Physicochemical characterization of inorganic deposits associated with granulomas in cutaneous sarcoidosis.

BACKGROUND: Sarcoidosis, characterized by epithelioid granulomas, is considered to be caused by a complex interplay between genetics and environmental agents. It has been hypothesized that exogenous inorganic particles as crystalline silica could be a causal or adjuvant agent in sarcoidosis onset. OBJECTIVES: To investigate the location, frequency and physicochemical characteristics of foreign materials and mineral tissue deposits in the granulomatous area of cutaneous sarcoidosis. METHODS: Skin biopsies (n = 14) from patients diagnosed with cutaneous sarcoidosis (mean age 43 years; 11 patients with extracutaneous involvement) were investigated using polarized light examination (PLE), µFourier Transform Infra-Red (µFT-IR) spectroscopy and Field Emission Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectroscopy (FE-SEM/EDX). RESULTS: Combined PLE, µFT-IR, FE-SEM/EDX analysis allowed to characterize mineral deposits in 7/14 biopsies (50%). It identified crystalline silica (SiO2 ) inside granulomas in three biopsies and calcite (CaCO3 ) at their periphery in 4. CONCLUSION: This study emphasizes the need of using combined methods for assessment of mineral deposits in granulomatous diseases. According to the location and characteristics of deposits, we can hypothesize that SiO2 particles contribute to the granuloma formation, whereas CaCO3 deposits are related to the granuloma biology. However, the significance of the association between SiO2 deposits and sarcoidosis is still disputed.

Lymphatic and blood microvasculature organisation in pulmonary sarcoid granulomas.

Pulmonary sarcoid granulomas are characterised by their elective distribution along collecting lymphatics. However, relationships between granulomas and intralobular lymphatics or blood microvascularisation have not been investigated. Therefore, we undertook a specific analysis of blood capillaries and lymphatics supplying sarcoid granulomas to identify additional clues to understanding the pathophysiogenesis of these lesions. Six pulmonary samples were immunolabelled with D2-40, anti-CD34 and anti-CD31 antibodies, paying particular attention to the relationships between lymphatics and granulomas, and the pattern of blood microvessels supplying sarcoid lesions. A morphometric study of granulomas included their distance to lymphatics and a three-dimensional reconstruction of a granuloma in its lymphatic context. Intralobular granulomas were closely associated with lymphatics; apart from a few granulomas, blood capillaries stopped at the outer border of the fibrous ring surrounding granulomas, and perigranuloma capillaries were particularly scarce. Our observations of the lymphatic and blood microvascular environment of intralobular pulmonary sarcoid granulomas provide evidence for the critical role of lymphatics in the emergence of these lesions. Moreover, pulmonary sarcoid lesions could be considered avascular structures, thereby providing new insights into the understanding of the granuloma physiology and the distribution of blood-borne therapeutic agents.

Expression of the neutrophil elastase gene during human bone marrow cell differentiation.

Neutrophil elastase, a potent serine protease carried and released by activated neutrophils, is not synthesized by neutrophils, but by their bone marrow precursor cells. Using in situ hybridization with 35S-labeled antisense and sense neutrophil elastase cRNA probes, the present study demonstrates that expression of the neutrophil elastase gene is tightly controlled in bone marrow precursors and occurs during a very limited stage of differentiation of the neutrophil myeloid series, almost entirely at the promyelocyte stage. Neutrophil elastase mRNA transcript levels are detectable to a limited extent in blasts, increase markedly in the promyelocyte stage, and then disappear as promyelocytes further differentiate. Control probes specific for myeloperoxidase, lactoferrin, and beta-globin mRNA transcripts, respectively, demonstrated contrasting gene expression. Myeloperoxidase mRNA transcripts were also found almost exclusively at the promyelocyte stage, but myeloperoxidase mRNA levels disappeared earlier than do neutrophil elastase mRNA levels, suggesting that expression of these genes may be differently controlled. In comparison, lactoferrin mRNA transcripts were detected late in the neutrophil lineage, while beta-globin mRNA was detected only in cells of the erythroid lineage. Together these observations suggest that the expression of the neutrophil elastase gene is likely under very tight control, and is likely different than that for other constituents of the neutrophil granules.

Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients.

BACKGROUND: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone. METHODS: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer (n=86). RESULTS: A highly significant association was observed, but restricted to premenopausal women (n=53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes (P<0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype (P<0.0001). CONCLUSION: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.

[Is hypoxia a factor in the progression of pulmonary sarcoidosis?] / L'hypoxie est-elle un facteur impactant l'évolution de la sarcoïdose pulmonaire ?

Sarcoidosis is a systemic granulomatous disease that can reduce life expectancy mainly due to pulmonary fibrosis resulting from granulomatous inflammation The lack of vascularization within pulmonary granulomas suggests that macrophages localized in the center of these structures are hypoxic. Hypoxia signaling pathways are known to be pro-inflammatory and pro-fibrotic in various pathological conditions. Recent data suggest an involvement of the transcription factor hypoxia-inducible factor (HIF) in the pathogenesis of sarcoidosis. This could represent a new research approach for the understanding and therapeutic management of sarcoidosis.

Diagnosis issues in sarcoidosis.

Multiple problems may be encountered during the diagnosis of sarcoidosis: at first diagnose sarcoidosis in an appropriate clinical setting, secondly, identify any manifestation to be linked to sarcoidosis at diagnosis work-up and during evolution; thirdly, recognize "danger" in sarcoidosis and parasarcoidosis syndromes, and finally, diagnose sarcoidosis recovery. Diagnosis is often delayed as presentation may be diverse, non-specific, or atypical. Diagnosis of sarcoidosis is based on three criteria: a compatible presentation; evidence of non-caseating granulomas and exclusion of any alternative diagnosis. However, even when all criteria are fulfilled, the probability of sarcoidosis diagnosis varies from definite to only possible depending upon the presence of more or less characteristic radio-clinical and histopathological findings and on the epidemiological context. Bilateral hilar lymphadenopathy and/or diffuse lung micronodules mainly along lymphatics are the most frequent highly suggestive findings. Evidence of granulomas relies on superficial biopsies of clinically suspected lesion when present or most often by bronchial endoscopy. The diagnosis of sarcoidosis may be difficult in absence of thoracic or skin manifestations and may require the benefit of hindsight before being definitive. Differential diagnoses, mainly tuberculosis, must be considered. The diagnosis of events during evolution relies on serial clinical, pulmonary function, radiographic evaluation and on extrapulmonary manifestations work-up, including electrocardiogram and blood biology. Affected organs need to be related to sarcoidosis using an appropriate diagnostic assessment instrument. To declare the recovery of sarcoidosis, all manifestations must have disappeared spontaneously or after 3-5 years post-treatment without relapse.

[The effect of air pollution in diffuse interstitial lung disease]. / Rôle de la pollution au cours des pneumopathies interstitielles diffuses.

Few studies have examined the effects of air pollution in diffuse interstitial lung disease and they have focused on small numbers of patients. Most data are available in idiopathic pulmonary fibrosis and studies suggest that the level of exposure to pollutants may influence the development of acute exacerbations (ozone and NO2), their incidence (NO2), decline in respiratory function (PM10) and death (PM10 and PM2.5). Several studies show an increase in the incidence of rheumatoid arthritis in people living near busy roads. In systemic scleroderma, hypersensitivity pneumonitis and sarcoidosis although negative effects of pollution have been reported the data are insufficient to be conclusive. Nevertheless, the observed effects of air pollution are consistent with those described for other chronic respiratory diseases. Exposure to pollution induces oxidative stress, chronic inflammation and shortening of telomeres, which are all mechanisms described in fibrogenesis. New epidemiological studies are needed with individual measurements of exposure to outdoor and indoor pollution, as well as fundamental studies to clarify the effect of pollution on fibrogenesis.

Detection of c-Ki-ras mutation by PCR/RFLP analysis and diagnosis of pancreatic adenocarcinomas.

BACKGROUND: The c-Ki-ras oncogene (also known as KRAS2) is activated by point mutations involving codon 12 in 72%-100% of primary pancreatic adenocarcinomas, but the gene is not activated in nonneoplastic tissues. Therefore, the detection of c-Ki-ras mutations can facilitate the diagnosis of pancreatic adenocarcinomas, which are not always identified with current tests. Detection is usually performed by oligonucleotide hybridization combined with polymerase chain reaction (PCR), RNAse mismatch cleavage assay, or non-isotopic mismatched PCR, methods that are not feasible for routine screening of large numbers of samples because they are time consuming and/or expensive. PURPOSE: Our purpose was to evaluate a rapid, non-radioactive method of detection of a mutation in codon 12 of the c-Ki-ras gene in pancreatic tumor samples obtained by fine-needle aspiration for diagnostic screening. METHODS: Twenty consecutive patients (15 with pancreatic adenocarcinoma, one with pancreatic cystadenocarcinoma, one with endocrine islet cell tumor, and three with chronic pancreatitis) were selected for this study. A sample of pancreatic tissue from each patient with a tumor or pancreatitis was obtained and evaluated by fine-needle aspiration biopsy under computerized tomography scan or ultrasound guidance using a two-needle coaxial technique. Pancreatic DNA from each of these samples was evaluated by PCR amplification and restriction fragment length polymorphism (RFLP) analysis with nucleotide substitution in PCR primers, creating BstNI restriction patterns that distinguished mutated from normal alleles. The accuracy of the PCR/RFLP assay was validated with DNA from SW480 and HT29 colonic carcinoma cell lines with known mutated and wild-type c-Ki-ras gene sequences. Sensitivity was tested with a series of titration experiments. RESULTS: PCR/RFLP analysis can detect a mutation present in 1% of cells. No amplification could be performed in four (20%) samples because of the absence of cells in the aspirated sample. In the 16 samples adequate for PCR/RFLP analysis, a c-Ki-ras gene mutation was detected in 11 (92%) of 12 adenocarcinomas. Overall, diagnosis was obtained by pathologic (cytomorphologic) examination alone in 13 samples (81%). The presence of malignant cells and/or mutated c-Ki-ras gene was detected in 12 of 12 adenocarcinomas but not in chronic pancreatitis or islet cell tumor. CONCLUSION: Screening of pancreatic tissue samples obtained by fine-needle aspiration for c-Ki-ras mutation using PCR/RFLP analysis combined with pathologic examination could facilitate diagnosis of pancreatic tumors.

[Structure and physiology of the pleura and the pleural space]. / Structure et physiologie de la plèvre et de l'espace pleural.

The pleural space, derived from the intraembryonic coelom, is limited by a serous membrane including the mesothelium formed by cells possessing not only the characteristic features of epithelial cells but also the potential of secretory cells (cytokines and growth factor). Blood supply to visceral pleurae differs depending on the species while the lymphatic circulation is directly connected to the pleural space via pores in the parietal pleura. Pleural physiology and movement of pleural fluid are directly related to the particular structures of the pleura.

p53 gene status as a predictor of tumor response to induction chemotherapy of patients with locoregionally advanced squamous cell carcinomas of the head and neck.

PURPOSE: To determine whether p53 gene status predicts tumor responses to platinum- and fluorouracil-based induction chemotherapy in locoregionally advanced squamous cell carcinomas of the head and neck. PATIENTS AND METHODS: Tumor responses of 105 patients were measured at the primary tumor site. Objective response and major response were defined by a 50% and 80% reduction in tumor size, respectively. All coding parts of p53 gene were directly sequenced. p53 expression in tumor cells was determined by immunohistochemistry. Human papillomavirus infection was detected by polymerase chain reaction. Odd ratios were adjusted by stepwise logistic regression analysis. RESULTS: p53 mutations, p53 expression, and tumor stage were sufficient to explain the variation in tumor responses to chemotherapy in multivariate models. p53 mutation was the only variable to significantly predict objective response (odds ratio, 0. 23; 95% confidence interval, 0.10 to 0.57; P =.002) and was the strongest predictor of major response (odds ratio, 0.29; 95% confidence interval, 0.11 to 0.74; P =.006). p53 expression (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.98) and tumor stage (odds ratio, 0.31; 95% confidence interval, 0.10 to 0.96) also predicted major response. Specific mutations (contact mutations) accounted for much of the reduction in the risk of major response associated with overall mutations. In complementary analyses, p53 expression was weakly predictive of major response in the subgroup with wild-type p53, and p53 mutations also predicted histologic response. CONCLUSION: p53 gene mutations are strongly associated with a poor risk of both objective and major responses to chemotherapy. Contact mutations are associated with the lowest risk of major response to chemotherapy.

Characterization of human pericardial macrophages.

This paper deals with the study of the cell population in 13 samples of normal human pericardial fluid. Large mononuclear cells (LMC) constituted 74.1 +/- 18.5% of the total cell population. These LMC possess the characteristics of macrophages firm adherence to glass intracytoplasmic presence of vimentin without keratin, ultrastructural observation of a lysosomal apparatus cytoenzymatic activities: acid phosphatases, naphthol AS.D acetate esterase and peroxidases, and phagocytosis of Baker's yeasts. All these data clearly show that macrophages are the main component of the pericardial fluid cell population and can be of great significance in the defense mechanisms and physiology of the pericardial space.

[Combined flow cytometry determination of S-phase fraction and DNA ploidy is an independent prognostic factor in node-negative invasive breast carcinoma: review of a series of 271 patients with stage I and II breast cancer]. / L'évaluation conjointe du contenu en ADN et de la fraction de cellules en phase S est un paramètre pronostique indépendant dans les cancers du sein de stades I et II.

PURPOSE: To assess the significance of S-phase fraction (SPF) and DNA ploidy evaluated by DNA flow cytometry as prognostic markers in stage I or II breast cancer. PATIENTS AND METHODS: A series of 271 patients, treated by surgery, radiotherapy+/-systemic therapy was analysed (median follow up: 64 months). Standardized flow cytometry cell preparation from frozen samples and consensus rules for data interpretation were followed. Three SPF classes were defined on the basis of tertiles after adjustment for ploidy. Four groups were defined based on combinations of DNA ploidy (DIP: diploid; ANEUP: aneuploid) and SPF: DIP and low SPF (DL, N=37), DIP and medium or high SPF (DMH, N=76), ANEUP and low SPF (AL, N=24), ANEUP and medium or high SPF (AMH, N=68). Local control rate (LCR), disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS) were correlated with DNA ploidy, SPF, DL to AMH groups, T and N stages, SBR grading, age, and hormonal status on univariate and multivariate analysis (Cox model). RESULTS: On univariate analysis, DFS and LCR were higher for DIP tumours. High SPF values were associated with shorter DFS. LCR, MFS, DFS, and OS rates were significantly different with an increasingly poorer prognosis from DL to AMH. On multivariate analysis, groups DL to AMH, histological node involvement and T stage were independently associated with MFS, and DFS. In N- patients, DL to AMH remained independent for MFS and DFS. For SBR III tumours, MFS and OS were significantly different in DL to AMH groups. These results strongly support the use of combined evaluation of DNA ploidy and SPF as independent parameters in clinical trials for N- stage I and II breast cancer.

Diagnostic efficacy of ultrasound-guided core-needle biopsy of peripheral lymph nodes in sarcoidosis.

BACKGROUND: Core-needle biopsy guided by ultrasound can be performed for investigating peripheral lymph node (PLN). The aim of this study was to determine the efficacy of this technique in sarcoidosis. METHODS: Retrospective review of files of all patients in the database of the radiology department of Avicenne university hospital who underwent PLN biopsies guided by ultrasound from January 2008 to June 2011 (n=292). Cases with either granulomas at histology with the procedure or with a final diagnosis of sarcoidosis were included in the study. RESULTS: The histological specimens were adequate in 282 out of 292 cases (96%) showing non-caseating granulomas in 22 cases (n=20 patients with a final diagnosis of sarcoidosis and n=2 patients with tuberculosis). After reviewing clinical files of the 282 patient, 22 were confirmed to have sarcoidosis, at initial presentation (n=19) or later during flare-up or relapse (n=3) with only 2 patients having no granuloma on PLN biopsy. PLN were palpable in 18 cases and only detected by (18F)FDG-PET/CT showing increased PLN uptake in 4 cases. The sensitivity and specificity of adequate biopsy were 91 and 99% and the positive and negative predictive values were 91 and 99%, respectively. CONCLUSION: Core-needle biopsy guided by ultrasound has a high efficacy for evidencing granulomas in sarcoidosis patients with PLN involvement either clinically palpable or in the presence of (18F)FDG-PET/CT uptake.

Calbindin-D9K gene expression in the lung of the rat. Absence of regulation by 1,25-dihydroxyvitamin D3 and estrogen.

Calbindin-D9K (CaBP9K) is classically considered to be the molecular expression of 1,25-dihydroxyvitamin D3. The hormone is known to regulate the rat CaBP9K gene in duodenal tissue at transcriptional and posttranscriptional levels. This study shows that the CaBP9K gene is expressed in the rat lung, and that this expression is probably not vitamin D- or estrogen-dependent. The CaBP9K gene is not expressed in alveolar macrophages, but CaBP9K messenger RNA (mRNA) was localized by in situ hybridization in alveolar epithelial cells. CaBP9K mRNA was detected as early as the 20th day of gestation. The quantity of CaBP9K mRNA gradually increased during growth, from 1-77 days after birth, whereas the CaBP9K concentration dramatically increased from day 19 to day 20 of gestation. Vitamin D-deficient male rats (8 weeks old) were given a single injection of 1,25-dihydroxyvitamin D3 (650 pmol/100 g body wt) and killed 1 h and 24 h after injection. The hormonal treatment resulted in a rise in duodenal CaBP9K mRNA, but no significant change in lung extracted CaBP9K mRNA. Mature ovariectomized rats were injected with 17 beta-estradiol (0.5 microgram/100 g body wt) and killed 24, 48, and 72 h later. The CaBP9K mRNA concentration in the uterus was markedly dependent on estrogen; that of the lung was not. The factors regulating the CaBP9K gene expression in the lung remain to be determined.

Predictive value of cytomegalovirus DNA detection by polymerase chain reaction in blood and bronchoalveolar lavage in lung transplant patients.

BACKGROUND: Despite promising results, the efficacy of polymerase chain reaction (PCR) for clinical management of cytomegalovirus (CMV) infection in transplanted patients is still controversial. METHODS: A prospective study of CMV detection, with concurrent shell vial cultures and PCR in blood and bronchoalveolar lavage (BAL), was conducted in 13 lung transplant recipients, monitored for 15 months (range: 1-42 months). CMV DNA was detected by PCR amplification of a 406-bp fragment in the Us region and a 290-bp fragment in the immediate early region of the viral genome. RESULTS: When comparing PCR to viral culture, the sensitivity and specificity of CMV DNA detection were 100% and 65.7% in blood (n=122) and 100% and 75% in BAL (n=104). The positive and negative predictive values of PCR for a forthcoming diagnosis of CMV infection were 50% and 97% in blood, and 67% and 85% in BAL. Seventeen CMV infections were evaluated at the end of treatment: when PCR was still positive either in blood or BAL, CMV infection relapsed within 35+/-5 days; when PCR was negative, CMV infection relapsed after 142+/-57 days (P=0.01). CONCLUSIONS: Negative CMV detection by PCR strongly advocates against a forthcoming CMV infection. PCR assay seems to be a good predictor for early recurrence of CMV infection, and would be useful for monitoring the response to antiviral therapy.

Different pattern of MRP localization in ciliated and basal cells from human bronchial epithelium.

The MRP (multidrug resistance-associated protein) transmembrane transporter, which actively transports a wide variety of lipophilic substrates out of cancer cells, has been suggested to play a major role in cell detoxification via efflux of glutathione conjugates. Because bronchial epithelial cells are constantly exposed to environmental pollutants, MRP might be a particularly important defense mechanism against xenobiotics. This study was therefore designed to investigate MRP localization by immunohistochemistry in bronchial epithelial cells collected by scraping from surgical specimens. In parallel, MRP mRNA was detected by reverse transcriptase chain reaction (rt-PCR) in bronchial cell lysates. However, the pattern of protein expression differed markedly according to cell type. In ciliated epithelial cells, immunostaining was restricted to the basolateral surface, without any labeling at the apical surface, which is at variance with the localization of CFTR and MDR1 proteins, other members of the same family of transporters. In basal cells, MRP was present over the entire circumference of the plasma membrane. Basal cells were identified by their morphology and specifically after incubation with an anticytokeratin 17 monoclonal antibody. In conclusion, the different patterns of localization suggest specific roles for MRP in basal and ciliated cells.

Immunohistochemical distribution of inter-alpha-trypsin inhibitor chains in normal and malignant human lung tissue.

The inter-alpha-trypsin inhibitor (ITI) family is a group of plasma proteins built up from heavy (HC1, HC2, HC3) and light (bikunin) chains synthesized in the liver. In this study we determined the distribution of ITI constitutive chains in normal and cancerous lung tissues using polyclonal antibodies. In normal lung tissue, H2, H3, and bikunin chains were found in polymorphonuclear cells, whereas H1 and bikunin proteins were found in mast cells. Bikunin was further observed in bronchoepithelial mucous cells. In lung carcinoma, similar findings were obtained on infiltrating polymorphonuclear and mast cells surrounding the tumor islets. Highly differentiated cancerous cells displayed strong intracytoplasmic staining with H1 and bikunin antiserum in both adenocarcinoma and squamous cell carcinoma. Moreover, weak but frequent H2 expression was observed in adenocarcinoma cells, whereas no H3-related protein could be detected in cancer cells. Local lung ITI expression was confirmed by RT-PCR. Although the respective role of inflammatory and tumor cells in ITI chain synthesis cannot be presently clarified, these results show that heavy chains as well as bikunin are involved in malignant transformation of lung tissue.(J Histochem Cytochem 47:1625-1632, 1999)

CFTR, MDR1, and MRP1 immunolocalization in normal human nasal respiratory mucosa.

CFTR (cystic fibrosis transmembrane conductance regulator), MDR1 (multidrug resistance), and MRP1 (multidrug resistance-associated protein), members of the ABC transporter superfamily, possess multiple functions, particularly Cl(-), anion, and glutathione conjugate transport and cell detoxification. They are also hypothesized to have a number of complementary functions. It is generally accepted that data obtained from nasal mucosa can be extrapolated to lower airway cell physiology. The aim of the present study was to investigate by immunohistochemistry the differential localization of CFTR, MDR1, and MRP1 in the normal mucosa of 10 human nasal turbinates. In ciliated epithelial cells, CFTR was inconstantly expressed at the apical cell surface, intense membranous labeling was observed for MDR1, and intense cytoplasmic labeling was observed for MRP1. In the glands, a higher level of expression was observed on serous cells, at the apical surface (for CFTR), on lateral membranes (for MDR1), and with an intracytoplasmic distribution (for MRP1). In conclusion, CFTR, MDR1 and MRP1 are expressed in the epithelium and glands of the nasal respiratory mucosa, but with different patterns of expression. These results suggest major roles for CFTR, MDR1, and MRP1 in serous glandular cells and a protective function for MDR1 and MRP1 in respiratory ciliated cells. (J Histochem Cytochem 48:1215-1222, 2000)

Interactions between cigarette smoking and the natural history of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is characterized by an inflammation of the walls of the respiratory airspaces that proceed to fibrotic alveolar derangement. Smoking habits are associated with changes in the number and the activation state of immune and inflammatory alveolar cells. Cigarette smoke could interact with the course of this disease. To evaluate the effects of smoking on IPF, 11 smokers and 16 nonsmokers were compared. Clinical presentation, PFTs, BAL cell populations, short-term glucocorticoid responsiveness and survival were evaluated. Similar PFT results were observed in both groups. Lymphocyte cells were higher in nonsmokers than in smokers. Glucocorticoid responsiveness was mainly observed in nonsmokers. Nonsmoking status was not associated with survival advantage. We conclude that the subset of IPF characterized by an aggressive onset, a BAL fluid high lymphocyte count and a substantial PFT improvement after therapy began, occurs predominantly in the absence of cigarette smoking habits.