Lung CT Densitometry in Idiopathic Pulmonary Fibrosis for the Prediction of Natural Course, Severity, and Mortality.

BACKGROUND: In this study, we retrospectively assessed the relationships among physiologic measurements, survival, and quantitative high-resolution CT (HRCT) scanning indexes in patients with idiopathic pulmonary fibrosis (IPF). METHODS: Seventy patients (48 male; mean [SD] age, 66.4 [9.0] years) with IPF were enrolled in the study. After segmentation of the lungs in thin-section CT scanning with the patient in the supine position at full inspiration, we assessed following parameters: mean lung attenuation (MLA), skewness, kurtosis, peak attenuation, total lung area, inflexion point with slope, and area right of the inflexion point (AROIP). Additionally, FVC, FEV1, total lung capacity, diffusing capacity or transfer factor of the lung for carbon monoxide (Dlco), and 6-min walk distance were analyzed. Univariate and multivariate analysis were used for the prediction of physiologic outcomes by HRCT scanning indexes and then were correlated to survival in a proportional hazards analysis. RESULTS: The strongest correlation was observed between MLA and FEV1, with an r of -0.63. MLA, peak attenuation, slope, attenuation, and AROIP correlated negatively with all physiologic measurements. AROIP was the best predictor of Dlco. Analysis for prediction of mortality showed that AROIP, kurtosis, and FVC were related significantly to survival. Multivariate regression revealed a significant impact of only AROIP (among age, sex, MLA, skewness, kurtosis, FVC, and Dlco) on survival. CONCLUSIONS: These data indicate that HRCT scanning indexes are correlated to physiologic measurements. The newly defined parameter, AROIP, is of additive value for prediction of outcome. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02951416; URL: www.clinicaltrials.gov.

Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which no effective therapy exists to date. To identify the molecular mechanisms underlying IPF, we performed comparative proteome analysis of lung tissue from patients with sporadic IPF (n = 14) and human donor lungs (controls, n = 10) using two-dimensional gel electrophoresis and MALDI-TOF-MS. Eighty-nine differentially expressed proteins were identified, from which 51 were up-regulated and 38 down-regulated in IPF. Increased expression of markers for the unfolded protein response (UPR), heat-shock proteins, and DNA damage stress markers indicated a chronic cell stress-response in IPF lungs. By means of immunohistochemistry, induction of UPR markers was encountered in type-II alveolar epithelial cells of IPF but not of control lungs. In contrast, up-regulation of heat-shock protein 27 (Hsp27) was exclusively observed in proliferating bronchiolar basal cells and associated with aberrant re-epithelialization at the bronchiolo-alveolar junctions. Among the down-regulated proteins in IPF were antioxidants, members of the annexin family, and structural epithelial proteins. In summary, our results indicate that IPF is characterized by epithelial cell injury, apoptosis, and aberrant epithelial proliferation.

Beta2-adrenergic stimulation blunts inhibition of epithelial ion transport by hypoxia of rat alveolar epithelial cells.

Hypoxia impairs alveolar fluid clearance by inhibition of Na(+) reabsorption, and also impairs beta(2) adrenergic signaling in alveolar epithelium. Since both are major rescue mechanisms preventing pulmonary edema, we studied whether acute and prolonged treatment with terbutaline would prevent hypoxic inhibition of ion transport. Short circuit currents (ISC) were measured on normoxic and hypoxic (1.5% O(2); 24h) primary rat alveolar type II (ATII) cells in absence and presence of terbutaline (1 to 100 microM, 24h). Control and pre-treated cells were stimulated acutely with terbutaline. Transepithelial transport was measured as short circuit current (ISC) in Ussing chambers. Terbutaline induced a rapid decrease ISC (-20%) followed by a slow raise. The transient change in ISC was not inhibited by amiloride but was prevented after Cl(-) depletion indicating a Cl(-) current. The slow increase after this transient was amiloride-sensitive indicating a Na(+) current. Total ISC, its amiloride-sensitive component, and the transient decrease upon terbutaline stimulation were decreased by hypoxia. 24h treatment with terbutaline stimulated these currents in normoxia and hypoxia, although stimulation was less in the latter. 24h treatment with terbutaline increased the capacity of Na(+)/K(+)-ATPase and ENaC as measured after permeabilization with amphotericin. These changes were not paralleled by altered mRNA expression. Acutely applied terbutaline induced a 4-fold increase in cAMP formation in normoxia; terbutaline-induced cAMP-formation was impaired by hypoxia (-20%). Pre-treatment with terbutaline for 24h decreased terbutaline-induced cAMP formation by 85%. Despite this desensitization, addition of terbutaline to terbutaline pre-treated cells caused a larger increase in Cl(-) and Na(+) transport both in normoxia and hypoxia than in non pre-treated cells. These results indicate that beta(2) adrenergic stimulation increased Na(+)- and Cl(-) transport in ATII cells even in hypoxia thus restoring normal reabsorption.