Idiopathic Pulmonary Fibrosis/usual Interstitial Pneumonia Research Articles

Impact of GAP score on surgical prognosis of non-small-cell lung cancer with usual interstitial pneumonia.

Post-surgical survival outcomes in patients with non-small-cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF) are expected to be worse than those in patients with other idiopathic interstitial pneumonias (IIPs). However, these remain unclear regarding patients with NSCLC and IPF histologically diagnosed as usual interstitial pneumonia [IPF(UIP)]. We aimed to assess the surgical and survival outcomes and identify prognostic factors in patients with NSCLC and IPF(UIP). This retrospective cohort study included patients with pathological stage I-III NSCLC and UIP. Prognostic factors and their association with lung cancer deaths (LCDs) and non-LCDs (NLCDs) were investigated. The overall survival of patients with UIP was significantly poorer than that of others with IIPs. The main causes of death were lung cancer (36%) and respiratory disease (44%). Multivariate analyses revealed the pathological stage of NSCLC ≥ II (hazard ratio [HR], 2.196; p = 0.009) and GAP stage ≥ II (HR, 2.821; p = 0.016) to be significant prognostic factors. NLCD incidence was significantly high in patients with GAP stage ≥ II. Recurrence occurred in 26 patients (36.1%); the period from recurrence to death was shorter in patients with IPF(UIP) than in patients without IPF(UIP). Patients with NSCLC and IPF(UIP) had poor prognosis after surgery. However, the prognosis varied greatly depending on the GAP stage. Considering the difficulty in managing post-surgical recurrence and high incidence of LCDs in patients with IPF(UIP), pursuing a radical resection is recommended in patients with GAP stage I. For patients with GAP stage ≥ II, comprehensive management of UIP is also necessary.

Squamous metaplasia is an indicator of acute exacerbation in patients with usual interstitial pneumonia / idiopathic pulmonary fibrosis

BackgroundAcute exacerbation (AE) is a potentially lethal event in patients with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF). However, to date, no pathological predictors of AE have been identified. This retrospective study aimed to elucidate the pathological features that could predict AE in patients with UIP. MethodsWe reviewed the pathological findings of 91 patients with UIP/IPF and correlated these findings with AE events. Thirteen histological variables related to acute lung injury were evaluated by three independent observers and classified as positive or negative. The patients’ clinical data during follow-up were collected and reviewed for AE. A recursive partition using the Gini index for the prediction of AE was performed, with each pathological finding as a candidate for branching. ResultsTwenty patients (22%) developed AE during the median follow-up duration of 40 months. Thirty-eight patients died (15 due to AE and 23 for other reasons). The median time interval from surgical lung biopsy to AE onset was 497 (interquartile range: 901–1657) days. Histologically, squamous metaplasia was positively associated with AE (odds ratio: 4.7, P = 0.015) and worse event-free survival in patients with UIP (P = 0.04). Leaf scoring based on the Gini index for recursive partition, including five positive findings (squamous metaplasia, neutrophilic infiltration, septal widening, Kuhn's hyaline, and fibrin), showed a sensitivity of 90% with a specificity of 74.7% (area under curve: 0.89). ConclusionsWe found that squamous metaplasia is an important histopathological finding that predicts AE events and tends to unfavorable outcome in patients with UIP/IPF.

Panel of serum biomarkers for differential diagnosis of idiopathic interstitial lung disease and interstitial lung disease-secondary to systemic autoimmune rheumatic disease.

Interstitial lung disease (ILD) may complicate the course of systemic autoimmune rheumatic disease (SARD) and diagnostic biomarkers are needed. Krebs von den Lungen-6 (KL-6), ferritin (FER) and interleukin 6 (IL-6) have been involved in the ILD development. Our study aimed to compare KL-6, FER, IL-6 and soluble mesothelin-related peptide (SMRP) concentrations in a cohort of idiopathic and SARD-ILD. 3169 patients were enrolled in the "UK Biomarkers in Interstitial Lung Disease (UK-BILD) Study". We selected patients affected by SARD-ILD and idiopathic ILD (usual interstitial pneumonia-idiopathic pulmonary fibrosis and fibrotic non-specific interstitial pneumonia). Serum marker concentrations were measured through chemiluminescent assays (Fujirebio Europe, Ghent, Belgium). 1013 patients were selected for the study: 520 (51.3%) had idiopathic ILD and 493 (48.7%) SARD-ILD. Idiopathic ILD patients displayed higher KL-6 values than SARD-ILD (p = 0.0002). FER and SMRP, though within normal ranges, were significantly higher in idiopathic ILD (p<0.0001). Logistic regression showed good sensitivity (69.4%) and specificity (80.4%) selecting the variables FER and KL-6 concentrations, age and gender-male correlated with a diagnosis of idiopathic ILD. Our study showed the excellent diagnostic value of KL-6 for detecting ILD, which irrespective of the final diagnosis and extent of disease, is always elevated and is a reliable biomarker of lung fibrosis in various diseases, ranging from idiopathic to autoimmune forms. Our study proposed an ILD differentiation model including clinical background. In this context, combination of serum markers and clinical data, as seen in our cohort, may lead to a further improvement in diagnostic accuracy for ILD.

Reliability of histopathologic diagnosis of fibrotic interstitial lung disease:\xa0an international collaborative standardization project

BackgroundCurrent interstitial lung disease (ILD) diagnostic guidelines assess criteria across clinical, radiologic and pathologic domains. Significant interobserver variation in histopathologic evaluation has previously been shown but the specific source of these discrepancies is poorly documented. We sought to document specific areas of difficulty and develop improved criteria that would reduce overall interobserver variation.MethodsUsing an internet-based approach, we reviewed selected images of specific diagnostic features of ILD histopathology and whole slide images of fibrotic ILD. After an initial round of review, we confirmed the presence of interobserver variation among our group. We then developed refined criteria and reviewed a second set of cases.ResultsThe initial round reproduced the existing literature on interobserver variation in diagnosis of ILD. Cases which were pre-selected as inconsistent with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) were confirmed as such by multi-observer review. Cases which were thought to be in the spectrum of chronic fibrotic ILD for which UIP/IPF were in the differential showed marked variation in nearly all aspects of ILD evaluation including extent of inflammation and extent and pattern of fibrosis. A proposed set of more explicit criteria had only modest effects on this outcome. While we were only modestly successful in reducing interobserver variation, we did identify specific reasons that current histopathologic criteria of fibrotic ILD are not well defined in practice.ConclusionsAny additional classification scheme must address interobserver variation in histopathologic diagnosis of fibrotic ILD order to remain clinically relevant. Improvements to tissue-based diagnostics may require substantial resources such as larger datasets or novel technologies to improve reproducibility. Benchmarks should be established for expected outcomes among clinically defined subgroups as a quality metric.

High-resolution CT in smoking-related interstitial lung diseases.

In addition to chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma, smoking can also cause interstitial lung diseases (ILDs) such as respiratory bronchiolitis (RB), RB with ILD (RB-ILD), desquamative interstitial pneumonia (DIP), Langerhans cell granulomatosis (LCG) and idiopathic pulmonary fibrosis-usual interstitial pneumonia (IPF-UIP). However, smoking seems to have a protective effect against hypersensitivity pneumonitis (HP), sarcoidosis and organising pneumonia (OP). High-resolution computed tomography (HRCT) has a pivotal role in the differential diagnosis. RB is extremely frequent in smokers, and is considered a marker for smoking exposure. It has no clinical relevance in itself since most patients with RB are asymptomatic. It is frequent to observe the association of RB with other smoking-related diseases, such as LCG or pulmonary neoplasms. In RB-ILD, HRCT features are more conspicuous and diffuse than in RB, but there is no definite cut-off between the two entities and any distinction can only be made by integrating imaging and clinical data. RB, RB-ILD and DIP may represent different degrees of the same pathological process, consisting in a bronchiolar and alveolar inflammatory reaction to smoking. Smoking is also a well-known risk factor for pulmonary fibrosis. Multidisciplinary discussion and follow-up can generally solve even the most difficult cases.

Morphological and molecular motifs of fibrosing pulmonary injury patterns.

Interstitial lung diseases encompass a large number of entities, which are characterised by a small number of partially overlapping fibrosing injury patterns, either alone or in combination. Thus, the presently applied morphological diagnostic criteria do not reliably discriminate different interstitial lung diseases. We therefore analysed critical regulatory pathways and signalling molecules involved in pulmonary remodelling with regard to their diagnostic suitability. Using laser‐microdissection and microarray techniques, we examined the expression patterns of 45 tissue‐remodelling associated target genes in remodelled and non‐remodelled tissue samples from patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), non‐specific interstitial pneumonia (NSIP), organising pneumonia (OP) and alveolar fibroelastosis (AFE), as well as controls (81 patients in total). We found a shared usage of pivotal pathways in AFE, NSIP, OP and UIP, but also individual molecular traits, which set the fibrosing injury patterns apart from each other and correlate well with their specific morphological aspects. Comparison of the aberrant gene expression patterns demonstrated that (1) molecular profiling in fibrosing lung diseases is feasible, (2) pulmonary injury patterns can be discriminated with very high confidence on a molecular level (86–100% specificity) using individual gene subsets and (3) these findings can be adapted as suitable diagnostic adjuncts.

Combined pulmonary fibrosis and emphysema as a clinicoradiologic entity: Characterization of presenting lung fibrosis and implications for survival.

The prevalence of classifiable and unclassifiable causes of lung fibrosis and its implications for survival are mostly unknown in combined pulmonary fibrosis and emphysema (CPFE). Patients with >10% involvement of both emphysema and lung fibrosis seen over 11 years at our institution were reviewed independently by expert radiologists for fibrotic and emphysematous findings and overall fibrotic CT pattern. Underlying interstitial lung disease (ILD) diagnoses and baseline demographic and clinical characteristics were collated and assessed for predictors of comparative survival. In this retrospective cohort, 179 CPFE patients were identified and categorized as 58 usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) (32%), 42 secondary ILD (23%), and 79 unclassifiable ILD (44%). The most prevalent (47%) radiologic pattern was 'unclassifiable', followed by 'consistent' and 'possible' UIP pattern in 38%. Adjusted predictors of mortality for the cohort as a whole included age (HR 1.03[1.01-1.06], P = 0.002), percent predicted diffusing capacity for carbon monoxide (unit HR 0.97 [0.96-0.99], P = 0.001), honeycombing (HR 1.58 [1.02-2.43], P = 0.04), and right ventricular dysfunction (HR 2.28 [1.39-3.97], P = 0.002). Survival was similar between CPFE with secondary ILD and CPFE with UIP/IPF, while CPFE with unclassifiable ILD had better comparative survival (Log rank = 0.026). Our findings suggest only about a third of CPFE patients represent suspected UIP/IPF; the majority were clinically and radiologically unclassifiable ILD whose survival was comparatively better. Identifiable or secondary causes of lung fibrosis in CPFE occurred in about a fifth of presenting patients.

Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF.

Pathology of Chronic Hypersensitivity Pneumonitis What Is It? What Are the Diagnostic Criteria? Why Do We Care?

- Chronic hypersensitivity pneumonitis (CHP) has emerged from obscurity during the past 15 years and is now recognized as a very common form of fibrosing interstitial pneumonia but one that is frequently misdiagnosed both clinically and on surgical lung biopsy as usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) or fibrotic nonspecific interstitial pneumonia. - To review the pathologic features of CHP. - Clinical, pathology, and radiology literature were used. - Upper lobe-predominant fibrosis and/or air-trapping on computed tomography scan are features of CHP but not UIP/IPF; however, radiologic separation is possible in only about 50% of cases. Morphologically, CHP sometimes mimics UIP/IPF, but CHP often shows isolated foci of peribronchiolar (centrilobular) fibrosis, frequently associated with fibroblast foci, and in CHP, fibrosis may bridge from the centrilobular region to another bronchiole, an interlobular septum, or the pleura ("bridging fibrosis"). This set of findings is uncommon in UIP/IPF. In addition, CHP may produce a picture of fibrotic nonspecific interstitial pneumonia. Although giant cells/granulomas are usually present in subacute hypersensitivity pneumonitis, they are much less frequently found in CHP, and their absence does not contradict the diagnosis. This diagnostic separation is clinically important because CHP is treated differently than UIP/IPF is (immunosuppressive agents versus antifibrotic agents); further, there are some data to suggest that removing the patient from antigen exposure improves outcome, and there is evidence that patients with CHP have a much better survival prognosis after lung transplantation than do patients with UIP/IPF. In most cases, accurate diagnosis of CHP requires consultation among clinicians, radiologists, and pathologists.

Chronic interstitial pneumonia in young patients undergoing lung transplantation or autopsy: clinico-radiologic-pathologic observations from a single institution.

To retrospectively evaluate high-resolution computed tomography (HRCT) findings and clinical diagnoses of chronic interstitial pneumonia (IP) with a poor prognosis in young patients (≤50years). HRCT images of 8 men and 7 women (mean age 34.8years) obtained before lung transplantation or autopsy were reviewed. After reviewing whole lung specimens and pathologic diagnoses, all patients were clinically diagnosed according to the 2010 idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) consensus statement. HRCT images revealed intralobular reticular opacity, air cysts, ground glass opacity, traction bronchiectasis, and interlobular septal thickening. Intralobular reticular opacity was the most extensive finding. Abnormal findings existed predominantly in both the peripheral and lower lung zones in only 1 patient. Classifications of HRCT patterns were "UIP" (n=2), "inconsistent with UIP" (n=11), and "indeterminate UIP" (n=2). Multidisciplinary diagnoses were "IPF/UIP" (n=1), "possible IPF/UIP" (n=1), "IP with connective tissue disease" (n=7), "fibrotic nonspecific IP" (n=1), and "unclassified IP" (n=5). The most extensive HRCT finding was intralobular reticular opacity. Most HRCT images differed from typical IPF/UIP, and IPF/UIP was uncommon in young patients with chronic IP with a poor prognosis.

Lung diffusing capacity for nitric oxide as a marker of fibrotic changes in idiopathic interstitial pneumonias.

Lung diffusing capacity for carbon monoxide (DLCO) is decreased in both usual interstitial pneumonia-idiopathic pulmonary fibrosis (UIP-IPF) and nonspecific interstitial pneumonia (NSIP), but is moderately related to computed tomography (CT)-determined fibrotic changes. This may be due to the relative insensitivity of DLCO to changes in alveolar membrane diffusive conductance (DMCO). The purpose of this study was to determine whether measurement of lung diffusing capacity for nitric oxide (DLNO) better reflects fibrotic changes than DLCO DLNO-DLCO were measured simultaneously in 30 patients with UIP-IPF and 30 with NSIP. Eighty-one matched healthy subjects served as a control group. The amount of pulmonary fibrosis was estimated by CT volumetric analysis of visually bounded areas showing reticular opacities and honeycombing. DMCO and pulmonary capillary volume (VC) were calculated. DLNO was below the lower limit of normal in all patients irrespective of extent and nature of disease, whereas DLCO was within the normal range in a nonnegligible number of patients. Both DLNO and DLCO were significantly correlated with visual assessment of fibrosis but DLNO more closely than DLCO DMCO was also below the lower limit of normal in all UIP-IPF and NSIP patients and significantly correlated with fibrosis extent in both diseases, whereas VC was weakly correlated with fibrosis in UIP-IPF and uncorrelated in NSIP, with normal values in half of patients. In conclusion, measurement of DLNO may provide a more sensitive evaluation of fibrotic changes than DLCO in either UIP-IPF or NSIP, because it better reflects DMCO.

Perfusion- and pattern-based quantitative CT indexes using contrast-enhanced dual-energy computed tomography in diffuse interstitial lung disease: relationships with physiologic impairment and prediction of prognosis.

To evaluate automated texture-based segmentation of dual-energy CT (DECT) images in diffuse interstitial lung disease (DILD) patients and prognostic stratification by overlapping morphologic and perfusion information of total lung. Suspected DILD patients scheduled for surgical biopsy were prospectively included. Texture patterns included ground-glass opacity (GGO), reticulation and consolidation. Pattern- and perfusion-based CT measurements were assessed to extract quantitative parameters. Accuracy of texture-based segmentation was analysed. Correlations between CT measurements and pulmonary function test or 6-minute walk test (6MWT) were calculated. Parameters of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) and non-IPF/UIP were compared. Survival analysis was performed. Overall accuracy was 90.47% for whole lung segmentation. Correlations between mean iodine values of total lung, 50-97.5th (%) attenuation and forced vital capacity or 6MWT were significant. Volume of GGO, reticulation and consolidation had significant correlation with DLco or SpO2 on 6MWT. Significant differences were noted between IPF/UIP and non-IPF/UIP in 6MWT distance, mean iodine value of total lung, 25-75th (%) attenuation and entropy. IPF/UIP diagnosis, GGO ratio, DILD extent, 25-75th (%) attenuation and SpO2 on 6MWT showed significant correlations with survival. DECT combined with pattern analysis is useful for analysing DILD and predicting survival by provision of morphology and enhancement. • Dual-energy CT (DECT) produces morphologic and parenchymal enhancement information. • Automated lung segmentation enables analysis of disease extent and severity. • This prospective study showed value of DECT in DILD patients. • Parameters on DECT enable characterization and survival prediction of DILD.

019. Idiopathic interstitial pneumonias: clinico-radiologic-pathologic diagnosis

Background The idiopathic interstitial pneumonias (IIPs) represent a heterogeneous group of lung diseases with effects on the lung parenchyma and airways characterized by chronic inflammation and progressive fibrosis and share similar features (clinical, radiological). The idiopathic interstitial pneumonias are classified based on clinical, histopathological and radiological criteria in idiopathic pulmonary fibrosis-usual interstitial pneumonia (IPF-UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and lymphocytic interstitial pneumonia (LIP).

The Idiopathic Pulmonary Fibrosis Honeycomb Cyst Contains A Mucocilary Pseudostratified Epithelium

BackgroundWe previously identified a MUC5B gene promoter-variant that is a risk allele for sporadic and familial Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (IPF/UIP). This allele was strongly associated with increased MUC5B gene expression in lung tissue from unaffected subjects. Despite the strong association of this airway epithelial marker with disease, little is known of mucin expressing structures or of airway involvement in IPF/UIP.MethodsImmunofluorescence was used to subtype mucus cells according to MUC5B and MUC5AC expression and to identify ciliated, basal, and alveolar type II (ATII) cells in tissue sections from control and IPF/UIP subjects. Staining patterns were quantified for distal airways (Control and IPF/UIP) and in honeycomb cysts (HC).ResultsMUC5B-expressing cells (EC) were detected in the majority of control distal airways. MUC5AC-EC were identified in half of these airways and only in airways that contained MUC5B-EC. The frequency of MUC5B+ and MUC5AC+ distal airways was increased in IPF/UIP subjects. MUC5B-EC were the dominant mucus cell type in the HC epithelium. The distal airway epithelium from control and IPF/UIP subjects and HC was populated by basal and ciliated cells. Most honeycombing regions were distinct from ATII hyperplasic regions. ATII cells were undetectable in the overwhelming majority of HC.ConclusionsThe distal airway contains a pseudostratified mucocilary epithelium that is defined by basal epithelial cells and mucus cells that express MUC5B predominantly. These data suggest that the HC is derived from the distal airway.

Epithelial cell restoration and regeneration in inflammatory lung diseases

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an acute-onset neutrophil-dominant inflammatory lung disease caused by or associated with various illness and injuries. The mortality rate related to this disorder can be as high as 40%. In contrast, idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) is a chronic progressive inflammatory lung disease of unknown etiology, with a mean survival of five years. There are no established treatments for either disease and novel therapies are eagerly desired. Lung epithelial cells were initially discovered to be derived from bone marrow stem cells and progenitor cells. As a result of progress made in regenerative medicine, several types of tissue stem cells and progenitor cells have been identified in the lungs, each of which is involved in tissue repair and regeneration at different levels of the bronchial tree. In terminal bronchioles and alveoli, where lung cells are specifically vulnerable to injuries caused by inflammatory cells, Clara cell-specific protein-positive epithelial cells, including bronchioalveolar stem cells, and a subgroup of alveolar epithelial type II cells, have been identified as lung tissue stem cell and progenitor cell candidates. Intratracheal administration of alveolar epithelial type II cells or epithelial progenitor cells has been shown to be effective in animal models of ALI/ARDS and IPF/UIP. As a novel strategy based on regenerative medicine, this could be a promising approach to treat inflammatory lung diseases.

Compartmentalized Expression of c-FLIP in Lung Tissues of Patients with Idiopathic Pulmonary Fibrosis

Increased apoptosis of alveolar epithelial cells and impaired apoptosis of myofibroblasts have been linked to the pathogenesis of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). Fas, a death receptor of the TNF-receptor superfamily, has been implicated in apoptosis of both cell types, though the mechanisms are poorly understood. The goals of this study were: (1) to examine the localization of Fas-associated death-domain-like IL-1beta-converting enzyme inhibitory protein (c-FLIP), an NF-kappaB-dependent regulator of Fas-signaling, in lung tissues from IPF/UIP patients and control subjects; and (2) to compare c-FLIP expression with epithelial cell and myofibroblast apoptosis, proliferation, and NF-kappaB activation. c-FLIP expression was restricted to airway epithelial cells in control lung tissues. In contrast, in patients with IPF/UIP, c-FLIP was also expressed by alveolar epithelial cells in areas of injury and fibrosis, but was absent from myofibroblasts in fibroblastic foci and from alveolar epithelial cells in uninvolved areas of lung tissue. Quantification of apoptosis and proliferation revealed an absence of apoptotic or proliferating cells in fibroblastic foci and low levels of apoptosis and proliferation by alveolar epithelial cells. Quantification of NF-kappaB expression and nuclear translocation revealed strong staining and translocation in alveolar epithelial cells and weak staining and minimal nuclear translocation in myofibroblasts. These findings suggest that: (1) c-FLIP expression is induced in the abnormal alveolar epithelium of patients with IPF/UIP, (2) the resistance of myofibroblasts to apoptosis in patients with IPF/UIP occurs independently of c-FLIP expression, and (3) increased NF-kappaB activation and c-FLIP expression by the alveolar epithelium may be linked.

Histopathologic Analysis of Sixteen Autopsy Cases of Chronic Hypersensitivity Pneumonitis and Comparison With Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia

Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by the inhalation of organic substances and certain inorganic chemicals. The histopathologic features of chronic HP (CHP) have not been studied extensively. We examined the pathologic characteristics of 16 autopsy cases of clinically confirmed CHP and compared them with 11 cases of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). To clarify the exact intralobular location of the fibrotic lesions, we conducted 3-dimensional reconstruction of fibrosis of CHP and IPF/UIP. Granuloma was not detected in any CHP case. Similar to IPF/UIP, honeycombing lesions were found dominantly in the lower lobes in most CHP cases; upper lobe dominance and asymmetrical distribution of honeycomb lesions were more frequent in CHP than in IPF/UIP. In all lungs affected by CHP, centrilobular fibrosis was outstanding, often connecting to the perilobular areas in the appearance of "bridging fibrosis," which was clearly demonstrated by 3-dimensional imaging. Centrilobular and bridging fibrosis were significantly more conspicuous in CHP than IPF/UIP; however, considerable overlap was found. It is important to thoroughly explore the possibility of antigen exposure in cases of lungs with UIP with centrilobular fibrosis to discriminate CHP from IPF/UIP.

The Medical Research Council chronic dyspnea score predicts the survival of patients with idiopathic pulmonary fibrosis

The Medical Research Council (MRC) chronic dyspnea scale (6-point) is used in different clinical conditions to grade breathlessness on daily activities. We have previously shown that in patients with histologically documented usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF), the MRC dyspnea scale is useful in estimating disease severity. The aim of this study was to further investigate the usefulness of the MRC scale in IPF as a marker of survival. The records of 25 patients with histologically documented UIP/IPF were retrospectively reviewed. Clinical parameters, pulmonary function tests, and arterial blood gases at the time of diagnosis, as well as survival time were retrieved and recorded for each patient. The impact of the different variables determined at diagnosis on survival was examined using the Kaplan-Meier and uni- and multi-variate Cox-regression analyses. Among the baseline clinical and physiologic parameters determined at the time of IPF diagnosis, the MRC score, the Tiffeneau index, and the total lung capacity were the only significant and independent predictors of survival. In specific, a high MRC score, a high Tiffeneau index, and a low total lung capacity at presentation were associated with shorter survival. In accordance with the previous work, our results indicate that the Tiffeneau index and total lung capacity (TLC) are the important determinants of survival in patients with IPF. In addition, we show that the simple MRC chronic dyspnea score estimated at the time of diagnosis is equally predictive of survival and may aid clinicians in assessing the prognosis of new cases of IPF.

Therapeutic Targeting of CC Ligand 21 or CC Chemokine Receptor 7 Abrogates Pulmonary Fibrosis Induced by the Adoptive Transfer of Human Pulmonary Fibroblasts to Immunodeficient Mice

Idiopathic interstitial pneumonias (IIPs) are a collection of pulmonary fibrotic diseases of unknown etiopathogenesis. CC chemokine receptor 7 (CCR7) is expressed in IIP biopsies and primary fibroblast lines, but its role in pulmonary fibrosis was not previously examined. To study the in vivo role of CCR7 in a novel model of pulmonary fibrosis, 1.0 x 10(6) primary fibroblasts grown from idiopathic pulmonary fibrosis/usual interstitial pneumonia, nonspecific interstitial pneumonia, or histologically normal biopsies were injected intravenously into C.B-17 severe combined immunodeficiency (SCID)/beige (bg) mice. At days 35 and 63 after idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblast injection, patchy interstitial fibrosis and increased hydroxyproline were present in the lungs of immunodeficient mice. Adoptively transferred nonspecific interstitial pneumonia fibroblasts caused a more diffuse interstitial fibrosis and increased hydroxyproline levels at both times, but injected normal human fibroblasts did not induce interstitial remodeling changes in C.B-17SCID/bg mice. Systemic therapeutic immunoneutralization of either human CCR7 or CC ligand 21, its ligand, significantly attenuated the pulmonary fibrosis in groups of C.B-17SCID/bg mice that received either type of IIP fibroblasts. Thus, the present study demonstrates that pulmonary fibrosis is initiated by the intravenous introduction of primary human fibroblast lines into immunodeficient mice, and this fibrotic response is dependent on the interaction between CC ligand 21 and CCR7.

Inflammatory Cell Phenotyping of the Pulmonary Interstitium in Idiopathic Interstitial Pneumonia

Background: Several studies have implicated the role of inflammation in the pathogenesis of lung damage in idiopathic interstitial pneumonias (IIPs). Investigations of inflammatory cells in IIP have show that eosinophils, neutrophils and T cells may be associated with a poorer prognosis. Objectives: The aim of our study was to map, by quantitative analysis, the number of inflammatory cells in the lung tissue of patients with non-specific interstitial pneumonia/non-specific interstitial pneumonia (NSIP/NSIP), acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD) and idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) and to correlate them with lung function tests and survival. Methods: After immunohistochemical staining, we quantified the content of inflammatory cells [macrophages, neutrophils (elastase+), plasma cells, and CD3, CD4 and CD8 T lymphocytes (TLs)] in 20 NSIP, 20 DAD and 20 UIP surgical lung biopsies. Results: The total density of inflammatory cells was significantly increased in DAD and NSIP when compared to UIP (p = 0.04). TLs were increased in DAD and NSIP when compared to UlP lungs (p < 0.05). The density of inflammatory cells in UIP showed significant differences in normal, intervening and dense fibrosis areas (p < 0.05). The most numerous cells infiltrating the mural fibrosis and honeycombing areas were plasma cells, neutrophils (elastase+), CD20+, CD3+, CD4+ and CD8+ (p < 0.05). In UIP, CD3+ TLs were directly correlated with forced expiratory volume in 1 s/forced vital capacity ratio × 100 (p = 0.05). CD68+ cells presented a significant positive correlation with the forced expiratory volume in 1 s (p = 0.04); neutrophil (elastase+) cells significantly correlated with residual volume (p = 0.02), residual volume/total lung capacity (p = 0.04) and carbon monoxide transfer factor (p = 0.03). The most important predictor of survival in UIP was CD3+ TLs (p = 0.05). Conclusion: The total density of inflammatory cells and lymphocytes presents a different distribution within the pulmonary parenchyma in AIP/DAD, NSIP/NSIP and IPF/UIP evolutionary adapted responses to injury. There is a localized distribution of inflammation in the normal, intervening and dense fibrosis areas of UIP for CD3+, associated with a lethal deterioration of the pulmonary function and poor survival. Our findings provide further evidence of the importance of inflammation in the pathophysiology of IIPs.