The Alveolar Epithelium and Pulmonary Fibrosis

Idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse pulmonary parenchymal diseases that are comprised of seven distinct clinical and pathological entities. Idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP) represent two of the most prevalent members of the disease group with major differences in their pathogenesis, clinical course and prognosis. IPF is a refractory and lethal IIP characterized by fibroblast prolifera- tion, deposition of extracellular matrix (ECM) and progressive lung scarring. The incidence of IPF is estimated at 15 to 40 cases per 100,000 per year, and the mean survival from the time of diagnosis is 3 to 5 years regardless of treatment. While its pathogenesis is incompletely understood, the currently accepted paradigm proposes that injury of the alveolar epithe- lium is followed by a burst of pro-inflammatory and fibroproliferative mediators that invoke responses associated with dysregulated repair of the damaged alveolar epithelium. Recently, there have been studies suggesting that the activation of the alveolar epithelial cells (AECs) may play an active role in the pathogenesis of pulmonary fibrosis. Here, we review the advances in recent studies on the role of the alveolar epithelium in pulmonary fibrosis. AECS: A BRIEF OVERVIEW OF STRUCTURE AND PHYSIOLOGICAL FUNCTIONS Two types of AECs populate the alveolar epithelium in normal adult lungs, alveolar epithelial type I (AT I) and al- veolar epithelial type II (AT II) cells. AT I pneumocytes comprise 40% of the AECs and cover 90% of the internal surface area of the lung. AT I cells are highly attenuated and form an interface with pulmonary capillaries that are inti- mately involved in gas exchange. These cells also take part in peptide and amino acid transportation across the lung by pinocytosis and transporter-mediated transport (1). Recently, AT I cells have been shown to be also important in the trans- portation of water and sodium across the lung (2, 3). AT II cells, on the other hand, AT II cells make up 16% of the parenchymal cells in the lung and account for only 5% of the alveolar surface. These cells are cuboidal cells that are situated between AT I cells and they contain characteristic lamellar bodies and apical microvilli. AT II cells synthesize, store and secrete the pulmonary surfactant (PS), which con- sists of lipids and their associated proteins and whose func- tion is to reduce the surface tension of the lung alveolus and prevent it from collapse or overdistension with respiration. AT II cells also regulate alveolar fluid balance in normal lungs and during the resolution of pulmonary edema (4) and the pathogenesis of acute lung injury with pulmonary edema is associated with an insufficient number of AT II cells and transportation of water into the lung alveolus. Recently, AT II cells have been shown to synthesize and secrete immuno- modulatory proteins important for host defense, including surfactant proteins A (SP-A) and D (SP-D) (5). SP-A can combine with lipid A in the lipopolysaccharide on the sur- face of bacterium and it also regulates the activities of