Figure 1

Proposed pathogenesis of PLCH. The primary event in the pathogenesis probably involves cigarette smoke-induced recruitment and activation of Langerhans cells to the small airways, a process that may result from a variety of potential mechanisms. Cigarette smoke activates epithelial cells and macrophages to produce cytokines and chemokines like granulocyte-macrophage colony-stimulating factor (GM-CSF), Chemokine (C-C motif) ligand 20 (CCL20 or Macrophage Inflammatory Protein-3 alpha), transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α) and osteopontin that promote recruitment, retention and activation of Langerhans cells. Cigarette smoke may also directly activate Langerhans cells. Langerhans cells conditioned by cigarette smoke may inappropriately recognize auto-antigens in the lungs and activate adaptive T cell responses that secondarily mediate injury in airway tissues. Chronic inflammation and cytokine production (particularly TGF-β) may promote local fibroblast activation and airway-centered fibrosis. The combination of airway centered inflammation and tissue remodeling promote dilatation of structures distal to the inflamed small airways and cystic formation. It is possible, although not proven, that autoimmunity directed to antigens expressed by epithelial or other lung cells, may promote premature emphysema. Host genetic factors are likely to be very important in disease development, while the potential role of infection or other environmental factors could be relevant in the induction of disease in some instances (although never proven).