The Witschi Hypothesis revisited after 35 years: genetic proof from SP-C BRICHOS domain mutations

Am J Physiol Lung Cell Mol Physiol. 2013 Dec;305(12):L906-11. doi: 10.1152/ajplung.00246.2013. Epub 2013 Oct 18.


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." On the basis of considerable experimental evidence, they proposed that lung fibrosis was initiated and propagated by microfoci of epithelial damage that, if unrepaired, upset the normal epithelial-fibroblast balance to create profibrotic microenvironments, without any obligatory contribution of "inflammatory" cells. Unfortunately, this theory was largely overlooked for many years. In the meantime, the repeated failure of attempts to treat idiopathic pulmonary fibrosis with anti-inflammatory 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 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: alveolar epithelial cells; epithelial-mesenchymal cross talk; idiopathic pulmonary fibrosis; lung fibrosis; type II pneumocyte.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Humans
  • Mutation / genetics*
  • Protein Structure, Tertiary
  • Pulmonary Alveoli / immunology
  • Pulmonary Alveoli / metabolism
  • Pulmonary Fibrosis / diagnosis
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / pathology
  • Pulmonary Surfactant-Associated Proteins / chemistry
  • Pulmonary Surfactant-Associated Proteins / genetics*


  • Pulmonary Surfactant-Associated Proteins