Mini-Symposium: Interstitial lung diseases in childhood Interstitial lung disease: Physiopathology in the context of lung growth Nadia Nathan 1,2,3 , Guillaume Thouvenin 1,2,3 , Brigitte Fauroux 1,2,3 , Harriet Corvol 1,2,3 , Annick Clement 1,2,3, * 1 Inserm, UMR-S U938, Paris, F-75012 France 2 Universite ´ Pierre et Marie Curie-Paris6, Paris, F-75012 France 3 AP-HP, Hoˆpital Trousseau, Pediatric Pulmonary Department, Paris, F-75012 France INTRODUCTION Interstitial lung diseases (ILDs) in children represent a hetero- geneous group of respiratory disorders characterized by the presence of diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with evidence of restrictive ventilatory defect and/or impaired gas exchange. 1–5 The main pathologic changes are derangements of the alveolar walls. ILD develops after epithelial damage which triggers the accumulation and activation of immuno-inflammatory cells, with subsequent migration and proliferation of fibroblasts and deposition of extra-cellular matrix. From numerous clinical studies, there is compelling evidence that expression and outcome of ILD in children differ from adult ILD, strongly suggesting that additional events related to lung growth and development play a critical role in disease progression. 6 This article reviews recent advances in the understanding of the mechanisms involved in the pathogenesis of ILD in children. ALTERED REPAIR PROCESS OF THE ALVEOLAR EPITHELIUM IN ILD The key pathologic feature of ILD is the altered repair of the alveolar surface with marked disruption in the integrity of the epithelium. 7,8 The alveolar epithelium consists of type I and type II alveolar epithelial cells (AECsI and AECsII). The alveolar surface is mainly covered by AECsI, which are membranous cells usually found overlying the capillaries. The AECsII are large cuboidal cells located in the alveolar corners. 9 They have the ability to divide, and are believed to serve as the progenitors of the alveolar epithelium, being capable of both self-renewal and of giving rise to AECsI through a process of transdifferentiation. Consistent with a central role of the alveolar epithelium in disease pathogenesis, AECs in idiopathic pulmonary fibrosis (IPF) appear morphologically abnormal, with hyperplastic AECsII and reactive elongated cells displaying an intermediate phenotype between AECII and AECI, suggesting an impaired transdifferentiation of AECII to AECI, which may contribute to the abnormal epithelium repair. 10–12 An important feature of the pathologic process observed in ILD is linked to an altered communication between epithelial and mesenchymal pulmonary components. Prolonged denudation of the basement membrane after injury contributes to altered interactions between AECs and mesenchymal cells, resulting in profound modifications of cell functions with imbalanced produc- tion of polypeptide mediators including cytokines, growth factors, oxidants, and proteases. 13–15 The population of fibroblasts and myofibroblasts progressively increases due to stimulation of proliferation by local mitogenic factors and reduction of apoptosis. The resulting aberrant tissue remodeling is characterized by disorganization of extracellular matrix component deposition, including fibrillar collagen, elastic fibers, fibronectin and proteo- glycans (Figure 1). This is associated with the formation of new blood vessels following the induction of angiogenic molecules, Paediatric Respiratory Reviews 12 (2011) 216–222 A R T I C L E I N F O Keywords: Interstitial lung disease Alveolar epithelial cells Endoplasmic reticulum stress Transforming growth factor-b Surfactant S U M M A R Y Interstitial lung diseases (ILDs) in children represent a heterogeneous group of respiratory disorders characterized by derangements of the alveolar walls. The key pathologic feature of ILDs is the altered repair of the alveolar surface after injury with a marked disruption in the integrity of the epithelium and, consequently, a dysregulated communication between epithelial and mesenchymal pulmonary components. Concomitant to the loss of cell-cell contact, epithelial cells undergo a process called epithelial to mesenchymal transition and acquire a mesenchymal identity. Among the factors involved in disease progression, transforming growth factor-b has been identified as a master switch in the induction of fibrosis. This article reviews recent advances in the understanding of the mechanisms involved in the pathogenesis of ILDs, and provides information on their adaptation in the context of lung growth. Crown Copyright ß 2011 Published by Elsevier Ltd. All rights reserved. * Corresponding author. AP-HP, Ho ˆpital Trousseau, Pediatric Pulmonary Depart- ment, Inserm, UMR-S U938, UPMC, Paris6, 26 Avenue du Docteur Arnold Netter, 75571 Paris cedex 12, France. E-mail address: annick.clement@trs.aphp.fr (A. Clement). Contents lists available at ScienceDirect Paediatric Respiratory Reviews 1526-0542/$ – see front matter . Crown Copyright ß 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2011.04.003