Despite the considerable progress in the classification of the idiopathic interstitial pneumonias (IIPs), the lack of an international standard has resulted in variable and confusing diagnostic criteria and terminology. The advent of high-resolution computerized tomography, the narrowed pathologic definition of usual interstitial pneumonia (UIP) and recognition of the prognostic importance of separating UIP from other IIP patterns have profoundly changed the approach to the IIPs. This is an international Consensus Statement defining the clinical manifestations, pathology, and radiologic features of patients with IIP. The major objectives of this statement are to standardize the classification of the idiopathic interstitial pneumonias (IIPs) and to establish a uniform set of definitions and criteria for the diagnosis of IIPs. The targeted specialties are pulmonologists, radiologists, and pathologists. A multidisciplinary core panel was responsible for review of background articles and writing of the document. In addition, this group reviewed the clinical, radiologic, and pathologic aspects of a wide spectrum of cases of diffuse parenchymal interstitial lung diseases to establish a uniform and consistent approach to these diseases and to clarify the terminology, definitions, and descriptions used in routine clinical practice. The final statement was drafted after a series of meetings of the entire committee. The level of evidence for the recommendations made in this statement is largely that of expert opinion developed by consensus. This classification of IIPs includes seven clinico-radiologic-pathologic entities: idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and lymphoid interstitial pneumonia. The need for dynamic interaction between pathologists, radiologists, and pulmonologists to accurately diagnose these disorders is emphasized. The level of evidence for the recommendations made in this Statement is largely that of expert opinion developed by consensus. This Statement is an integrated clinical, radiologic, and pathologic approach to the classification of the IIPs. Use of this international multidisciplinary classification will provide a standardized nomenclature and diagnostic criteria for IIP. This Statement provides a framework for the future study of these entities. Key Messages * Unclassifiable interstitial pneumonia : Some cases are unclassifiable for a variety of reasons (see text). † This group represents a heterogeneous group with poorly characterized clinical and radiologic features that needs further study. ‡ COP is the preferred term, but it is synonymous with idiopathic bronchiolitis obliterans organizing pneumonia.

Experimental pathologic studies suggest that Clara cells are one of the types of airway stem cells but the proliferation of Clara cells in human lungs has not yet been examined. The purpose of this study was to assess in conducting airways of normal human lungs: (1) the number of Clara cells; and (2) the contribution of Clara cells to the proliferation compartment. Samples of histologic normal tissue were taken from seven lungs obtained by autopsy. A triple sequential (immuno)histochemical staining was performed, using MIB-1 as a proliferation marker and anti-CC10 for the identification of Clara cells; subsequently, a PAS stain was carried out as a marker for goblet cells, as these cells were reported to be CC10-immunoreactive in an unknown proportion. Clara cells were virtually absent in the proximal airway epithelium. The number of Clara cells in the terminal bronchioles was 11 +/- 3% (mean +/- SD) and in respiratory bronchioles 22 +/- 5%. The overall proliferation compartment of the conducting airway epithelium was 0.83 +/- 0.47%; the contribution of Clara cells was 9%. In the terminal bronchioles 15% of proliferating airway epithelial cells were Clara cells, and in the respiratory bronchioles this number increased to 44%. The contribution of Clara cells to the proliferation compartment of normal human tracheobronchial epithelium is substantial, demonstrating a role of the Clara cell in the maintenance of the normal epithelium of the distal conducting airways in humans.

Two roles have been suggested for basal cells on the basis of studies performed with laboratory animals: (1) anchoring of the tracheobronchial epithelium; and (2) being the epithelial stem cell. Parabasal cells located just above the basal cells have also been shown to contribute to cell renewal. However, a systematic study of the composition and proliferation of basal and parabasal cells in normal human lungs is lacking. The aims of this study were to determine in normal human conducting-airway epithelium: (1) the number of basal and parabasal cells; and (2) the contribution of basal and parabasal cells to the proliferation fraction. Samples of histologically normal tissue, free of pulmonary disease, were taken from seven lungs obtained by autopsy. Immunohistochemical staining was performed with the primary antibody MIB-1 as a proliferation marker and the antikeratin antibody 34betaE12 as a marker for basal and parabasal cells. In the largest conducting airways (diameter >= 4 mm), the percentages of basal and parabasal cells were 31% and 7%, respectively; the contribution to the proliferation compartment was 51% for basal and 33% for parabasal cells. In the smallest airways (diameter < 0.5 mm), 6% of epithelial cells were basal cells, with a 30% contribution to the proliferation compartment, whereas parabasal cells were absent. The high fraction of basal and parabasal cells contributing to the proliferation compartment of normal human conducting-airway epithelium supports the theory that cells at or near the basement membrane are likely to be progenitor cells.

Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Asthma is commonly diagnosed using physiological measures, but alterations in airway structure are the defining features of asthma. Damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, thickening and aberrant collagen, and protein composition of the basement membrane are well established elements of the asthmatic airway. 1,2 The injury to the bronchial epithelium in asthma is marked by loss of columnar epithelial cells. Extensive loss of cells and denuded basement membrane with few basal cells remaining on the airway surface are noted in severe asthma, but shedding of airway epithelium is present even in clinically mild asthma. 2,3 Physical loss of epithelial lining cells is considered one proximate cause of the airway hyperresponsiveness to inhaled mediators, and has been speculated to contribute to asthmatic airway remodeling, in particular abnormal collagen synthesis. Evidence from organ culture systems supports the concept of an epithelial-mesenchymal unit in which loss of epithelium leads to mucosal myofibroblast and fibroblast proliferation, and collagen deposition. 2,4 -6 Thus, if the epithelial injury and loss could be understood and prevented in asthma, the clinical symptoms of airway hyperresponsiveness and long-term progressive sequelae in the airways, which contribute to fixed airflow limitation, might be prevented.Several reports have proposed that loss of epithelial cells is because of apoptosis based on immunostaining for the proteins that regulate apoptosis, or by detection of DNA strand breaks by immunostaining with the terminal dUTP nick-end labeling (TUNEL) assay. 7-11 However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment. Although nonspecific events related to increased levels of reactive oxygen and

To investigate the antioxidant response of respiratory epithelium to the chronic airway inflammation in asthma, the major intracellular antioxidants [copper and zinc-containing superoxide dismutase (Cu,Zn-SOD) and manganese-containing SOD (Mn-SOD), catalase, and glutathione peroxidase] were quantitated in bronchial epithelial cells of healthy control and asthmatic individuals. Although catalase and glutathione peroxidase in bronchial epithelium of asthmatics were similar to control SOD activity in asthmatics not on inhaled corticosteroid (-CS) was lower than asthmatics on inhaled corticosteroid (+CS) and controls. Investigation of Mn-SOD and Cu,Zn-SOD activities revealed that the lower SOD activity in asthmatics -CS was because of decreased Cu,Zn-SOD activity. However, Mn-SOD and Cu,Zn-SOD mRNA and protein levels were similar among asthmatics -CS, asthmatics +CS, and controls. Importantly, Cu,Zn-SOD specific activity in asthmatics -CS was decreased in comparison with control and asthmatics +CS. Furthermore, in paired comparisons of asthmatics -CS and +CS, inhaled corticosteroids resulted in normalization of bronchial epithelial Cu,Zn-SOD specific activity. These findings suggest loss of Cu,Zn-SOD activity in asthma is related to inflammation, perhaps through oxidant inactivation of Cu,Zn-SOD protein.