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Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the delineation of primary pathways has proven to be elusive.<\/jats:p><jats:p>In this review susceptibility and injurious agents, such as viruses and gastro-oesophageal reflux, and their probable role in initiating disease will be discussed. Further topics that are elaborated are candidate ancillary pathways, including immune mechanisms, oxidative and endoplasmic reticulum stress, activation of the coagulation cascade and the potential role of stem cells. This review will try to provide the reader with an integrated view on the current knowledge and attempts to provide a road map for future research.<\/jats:p><jats:p>It is important to explore robust models of overall pathogenesis, reconciling a large number of clinical and scientific observations. 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