Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and “endotyped” human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

commentary review reports primary research AE2 = alveolar epithelial cell type II; BAL = bronchoalveolar lavage; GM-CSF = granulocyte-macrophage colony-stimulating factor; ICAM = intercellular cell-adhesion molecule; KGF = keratinocyte growth factor; MCP-1 = monocyte chemotactic polypeptide-1; RANTES = regulated on activation, normal T cell expressed and secreted; SP = surfactant protein; TGF = transforming growth factor; TNF = tumour necrosis factor; VCAM = vascular celladhesion molecule.Available online http://respiratory-research.com/content/2/1/033 IntroductionAs early as 1954, CC Macklin had postulated some of the most important functions of the great pneumocyte, ie the pneumocyte type II or alveolar epithelial type II (AE2) cell ( Fig. 1) [1]. Macklin presumed that these cells secrete material that provides low surface tension, enhances clearance of inhaled particles, is bacteriostatic, and helps prevent transudation of interstitial fluid into the alveolus. He further reported that these cells proliferate after lung injury by osmium tetroxide fumes [1]. By 1977, enough data had been collected to stimulate Mason and Williams [2] to formulate the concept of the AE2 cell as a "defender of the alveolus". It was established that the main functions were synthesis and secretion of surface-active material, hyperplasia in reaction to alveolar epithelial injury, and serving as the progenitor for AE1 cells, which form the epithelial component of the thin air-blood barrier. Nevertheless, several "postulated" functions were listed, for example, secretion of other substances, modulation of the alveolar hypophase, and adaptation in response to lung injury [2]. In the following 23 years, an increasing number of studies revealed many more details concerning the role of the AE2 cell in surfactant delivery and alveolar epithelial repair (see Supplementary Table 1) and a considerable number of supplementary functions have been established (see Supplementary Table 2). This review covers most aspects of current knowledge of AE2 cell functions. The AE2 cell as the source of alveolar surfactant Composition of surfactantAlthough the presence of a surface-active agent in the mammalian lung was postulated by von Neergaard as early as 1929 [3], it was the work of Pattle Clements [5] that opened a new scientific field (for review of historical aspects, see [6]). This surface-active agent, termed surfactant, was characterised in numerous biochemical studies of bronchoalveolar lavage (BAL) material and is now known to be composed of ≈90% (mass) lipids (with ≈80-90% phospholipids) and of ≈10% proteins. Its composition may deviate greatly in pathologic states (for review, see eg [7]). Unlike most other lipid-rich components of cells and organs, the surfactant lipids are characterised by an unusually high level of saturated fatty acid chains, such as the predominant dipalmitoylphosphatidylcholines, which contribute substantially to the unique properties of pulmonary surfactant (for review, see eg [8]). The protein fraction comprises a hi...

This study demonstrates that IL-37 is able to ablate a TH2 cell-directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Rα as well as the orphan receptor SIGIRR/IL-1R8.

A model of inducible expansion of the gas exchange area in adult mice would be ideal for the investigation of molecular determinants of airspace regeneration in vivo. Therefore, the post-pneumonectomy (post-PNX) compensatory lung growth in adult C57BL/6 mice was characterised in this study.Mice underwent left-sided PNX. Right lung volume was assessed on days 1, 3, 5, 7, 10 and 21 after PNX, and total DNA and cellular proliferation of the right lung were determined. Lung histology was studied using immunohistochemistry and quantitatively characterised by detailed stereological investigations. Pulmonary function was assessed using a mouse body-plethysmograph.Following PNX, right-lung volume rapidly restored the initial volume of left and right lung. Total DNA increased significantly over 21 days and equalled the total DNA amount of both lungs in the control mice. Septal cell proliferation significantly increased after PNX, and included endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. Stereological investigations of left and right control lungs versus right lungs 21 days after PNX indicated complete restoration of body mass-specific alveolar surface area. Pulmonary function testing showed marked alteration at 3 days and normalisation at 21 days post-PNX.In conclusion, well reproducible reconstitution of alveolar gas-exchange surface based on septal tissue expansion may be provoked by pneumonectomy in adult mice. Eur Respir J 2004; 24: 524-532. Several pulmonary diseases originate from or are deteriorated by the loss of alveolar septae or, alternatively, remodelling processes of the septal walls, which result in severely compromised gas exchange within the alveoli. The principal ability of mammals to completely restore lung function after major losses of lung tissue by compensatory development of additional gas-exchange surface areas provides a rationale for identifying intrinsic regenerative programmes of the lung that may be employed for therapeutic purposes.The molecular basis of alveolar generation and alveolar remodelling is presently not well understood [1]. Furthermore, the cellular components which contribute to repair and remodelling of pulmonary tissue still await ultimate elucidation. Solutions to the problems concerning repair and regeneration of lung tissue for restoration of functional alveoli are at the cutting edge of identifying novel therapeutic options for lung diseases like chronic obstructive pulmonary disease (COPD) and fibrosis.It has been previously reported that partial resection of the lung results in a rapid compensatory growth process of the remaining lung tissue, restoring normal lung volume, cell mass and organ function, in a variety of mammalian species [2][3][4][5][6]. Compensatory lung growth following unilateral pneumonectomy (PNX) has been documented for dogs, rabbits, ferrets, rats and mice. However, it has been most extensively studied in rats, and the time course, volumetric and morphological changes are well characterised in this species [7,8]...

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules. Blockade of RAGE has been reported to considerably improve liver function and accelerate regeneration after hepatectomy. The aim of this study was to investigate the cell type-specific expression of RAGE, and to examine whether transdifferentiation of hepatic stellate cells (HSC) into myofibroblasts (MFB) is associated with changes in RAGE expression. Northern blot analysis revealed that RAGE mRNA was exclusively expressed by HSC isolated from rat liver, while no transcripts were seen in hepatocytes, Kupffer cells, or sinusoidal endothelial cells. Expression of RAGE mRNA was up-regulated during transdifferentiation of HSC into MFB. Concomitantly, expression of RAGE protein was increased as confirmed by Western blotting and immunohistochemistry. As assessed by radioactive labeling, transforming growth factor ␤ 1 (TGF-␤ 1 ) induced a timedependent 2-to 15-fold increase in the de novo synthesis of RAGE protein, which was completely abolished using PD098059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) kinase. As shown by double-immunofluorescence staining, RAGE colocalized with ␣-smooth muscle actin, and immunoelectron microscopy demonstrated the most prominent labeling for RAGE at filopodial membranes of MFB. In conclusion, this study demonstrates that expression of RAGE is restricted to rat HSC, and that expression is up-regulated during activation of HSC and Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules. 1 The transmembrane protein consists of an extracellular N-terminal V-type domain and two C-type domains, a single transmembrane domain, and a short, highly charged cytosolic tail at the C-terminus. 2-4 High levels of RAGE were noted in a range of tissues during embryonic development, particularly in the central nervous system, while RAGE expression decreases to low levels as animals mature. 5 Interaction of RAGE with diverse ligands was demonstrated to be relevant to distinct pathologic and developmental processes. 6 One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products (AGEs), which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. 3,4,7 RAGE has also been proposed to act as a signal transduction receptor for amyloid-␤ peptide, known to accumulate in Alzheimer's disease, 4,8 and for transthyretin, which is implicated in the pathology of familial amyloidotic polyneuropathy. 9 Binding of these ligands to RAGE results in the generation of intracellular oxidative stress and subsequent activation of the transcription factor, nuclear factor-B (NF-B). [10][11][12] Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop resulting in sustained RAGE up-regulation, which has been proposed to set the stage for chronic cellular activation and tissue damage. 4 In ...