................................................................................11 Pathogenesis of AFS .....................................................................................................................14 IgE vs Non-IgE mediated inflammation ....................................................................................14 Controversies of the role of fungi in the pathogenesis of CRS and AFS......................................16 Putative inflammatory mediators in AFS...................................................................................18 Treatment of AFS..........................................................................................................................18 Summary of AFS and EMCRS ......................................................................................................20 Biofilms ............................................................................................................................................20 Superantigens ....................................................................................................................................21 Aspirin sensitivity..............................................................................................................................22 Immune disorders ..............................................................................................................................22 Innate immunity in the human sinonasal tract .....................................................................................23 Introduction of innate immunity ....................................................................................................23 The sinonasal tract and innate immunity ........................................................................................23 The inflammatory response in chronic rhinosinusitis .................................................................24 The immune system ......................................................................................................................26 Table 2 .....................................................................................................................................26 Innate immune recognition ............................................................................................................28 Pattern-recognition receptors .........................................................................................................28 Linking innate immune responses and the acquired immune response ............................................29 Cellular components of innate responses........................................................................................30 Soluble factors in innate responses.................................................................................................32 Disorders of Innate immunity.............................................................................................................33 Host-defence functions of human nasal antimicrobial polypeptides.....................................................33 Nasal secretions analysed by minimally manipulated suction or nasal lavage ......................................34 Human defensins...........................................................................................................................34 Human cathelicidins ..........................................................................................................................35 Introduction ..................................................................................................................................35 Role of the cathelin-like domain................................................................................................37 Antimicrobial activity of cathelicidin hCAP18 or LL-37 ................................................................37 Cathelicidins immunomological functions .....................................................................................38 Chemotaxis...............................................................................................................................38 Modulation of gene expression in immune cells ........................................................................39 Wound healing and angiogenesis ..............................................................................................39 Binding to Lipopolysaccharide (LPS)........................................................................................40 Putative receptors and signaling pathways involved in the effects of LL-37 on cells .......................40 Regulation of cathelicidin gene expression.....................................................................................41 Inactivation of cathelicidins...........................................................................................................42 Studies of cathelicidins in otorhinolaryngology associated diseases................................................43 Surfactant Proteins.............................................................................................................................43 Introduction..............................................................................................................................43 Protein Structure.......................................................................................................................44 Surfactant Protein A......................................................................................................................44 Surfactant protein D ......................................................................................................................45 Synthesis of SP-D.....................................................................................................................46 2 Microbial targets: SP-D as a pattern recognition receptor ...............................................................47 SP-D immunological functions......................................................................................................48 Phagocytosis.............................................................................................................................48 Chemotaxis...............................................................................................................................48 Modulation of T cell responses by SP-A and SP-D....................................................................49 Apoptosis .................................................................................................................................49 Interaction of SP-D with allergens .................................................................................................50 SP-D gene regulation.....................................................................................................................51 Pulmonary and extra-pulmonary distribution of SP-D ....................................................................52 Surfactant protein-D gene targeted mice ........................................................................................53 Inactivation of SP-D......................................................................................................................54 Studies of SP-A, SP-D in otorhinolaryngology associated disease ..................................................55 Conclusion ........................................................................................................................................55