Over 35 years ago Wanda Haschek and Hanspeter Witschi published a theory for the pathogenesis of lung fibrosis that dared to challenge the longstanding view of lung fibrosis as an “inflammatory disease. regimens has led some investigators to revive the theory referred to in decades past as “The Witschi Hypothesis.” This manuscript briefly reviews more recent evidence in support of the “Severity of Epithelial Injury” Hypothesis proposed by Haschek and Witschi. More important it offers the updated CP-466722 viewpoint that mutations in the BRICHOS domain of surfactant protein C which cause interstitial lung disease and induce cell death specifically in lung epithelial cells in effect provide genetic proof that the Witschi Hypothesis is indeed the correct theory to explain the pathogenesis of fibrosis in the lungs. Keywords: lung fibrosis idiopathic pulmonary fibrosis alveolar epithelial cells type II pneumocyte epithelial-mesenchymal cross talk this article is intended to address one side which we believe is the correct side of a debate that continues to be held each year at the annual American Thoracic Society (ATS) and European Respiratory Society (ERS) meetings and every other year at the International Colloquium on Lung and Airway Fibrosis (ICLAF). The debate concerns the pathogenesis of pulmonary fibrosis which was for many years believed to be an “inflammatory disease. ” As will be reviewed briefly below there is much evidence against this traditional CP-466722 view. The correct side of this debate which has been slowly gaining acceptance is the alternate concept that lung fibrogenesis is initiated and propagated by alveolar epithelial “disrepair ” “activation ” or simply “death ” regardless of the presence or absence of inflammation. To those readers who consider the origin of this concept to be relatively recent it is not: it was proposed over 35 years ago by Haschek and Witschi (15) on the basis of considerable experimental evidence that seems to this author at least to have been forgotten or worse ignored. For reasons unclear but likely not in any way CP-466722 disrespectful to Dr. Haschek in the years and decades following the initial publication the ideas first discussed in this seminal paper became known and referred to as the “Witschi Hypothesis ” to be discussed in more detail below. The writing of this Perspective was stimulated by two CP-466722 recent events that I (B. D. Uhal) would like to share. For many years I regularly attended the biennial ICLAF meeting the last edition of which was held in Modena Italy October 2012 under the superb organization and hospitality of Prof. Luca Richeldi of the University of Modena and Reggio Emilia. At the 2012 edition the organizers held successful and informative breakout sessions at which all attendees split into two groups to debate among other topics the “inflammatory” vs. “epithelial” theories described above. Shortly after the debate began I joined the discussion and asked my breakout group of approximately 50 persons “How many people in the room remember the Witschi Hypothesis?” To my astonishment and dismay only two hands arose from a room filled with scientists all of whom are currently working on lung fibrogenesis research. I remember at that moment hoping sincerely that some of those who did not raise their hands were just asleep perhaps from excess grappa the previous evening or perhaps simply didn’t remember the name associated with the groundbreaking work to which I had referred. My short recital of the ideas that Haschek and Witschi so elegantly discovered was greeted with approving nods from the two souls who raised their hands but blank stares from most others. That memory planted in my head the seed for this writing but it germinated the following May CP-466722 at the ATS International Congress in Philadelphia where similar Tsc2 debates were held again with both sides of the debate “agreeing to disagree” as usual. But the single event that galvanized my resolve to write was my meeting of a young scientist who shall go unnamed here who presented an excellent and well-attended experimental study. Among his findings was a set of data that in his words appeared to “very surprisingly dissociate the processes of.