Vitamin D and disease severity in bronchiectasis.

BACKGROUND: Bronchiectasis is a complex respiratory disease characterised by permanent dilatation of bronchi. Vitamin D plays a role in infective disease by modulating the inflammation. Patients affected by bronchiectasis are frequently Vitamin D deficient and it correlates with lung function decline. We want to understand if there is a correlation between Vitamin D and clinical and radiological severity of bronchiectasis. METHODS: We included 57 patients (17 males/40 female with mean age 60 ±â€¯12 years) between October 2017 and March 2018. We excluded patients with cystic fibrosis, traction bronchiectasis and reporting Vitamin D supplementation. Bronchiectasis severity index (BSI) and Bhalla score were calculated, blood inflammatory markers and Vit. D were measured and lung function tests were performed. RESULTS: Vitamin D is deficient in 64% of patients, sufficient in 36% and normal in 7%. Mean BSI is 7.5 ±â€¯5 and mean Bhalla score is 16 ±â€¯4. Vitamin D levels correlate with Bhalla score (R2 = 0.68, p < 0.001) and BSI (R2 = 0.58, p < 0.0001). The correlation appears to be stronger than other markers of inflammation such as ESR and CRP [R2 = 0.33, p = 0.001 and R2 = 0.39, p = 0.001 respectively]. CONCLUSIONS: We consider Vitamin D as a good predictor of clinical and radiological severity of bronchiectasis.

Predictors of response to omalizumab and relapse in chronic spontaneous urticaria: a study of 470 patients.

BACKGROUND: Chronic spontaneous urticaria (CSU) is defined as spontaneous occurrence of wheals and/or angioedema for ≥6 weeks. Omalizumab is a monoclonal anti-IgE antibody effective in refractory CSU, but its mechanism of action and markers predictive of response remain not completely defined. OBJECTIVES: To correlate baseline levels of two proposed biomarkers, total IgE (bIgE) and d-dimer (bd-dimer), and clinical parameters to omalizumab response and to relapses after drug withdrawal. METHODS: In this retrospective Italian multicentre study, clinical data were collected in 470 CSU patients, and bIgE and bd-dimer were measured in 340 and 342 patients, respectively. Disease activity was determined by Urticaria Activity Score 7 (UAS7) at week 1 and 12 after omalizumab starting. Relapses were evaluated during a 2- and 3-month interval after a first and a second course of treatment, respectively. RESULTS: bIgE correlated to a good response to omalizumab since levels were significantly higher in responders than non-responders (P = 0.0002). Conversely, bd-dimer did not correlate to response. There was no correlation between both bIgE and d-dimer and either first or second relapse. Disease duration was significantly longer in patients who experienced either first or second relapse (P < 0.0001 and P = 0.0105, respectively), while baseline UAS7 correlated only to first relapse (P = 0.0023). CONCLUSIONS: Our study confirms bIgE as a reliable biomarker predicting response to omalizumab in CSU, while it does not support the usefulness of bd-dimer unlike previous findings. CSU duration before omalizumab and baseline UAS7 may be clinical markers of relapse risk.

Higher serum levels of periostin and the risk of exacerbations in moderate asthmatics.

BACKGROUND: In asthma, exacerbations and poor disease control are linked to airway allergic inflammation. Serum periostin has been proposed as a systemic biomarker of eosinophilic inflammation. This pilot study aims at evaluating whether in patients with moderate asthma, higher baseline levels of serum periostin are associated with a greater risk of exacerbation. METHODS: Fifteen outpatients with moderate allergic asthma were recruited. Serum concentrations of periostin were assessed (ELISA) at baseline, and the frequency of asthma exacerbations was recorded during a one-year follow-up. RESULTS: Patients (M/F: 10/5, mean age of 47.6 ± 11.0 years) had mean ACQ score of 5.5 ± 4.2 and FEV1%pred of 81.9 ± 21.7 %. Baseline serum levels of periostin did not correlate with lung function parameters, nor with the ACQ score (p ≥0.05 for all analyses). Five subjects (33 % of the study group) reported one or more exacerbations during the following year. Baseline serum levels of periostin were significantly higher in subjects who experienced one or more exacerbations during the one year period of follow-up, compared with subjects with no exacerbations: median serum periostin level was 4047 ng/ml (range: 2231 to 4889 ng/ml) and 222 ng/ml (range 28.2 to 1631 ng/ml) respectively; p = 0.001. CONCLUSION: The findings of the present pilot study could form the basis for the design of larger studies aiming at developing strategies to identify asthmatic patients at risk for exacerbations.

In vitro antiproliferative effect of trastuzumab (Herceptin(®)) combined with cetuximab (Erbitux(®)) in a model of human non-small cell lung cancer expressing EGFR and HER2.

Lung cancer is the leading cause of cancer death. For this reason, new therapies are needed for the treatment of this devastating disease. In this study, we investigated the effects of combining cetuximab and the trastuzumab on the growth of a model of human non-small cell lung carcinoma cell line (A549). The results were compared with those obtained from a human lung squamous carcinoma cell line (NCI-H226). Both cell lines were treated with cetuximab and trastuzumab, alone or in combination, at various concentrations, for 24, 48 and 72 h. Cell proliferation was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. EGFR and HER-2 mRNA expression was detected by reverse transcription polymerase chain reaction, and the gene amplification status of receptors was evaluated by fluorescence in situ hybridisation. The colorimetric proliferation assay showed that trastuzumab combined with cetuximab significantly inhibited A549 cells at a dose of 40 µg/ml after 72 h of treatment (p < 0.05), while no time-dose dependent inhibition was observed in NCI-H226 cells. The combined treatment influenced both levels of EGFR and HER-2 mRNA in A549 cells and only EGFR mRNA levels in NCI-H226 cells. Fluorescence in situ hybridisation showed that both cell lines were aneuploid for the two genes with equally increased EGFR and CEN7 signals, as well as HER-2 and CEN17 signals, indicating a condition of polysomy without amplification. The preliminary results of this study encourage further investigations to elucidate the downstream events involved and to understand how these mechanisms influence non-small cell lung cancers growth.

Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology.

Several clinical trials have recently targeted specific pathways implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, IPF remains plagued by a median survival of 3 yrs and emphasises the need for further research with new insights and perspectives. The prevailing pathogenic hypotheses assume that either an inflammatory process or an independent epithelial/fibroblastic disorder may propagate the disease process. Based on knowledge developed with considerable scientific evidence, we provide our perspectives with an alternative point of view that IPF be considered as a neoproliferative disorder of the lung. Genetic alterations, response to growth and inhibitory signals, resistance to apoptosis, myofibroblast origin and behaviour, altered cellular communications, and intracellular signalling pathways are all fundamental pathogenic hallmarks of both IPF and cancer. The concept of IPF as a lethal malignant disorder of the lung might extend beyond the pathogenic link between these two diseases and disclose new pathogenic mechanisms leading to novel therapeutic options, adopted from cancer biology. Moreover, this vision might dawn the awareness of the public, political and scientific community of this devastating disease from an angle different from the current perception and provoke new ideas and studies to get a better understanding to control the otherwise relentless progressive disease.

Intranasal steroid reduces exhaled bronchial cysteinyl leukotrienes in allergic patients.

BACKGROUND: Allergic rhinitis (AR) precedes and is often associated with bronchial asthma. Indeed, local and systemic inflammations in both conditions are very similar. Cysteinyl-leukotrienes (cys-LTs) are generated during early- and late-phase allergic reactions and induce smooth-muscle contraction, microvascular leakage, and mucous hypersecretion. Cys-LTs are detected in exhaled breath condensate (EBC) of asthmatics and regardless of bronchial symptoms, they are also found in EBC of rhinitic patients. OBJECTIVE: To evaluate cys-LTs in EBC of allergic patients and to assess the activity of nasal fluticasone propionate (FP) on EBC cys-LTs levels. METHODS: Cys-LTs coefficient of variation (CV) was evaluated from different EBC in 5 healthy volunteers. Cys-LTs levels from EBCs in 13 healthy controls and 56 allergic rhinitic (n=31) and rhinitic/asthmatic (n=25) patients were also evaluated at baseline. Subsequently patients were randomized to receive either FP 100 microg/day per nostril or placebo for 2 weeks and then re-evaluated for EBC cys-LTs. RESULTS: The CV was 14.12%. EBC cys-LTs in allergic patients were significantly higher than in healthy subjects (70.9 vs. 20.6 pg/mL (median), P<0.05), while it did not differ between asthmatic/rhinitic and purely rhinitic patients. Treatment significantly reduced cys-LTs (from 93.6 to 19.9 pg/mL, P<0.001). This effect was evident both in asthmatic/rhinitic and in rhinitic patients. CONCLUSION: Treatment of AR with FP significantly reduces the levels of cys-LTs, major noninvasive markers of lower airway inflammation, suggesting that upper and lower airway inflammation is present and should be thus treated as a whole in subjects with AR with and without asthma.

Cellular and molecular effects of protons: apoptosis induction and potential implications for cancer therapy.

Due to their ballistic precision, apoptosis induction by protons could be a strategy to specifically eliminate neoplastic cells. To characterize the cellular and molecular effects of these hadrons, we performed dose-response and time-course experiments by exposing different cell lines (PC3, Ca301D, MCF7) to increasing doses of protons and examining them with FACS, RT-PCR, and electron spin resonance (ESR). Irradiation with a dose of 10 Gy of a 26,7 Mev proton beam altered cell structures such as membranes, caused DNA double strand breaks, and significantly increased intracellular levels of hydroxyl ions, are active oxygen species (ROS). This modified the transcriptome of irradiated cells, activated the mitochondrial (intrinsic) pathway of apoptosis, and resulted in cycle arrest at the G2/M boundary. The number of necrotic cells within the irradiated cell population did not significantly increase with respect to the controls. The effects of irradiation with 20 Gy were qualitatively as well as quantitatively similar, but exposure to 40 Gy caused massive necrosis. Similar experiments with photons demonstrated that they induce apoptosis in a significantly lower number of cells and in a temporally delayed manner. These data advance our knowledge on the cellular and molecular effects of proton irradiation and could be useful for improving current hadrontherapy protocols.

[Prevalence of respiratory symptoms, reduction in lung function and allergic sensitization in a group of traffic police officers exposed to urban pollution]. / Prevalenza di sintomi respiratori, riduzione della funzionalità polmonare e sensibilizzazione allergica in un gruppo di vigili urbani esposti al traffico urbano.

BACKGROUND: Environmental factors are believed to play a critical role in the development of allergic respiratory diseases, such as asthma and rhinitis. Particularly, the role of urban pollution in the pathogenesis of these diseases is debated. OBJECTIVES: The aim of the study was to investigate whether subjects with a well-defined occupational history of exposure to road traffic fumes presented an increased prevalence of respiratory symptoms of chronic bronchitis (cough), asthma (wheeze), and allergic sensitisation to the most common allergens and reduced lung function compared with an unexposed control group. METHODS: The study was conducted on 484 traffic police in Catania (465 men and 19 women), with a mean age of 45 +/- 7.9 years, who were subdivided into three groups. The first group included traffic police assigned to traffic direction, the second group included traffic police working in administrative offices, the third group included all traffic police who did not fall into the previous groups. In the first group, "truly exposed" subjects were identifed as police officers assigned to traffic direction in the last 8 years. Similarly, in the second group, "truly non-exposed" subjects were identified as police officers working in offices in the last 8 years. RESULTS: Statistical analysis showed a significant difference in mean age between the truly exposed group and the truly non-exposed group (p < 0.01). The truly exposed group showed a greater prevalence of symptoms (cough, wheeze and dyspnoea), and positive reaction to skin allergy tests compared with the "truly non-exposed group", but this increase did not reach statistical significance. Alterations of the respiratory function tests were more frequent in the non-exposed (14.3%) compared to the exposed group (9.6%). The highest prevalence of cough, dyspnoea and wheezing was detected in smokers compared to non-smokers and to ex-smokers within each group. CONCLUSIONS: Our results show a major prevalence of respiratory symptoms and allergic sensitisation in exposed traffic police compared with non-exposed police, although this did not reach statistical significance. Further epidemiological studies conducted on larger samples are required to better understand the role of road traffic pollution in inducing allergic respiratory diseases.

Effect of rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 on bleomycin-induced lung injury.

Thiazolidinedione rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), are two peroxisome proliferator-activated receptor (PPAR)-gamma ligands. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury. An increase in immunoreactivity to nitrotyrosine, poly(ADP ribose) polymerase (PARP) and inducible nitric oxide synthase as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated mice. Administration of the two PPAR-gamma agonists rosiglitazone (10 mg x kg(-1) i.p.) and 15d-PGJ2 (30 microg x kg(-1) i.p.) significantly reduced the: 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) oedema formation, and 5) histological evidence of lung injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine, PARP and inducible nitric oxide synthase formation. In addition, treatment with the PPAR-gamma antagonist bisphenol A diglycidyl ether (1 mg x kg(-1) i.p. 30 min before the rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists. These results demonstrate that the two peroxisome proliferator-activated receptor-gamma agonists, rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, significantly reduce lung injury induced by bleomycin in mice.

Effect of immunotherapy on asthma progression, BHR and sputum eosinophils in allergic rhinitis.

BACKGROUND: Bronchial hyperresponsiveness (BHR) and airway inflammation are frequently associated with allergic rhinitis, and may be important risk factors for the development of asthma. Specific immunotherapy (SIT) reduces symptom in subjects with allergic rhinitis, but the mechanisms are not clear. AIMS OF THE STUDY: To assess the effect of Parietaria-SIT on asthma progression, rhinitic symptoms, BHR, and eosinophilic inflammation. METHODS: Nonasthmatic subjects with seasonal rhinitis were randomly assigned to receive Parietaria pollen vaccine (n = 15) or matched placebo (n = 15). Data on symptoms and medication score, BHR to methacholine, eosinophilia in sputum were collected throughout the 3-year study. RESULTS: By the end of the study, in the placebo group, symptoms and medication scores significantly increased by a median (interquartile range) of 121% (15-280) and 263% (0-4400) respectively (P < 0.01), whereas no significant difference was observed in the SIT group. We found no significant changes in sputum eosinophils and BHR to methacholine in both groups throughout the study. Nine of 29 participants developed asthma symptoms during the study; of these, only two subjects (14%) in the SIT-treated group (P = 0.056). CONCLUSIONS: Parietaria-SIT reduces symptom and rescue medication scores, but no changes in BHR to methacholine or sputum eosinophilia were observed. Moreover, Parietaria-SIT appears to prevent the natural progression of allergic rhinitis to asthma, suggesting that SIT should be considered earlier in the management of subjects with allergic rhinitis.

Monitoring of seasonal variability in bronchial hyper-responsiveness and sputum cell counts in non-asthmatic subjects with rhinitis and effect of specific immunotherapy.

Bronchial hyper-responsiveness (BHR) is documented in a proportion of non-asthmatic individuals with allergic rhinitis (NAAR) and reflects inflammatory events in the lower airways. Natural exposure to allergens is known to modulate BHR and the level of airway inflammation in asthma, but less consistently in NAAR. Specific immunotherapy (SIT) attenuates symptoms possibly by reducing BHR and airway inflammation. The influence of natural exposure to Parietaria pollen on BHR and sputum cell counts of NAAR was investigated and the effect of Parietaria SIT examined. Thirty NAAR, monosensitized to Parietaria judaica, participated in a randomized, double-blind, placebo-controlled, parallel group study of the effects of a Parietaria pollen vaccine on symptoms/medication score, BHR to inhaled methacholine and adenosine 5'-monophosphate (AMP), and cell counts in the sputum collected out of and during the pollen seasons for 36 months. Seasonal variation in BHR to inhaled methacholine and AMP and changes in sputum cell counts were documented. Changes were consistent for AMP, but not methacholine, and invariably associated with modifications in sputum eosinophils and epithelial cells. The clinical efficacy of Parietaria SIT was associated with a decline in the seasonal deterioration of BHR to AMP, whereas no significant effect was observed on BHR to methacholine or sputum cell differentials. Between-groups comparison of the seasonal changes in PC15 methacholine values and sputum cell differentials calculated as the AUC were not statistically significant, whereas a significant difference in PC15 AMP was demonstrated throughout the study (P=0.029), the median (inter-quartile range) AUC values being 2478.5 (1153.3-3600.0) and 1545.5 (755.3-1797.9) for the SIT- and placebo-treated group, respectively. Bronchial airways of NAAR exhibit features of active inflammation that deteriorate during natural allergen exposure, particularly with regard to BHR to AMP. The clinical efficacy of Parietaria SIT was exclusively associated with attenuation in seasonal worsening of PC15 AMP, suggesting that AMP may be useful in monitoring changes in allergic inflammation of the airways.

Acute interstitial pneumonia: report of a series.

Four cases of acute interstitial pneumonia (AIP) are described with special emphasis on clinical background, lung imaging and bronchoalveolar lavage findings. A retrospective chart review of four patients with histologically-proven AIP, diagnosed between 1998 and 2000, was carried out. Clinical data, bronchoalveolar lavage (BAL) findings, high-resolution computed tomography (HRCT) and histological features were analysed. Three patients died and only one is in follow-up. HRCT showed areas of ground glass attenuation and alveolar consolidation in all patients. Histology, documented by open lung biopsy or autopsy specimens, was consistent with the organising form of diffuse alveolar damage pattern. BAL findings were characteristic, with a huge neutrophilia associated with scattered atypical type II pneumocytes collected in clusters with extracellular amorphous material (fragments of hyaline membranes) observed in two out of three cases. In this paper, four cases of acute interstitial pneumonia are reported in detail. The poor prognosis associated with this entity has been confirmed and the possible diagnostic role of the bronchoalveolar lavage is emphasised.

Role of oxidative stress in pulmonary fibrosis.

Pulmonary fibrosis can be observed as an end state in a number of chronic inflammatory pulmonary diseases. Although the mechanisms by which lung fibrosis develops are not fully ascertained, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. Damage and alteration of alveolar epithelial cells is one of the hallmarks of interstitial lung fibrosis. Recently, it has been demonstrated that the presence of oxidative stress may lead to the damage, activation and/or apoptosis of alveolar epithelial cells either directly, through an imbalanced intracellular redox equilibrium, or indirectly, by activating redox-sensitive effector pathways, such as transcription factors and angiotensin converting enzyme, increasing the conversion of angiotensinogen into angiotensin II that can be considered a mediator of oxidative stress, capable of inducing apoptosis. Furthermore, it has been demonstrated that angiotensin II acts as a proinflammatory cytokine and is effective in activating fibroblasts through the release of transforming growth factor (TGF-beta). As well as activation, differentiation, proliferation and apoptosis of fibroblasts seem related to the oxidant/antioxidant balance, and the maintenance of a high intracellular level of reduced glutathione (GSH) is considered crucial in providing a reducing environment within the cell, able to protect against oxidative stress. In those conditions where oxidants, either inhaled or produced by inflammatory cell, increase, the ratio between GSH and oxidized glutathione (GSSH) may lower, influencing a variety of cellular redox-sensitive signaling processes such as the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that lead to a transcriptional up-regulation of a number of genes involved in inflammation and/or fibrogenesis, including cytokines [interleukin (IL)-1,, tumor necrosis factor (TNF-alpha), IL-6] chemokines (IL-8), adhesion molecules (VCAM-1, ICAM-1) and growth factors (GM-CSF). In addition, several studies have shown that oxidative stress may also affect the immune response by inducing an up-regulation of HLA-DR as well as the expression of two costimulatory molecules such as CD40 and CD86, determining a persistent state of immune activation, and affecting the Th1/Th2 balance, modulating the T-cell effector response towards the Th2 phenotype. It is clear that a better understanding of the precise sequence of events that make the difference between normal tissue repair and fibrosis, including the role played by oxidative stress, will certainly improve our therapeutic approach to pulmonary fibrosis.

Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis.

BACKGROUND: Recently, several studies have shown that heparin possesses various anti-inflammatory and antiallergic properties. It has been proposed that heparin might play an important role in limiting the inflammatory events associated with asthma and allergic rhinitis by neutralizing inflammatory mediators, such as eosinophil cationic protein and major basic protein, and by limiting eosinophil recruitment. OBJECTIVE: To test the hypothesis that heparin can limit the extent and magnitude of eosinophilic inflammation, we examined the effect of inhaled intranasal heparin on nasal response to allergen challenge in 10 patients with allergic rhinitis. METHODS: The capacity of heparin to reduce nasal response was studied by evaluating symptom score, eosinophil cationic protein concentration, and eosinophil counts in nasal lavage fluids 10, 60, and 360 minutes after allergen challenge. RESULTS: Pretreatment with intranasal heparin produced a significant reduction in symptom score 10 minutes after allergen challenge and reduced the eosinophil influx at each time point after antigen challenge, statistical significance being reached 60 and 360 minutes after allergen challenge. Similarly, the amount of eosinophil cationic protein in the nasal wash was reduced at each time point; this reached statistical significance 360 minutes after allergic challenge. CONCLUSION: Heparin was shown to provide protection with respect to nasal allergen challenge. The mechanism by which heparin produces its protective activity seems to be related to the neutralization of eosinophil cationic protein as well as to the reduction of eosinophil recruitment.

Normal human lung fibroblasts differently modulate interleukin-10 and interleukin-12 production by monocytes: implications for an altered immune response in pulmonary chronic inflammation.

The ability of lung fibroblasts to modulate the immune response has been evaluated by analyzing the synthesis and release of interleukin (IL)-10 and IL-12 by lipopolysaccharide (LPS)-stimulated peripheral blood monocytes exposed to pulmonary fibroblast conditioned medium (FCM). IL-10 and IL-12 contents and gene expression were markedly modified by treatment with FCM as measured by ELISA (+97.5 +/- 12.8% and -68 +/- 7.3% for IL-10 and IL-12, respectively), immunocytochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR). These effects appeared to be mediated by prostaglandin E(2) (PGE(2)) as the modified release of both cytokines was reduced by treatment with indomethacin and mimicked by addition of exogenous PGE(2.) As a result of the enhanced production of IL-10, exposure of LPS/interferon (IFN)-gamma-activated monocytes to FCM was also able to reduce the expression of the class II major histocompatibility complex (MHC) molecule, human leukocyte-associated antigen-DR (HLA-DR) (-51.8 +/- 8.7%) and of the costimulatory molecule, CD40 (-53.9 +/- 11.7%). The expression of both molecules was completely restored when monocytes were pretreated with a neutralizing anti-IL-10 monoclonal antibody. The FCM obtained from fibrotic lung fibroblasts was instead less efficacious in potentiating LPS-stimulated IL-10 release and, consequently, in reducing HLA-DR and CD40 expression, suggesting that an impairment of the immune regulation operated by fibroblasts may be involved in the maintenance of chronic pulmonary inflammation.

Different expression of TNF-alpha receptors and prostaglandin E(2 )Production in normal and fibrotic lung fibroblasts: potential implications for the evolution of the inflammatory process.

Normal human lung fibroblasts downregulate the production of tumor necrosis factor (TNF)-alpha by activated monocytes through the production of prostaglandin E(2) (PGE(2)), contributing to the local control of the inflammatory process. In this study, we provide evidence that fibroblasts derived from diseased tissue, such as fibrotic lung fibroblasts, exhibit different functional features compared with normal cells, with particular regard to their modulatory role. Indeed, fibrotic fibroblasts (FF) spontaneously produced less PGE(2) (3,300 +/- 410 pg/ml) compared with normal fibroblasts (NF) (7,500 +/- 270 pg/ml) and, as a consequence, they showed a reduced ability to downregulate the production of TNF-alpha by lipopolysaccharide (LPS)- activated monocytes. The percentage of inhibition induced by normal cells on the production of TNF-alpha by LPS-activated monocytes was 61 +/- 5.9%, whereas the inhibitory effect exerted by fibrotic cells was reduced to 32 +/- 4% (P < 0.01). We have also observed that the ability of TNF-alpha to induce PGE(2) was impaired in FF and was related to a reduced expression of cyclooxygenase 2. This was possibly due to the reduction of the expression of TNF receptors (TNFRs) in fibrotic cell lines compared with normal cell lines. Flow cytometry revealed that the mean fluorescence intensity (MFI) of both isoforms of TNFR was significantly lower in FF compared with NF. The MFI of TNFR1 was 3. 55 +/- 0.12 for NF and 1.78 +/- 0.35 for FF (P < 0.001). The MFI of TNFR2 was 1.95 +/- 0.27 for NF and 0.99 +/- 0.16 for FF (P < 0.01). The analysis of the effect of TNF-alpha on some functions associated with collagen metabolism in NF and FF showed an increase of the expression of the receptor for collagen type I (alpha(2)beta(1) integrin) in NF (42 +/- 10%) and an even larger increase in FF (102 +/- 23%) (P < 0.05). Interestingly, unlike NF, TNF-alpha failed to increase matrix metalloproteinase 1 levels in FF and did not cause any growth inhibition in these cells. The reduced capability of fibrotic cells to produce PGE(2) either spontaneously or after TNF-alpha treatment may lead to an unrestrained release of TNF-alpha from activated monocytes and, as a result of the reduced expression of TNFRs, to a different response of these cells to TNF-alpha. These changes may be important in the evolution of the inflammatory process, potentially contributing to its transformation into a chronic and self-perpetuating process.

Bronchial hyperresponsiveness and airway inflammation markers in nonasthmatics with allergic rhinitis.

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma which is often associated with airways inflammation. However, some patients with allergic rhinitis and no clinical evidence of asthma also exhibit BHR. This study therefore investigated whether inflammatory cell infiltrate is present in the induced sputum of nonasthmatic subjects with allergic rhinitis during the pollen season and examined its relationship with airway hyperresponsiveness to inhaled methacholine and adenosine 5'-monophosphate (AMP). Twenty subjects (12 allergic rhinitis, eight nonallergic controls) underwent methacholine and AMP challenge and sputum induction with hypertonic saline on separate days. Cell differentials were calculated from whole sputum samples. A significantly greater number of eosinophils was found in the sputum of nonasthmatic subjects with allergic rhinitis compared to that of nonallergic controls, their median (range) percentages being 17.5 (4-47) and 1.5 (0-5) (p<0.001) respectively. Although sputum eosinophilia failed to be significantly associated with methacholine responsiveness (r(s)=-0.50; p=0.095), the provocative concentration of AMP causing a 20% fall in forced expiratory volume in one second correlated strongly and significantly with the absolute number of eosinophils (r(s)= -0.73; p=0.007). Eosinophil cationic protein levels in the sputum of rhinitic subjects were significantly elevated compared to controls and correlated with eosinophil number (r(s)=0.67; p=0.017). These findings support the view that bronchial eosinophilia alone is insufficient to cause asthmatic symptoms. Diverse agonists for assessing bronchial hyperresponsiveness are selectively associated with airway inflammation in allergic rhinitis.

A double-blind, placebo-controlled comparison of treatment with fluticasone propionate and levocabastine in patients with seasonal allergic rhinitis. FLNCO2 Italian Study Group.

Fluticasone propionate aqueous nasal spray (FPANS) is a topically active glucocorticoid which has been successfully used for the treatment of seasonal allergic rhinitis (SAR). Topical levocabastine is a highly selective H1 antagonist which has been proposed as an alternative treatment of SAR. The purpose of this study was to compare the clinical efficacy of two topical nasal treatments, FPANS and levocabastine, in the treatment of SAR. Additionally, the effect of treatments on nasal inflammation was examined during natural pollen exposure. A group of 288 adolescent and adult patients with at least a 2-year history of SAR to seasonal pollens participated in a multicenter, doubleblind, double-dummy, and placebo-controlled study. Patients were treated with either FPANS 200 microg, once daily (n = 97), or topical levocabastine, 200 microg, given twice daily (n = 96), or matched placebo (n = 95) for a period of 6 weeks, starting from the expected beginning of the pollen season. Clinically relevant pollens included Parietaria, olive, and grass. Assessment of efficacy was based on scores of daily nasal symptoms and on nasal cytology of nasal lavage. Nasal lavage was performed immediately before, during, and at the end of treatment in 39 patients. FPANS significantly increased the percentage of symptom-free days for nasal obstruction on waking and during the day, rhinorrhea, sneezing, and itching. FPANS provided a better control for night and day nasal obstruction (P<0.02 and P<0.01) and rhinorrhea (P<0.01) than levocabas tine. In addition, fewer patients treated with FPANS used rescue medication (P<0.025). The percentage of eosinophils in nasal lavage was reduced only during treatment with FPANS. The results of this study indicate that FPANS 200 microg, once daily, provides a better clinical effect than levocabastine 200 microg, twice daily, in patients with SAR. Unlike levocabastine, FPANS significantly attenuates nasal eosinophilia during pollen exposure, a feature which may explain its therapeutic efficacy.

Spontaneous pneumomediastinum with subcutaneous emphysema: unusual presenting feature of a common condition.

Pneumomediastinum refers to the presence of free air in the mediastinum and is frequently associated with subcutaneous emphysema. It is known that a number of medical and surgical conditions may be complicated by pneumomediastinum. However, here we report the case of a young female in whom pneumomediastinum was the presenting feature of a widespread medical condition rather than its complication.