TFF (trefoil factor family) peptides and their potential roles for differentiation processes during airway remodeling

Several lines of defense maintain the surface integrity of the delicate airway epithelium which is regularly subjected to severe trauma. These defense mechanisms include protection by the mucus layer, rapid repair by restitution (cell migration) and regeneration via proliferation and differentiation. Luminal surveillance peptides such as epidermal growth factor (EGF) and trefoil factor family (TFF) peptides support synergistically these processes. TFFs are well known particularly for their key role in mucosal restitution and there is an increasing body of evidence that TFFs also support mucosal differentiation processes. Mucus overproduction during inflammatory and obstructive airway diseases is a partial consequence of an increase in the number of goblet cells due to cell division (goblet cell hyperplasia) or differentiation (goblet cell metaplasia). Particularly the latter process reflects the plasticity of the airway epithelium and causes intense airway remodeling. Goblet cells are derived, at least in part, from Clara cells, which trans-differentiate from a serous into a mucous phenotype. This process is critically dependent upon IL-13. In a recent report (Kouznetsova et al. AJRCMB 36:286-297, 2007) using a murine asthma model it was shown that trans-differentiating Clara cells specifically express Tff1 which is stored in a specific subset of secretory, granules. This points to a role for Tff1 as an autocrine factor for the trans-differentiation of Clara cells toward goblet cells. Such a role of TFFs for differentiation processes of the airways is supported by another recent study (LeSimple et al. AJRCMB 36:296-303, 2007) where induction of TFF3 synthesis was shown with differentiation in in vivo humanized tracheal xenograft and in vitro air-liquid interface culture models. Furthermore, exogenous TFF3 promoted differentiation of ciliated cells in an EGF receptor-dependent manner. Taken together, both studies imply that TFFs may play key roles for various differentiation processes of the airways and they could be promising novel targets in order to treat severe chronic and acute airway diseases.