FITC-induced murine pulmonary inflammation: CC10 up-regulation and concurrent Shh expression.

We describe an immunohistochemical study of the acute and chronic effects of fluorescein isothiocyanate (FITC) on Sonic hedgehog (Shh) expression and Clara cell secretory protein (CC10) up-regulation in murine lung. FITC was dissolved in PBS and instilled non-surgically into adult mouse lungs via the trachea. During the acute phase (120h) of the FITC response, CC10 staining within Clara cells increased markedly but the protein did not leak into the tissue spaces or the airways, and no fibrosis was apparent. An immune response was evident, characterised by infiltrating T and B lymphocytes. There was no concomitant expression of Shh. During the chronic phase (6 months post-instillation), significant tissue degeneration was observed in the airways. There was moderate to severe fibrosis in the lung fields that stained positively for FITC and significant inflammatory cell infiltrate was observed. Shh was expressed, and CC10 showed multiple sites of diffuse staining consistent with release from Clara cells into alveolar air spaces. PBS controls showed no fibrosis after 6 months, but there was positive Shh staining below the airway epithelia and minimal extracellular CC10 staining. The results may throw some light on the role of CC10 in pulmonary inflammation. The relationship of Shh expression and CC10 leakage to lung damage and repair is discussed.

Expression of the developmental Sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes.

During pulmonary development, Sonic hedgehog (Shh) and transforming growth factor beta1 (TGF-beta1) signalling both contribute to branching morphogenesis. In interstitial lung disease, the complex alveolar structure of the lung is disrupted and remodelled, which leads to fibrosis, loss of respiratory surface, morbidity, and mortality. It is well documented that TGF-beta1 is involved in fibrosis. However, little is known about Shh signalling in damaged epithelia. This study examined whether or not components of the Shh signalling pathway, as well as TGF-beta1, are expressed in human fibrotic lung disease (cryptogenic fibrosing alveolitis and bronchiectasis) and in murine experimental models of fibrotic and non-fibrotic chronic pulmonary inflammation. Using immunohistochemistry, it was observed that Shh, like TGF-beta1, is up-regulated in epithelial cells at sites of fibrotic disease but not non-fibrotic inflammation. The Shh receptor patched was detected in infiltrating mononuclear cells and alveolar macrophages, as well as normal resting peripheral blood T lymphocytes. Neither Shh nor patched is expressed by hyperproliferative goblet cells in inflammatory epithelium. This study demonstrates that patched is present in human peripheral CD4 and CD8 lymphocytes at both protein and mRNA levels. Taken together, these results suggest that components of the highly conserved Shh signalling pathway may play a role in the remodelling of damaged pulmonary epithelium and that damaged epithelium and cells of the immune system may communicate via this pathway.