Chronic rhinosinusitis with nasal polyposis and biological agents: the ARIA-ITALY Survey.

Summary: Background. Chronic rhinosinusitis (CRS) is an inflammatory disease that affects the nasal mucosa and the paranasal sinuses. CRS can be associated by nasal polyposis (CRSwNP phenotype) in up to 30% of patients and it is frequently associated with bronchial asthma. CRSwNP shows predominantly an underlying activation of type 2 inflammatory pathways with the involvement of eosinophils, IgE, interleukin (IL)-4, IL-5 and IL-13. Biological drugs that target these inflammatory cytokines are currently a therapeutic option recognized by guidelines for the treatment of uncontrolled form of the disease. Methods. As part of the activity of the "ARIA-Italy" working group, a panel of 255 Italian Ear, Nose and Throat (ENT) specialists, pneumologists and immuno-allergologists actively participated in this national survey and answered a series of questions geared toward understanding the main criteria for patient characterization and therapeutic decision, highlighting multidisciplinarity, and the implementation of the management of CRSwNP patients, as a part of the precision medicine concept and the appropriate use of the biologicals. Results. Two hundred and fifty-five experts and specialists participated in the survey. Conclusions. The results of this survey obtained from an extensive number of active specialists throughout Italy allow some important concluding remarks to be drawn. The main points of agreement were that multidisciplinary care teams provide many benefits but that, once the team is established, meetings and communication between members must be coordinated. Finally, the dissemination of national disease registries and the continuous updating of guidelines and position papers related to CRSwNP and comorbidities should be encouraged.

Clinical course of IPF in Italian patients during 12 months of observation: results from the FIBRONET observational study.

BACKGROUND: FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF). METHODS: Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted). RESULTS: 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study. CONCLUSIONS: FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF. TRIAL REGISTRATION: NCT02803580.

What We Know About the Pathogenesis of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with the pathologic and radiologic pattern of usual interstitial pneumonia. Prognosis is poor, and most patients die of respiratory failure within 3 to 6 years from the onset of symptoms. Although our understanding of the pathogenesis of IPF has improved over the past two decades, the mechanisms responsible for this disorder have not been clearly defined. Aging is the single most important risk factor, but genetic, environmental, and diverse exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease, traction injury) play contributory roles. In this review, we focus on pathogenetic mechanisms that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role. Current pharmacological treatment strategies for IPF have only modest value, principally by slowing the course of disease progression. Unfortunately, improvement or cure has not yet been achieved with pharmacological agents. The challenge for the future is to improve the comprehension of the mechanisms involved in the inception and evolution of IPF and their articulated interactions. This is fundamental not only to conceive and develop new drugs against this dreadful disease but also to apply different therapeutic approaches such as drug repositioning and personalized therapies in the management of IPF.

Low molecular weight heparin -induced miRNA changes in peripheral blood mononuclear cells in pregnancies with unexplained recurrent pregnancy loss.

Unexplained recurrent pregnancy loss (uRPL) is a clinical condition for which there is a lack of evidenced-based therapies. However, in clinical practice, low molecular weight heparin (LMWH) has been widely used as an empirical therapy since immune effects have been hypothesized in modulating immune tolerance at the fetal-maternal interface. Epigenetic mechanisms are involved in establishing of immune tolerance, at fetal-maternal interface. To investigate potential induced immune-epigenetic changes at maternal periphery level, which could reflect the maternal-fetal interface condition, seems to open up new therapeutical strategies, since microRNAs circulating in maternal plasma and in peripheral blood mononuclear cells (PBMCs) may be specific and sensitive immunological markers/predictors of adverse pregnancy outcomes such as RPL. Our aim in this pilot study is to evaluate potential LMWH effects on genes regulating immunological response key mechanisms related to maternal-fetal tolerance processes, by studying circulating miRNAs in maternal peripheral blood. We tested a panel of selected miRNAs on three groups: 18 healthy pregnant women, 20 pregnant women affected by uRPL, 18 pregnant women affected by uRPL, treated with LMWH. The majority of differentially expressed miRNAs (miR 374a-5p, 19a-3p, 30e-5p, 128-3p, 155-5p and 200c-3p) were found to be modulated by LMWH, which seems to have a positive function in RPL patients, by bringing patients' values back to those comparable to the control ones. Selected microRNA panels would appear to be an effective clinical tool for uRPL diagnosis and management. LMWH-modified miRNA expression levels could be targets for immunotherapy, as LMWH would appear to restore physiological miRNA levels, which are dysregulated in uRPL.

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.

Nanofat 2.0: experimental evidence for a fat grafting rich in mesenchymal stem cells.

Different strategies have been developed in the last decade to obtain fat grafts as rich as possible of mesenchymal stem cells, so exploiting their regenerative potential. Recently, a new kind of fat grafting, called "nanofat", has been obtained after several steps of fat emulsification and filtration. The final liquid suspension, virtually devoid of mature adipocytes, would improve tissue repair because of the presence of adipose mesenchymal stem cells (ASCs). However, since it is probable that many ASCs may be lost in the numerous phases of this procedure, we describe here a novel version of fat grafting, which we call "nanofat 2.0", likely richer in ASCs, obtained avoiding the final phases of the nanofat protocol. The viability, the density and proliferation rate of ASCs in nanofat 2.0 sample were compared with samples of nanofat and simple lipoaspirate. Although the density of ASCs was initially higher in lipoaspirate sample, the higher proliferation rate of cells in nanofat 2.0 virtually filled the gap within 8 days. By contrast, the density of ASCs in nanofat sample was the poorest at any time. Results show that nanofat 2.0 emulsion is considerably rich in stem cells, featuring a marked proliferation capability.

Progenitor cells from the adult mouse brain acquire a neuronal phenotype in response to beta-amyloid.

Neurospheres from adult mouse subventricular zone (SVZ) were grown in suspension cultures for 12-15 days. Neurospheres consisted mainly of neural precursor cells (NPCs) immunoreactive for nestin and also contained nestin-negative precursors. We used these neurospheres to determine the effects of synthetic beta-amyloid fragments (both betaAP(1-42) and betaAP(25-35)) on NPC proliferation, differentiation and survival. We show that neurospheres exposed to 25 microM betaAP(25-35) or betaAP(1-42) for 24 h (a toxic condition for mature neurons) did not undergo apoptosis. Instead, betaAP(25-35) orientated nestin-negative precursors towards nestin-positive NPCs and turned nestin-positive NPCs into neuroblasts. Intracerebroventricular infusion of full-length betaAP(1-42) increased the population of PSA-NCAM-positive cells in the SVZ, without affecting proliferation. We conclude that betaAP influences the fate of progenitor cells, driving their differentiation towards a neuronal lineage.

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.

Mitogenic effect of nerve growth factor (NGF) in LNCaP prostate adenocarcinoma cells: role of the high- and low-affinity NGF receptors.

We have investigated the effect of nerve growth factor (NGF) in the androgen-dependent, prostate adenocarcinoma LNCaP cell line. Exposure of LNCaP cells to NGF resulted in a significant increase of cell proliferation. The effect was concentration dependent and equally present in serum- or charcoal-stripped serum-supplemented and serum-deprived conditions. The mitogenic action of NGF was accompanied by an enhanced expression of prostate-specific antigen (PSA) and resulted additive to the proliferative effect of dihydrotestosterone. The proliferative effect of NGF appeared to be mediated by the high-affinity NGF receptor, p140trka. Only p140trka, but not the low-affinity NGF receptor, p75LNGFR, was expressed in LNCaP cells; both the proliferative response and the phosphorylation of p140trka upon NGF treatment were prevented by the tyrosine kinase inhibitor K252a. LNCaP cells transiently transfected with the cDNA encoding for p75LNGFR appeared more sensitive to NGF, as demonstrated by the increased number of p75LNGFR-transfected LNCaP cells exposed for 72 h to NGF compared with wild LNCaP cultures. However, p75LNGFR-transfected LNCaP cells rapidly underwent apoptotic death when deprived of NGF. Our study demonstrates the physiological relevance of NGF in the regulation of prostate cell proliferation and the relative contribution of the high- and low-affinity NGF receptors in this control.

[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.

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study.

BACKGROUND: In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS: We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS: At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS: In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

Tumor necrosis factor-alpha induces apoptosis in immortalized hypothalamic neurons: involvement of ceramide-generating pathways.

To investigate possible effects that may contribute, together with a direct action on neurohormone secretion, to the impairment of gonadal axis function during inflammation, we evaluated the effect of TNF alpha on the growth and viability of GT1-7 hypothalamic neurons and the intracellular transduction pathways involved in these effects. TNF alpha caused a reduction of cell number and an induction of apoptotic death. These effects were mimicked by cell-permeable analogs of ceramide and by neutral or acidic sphingomyelinase. Exposure to acidic sphingomyelinase induced a persistent (up to 48 h) reduction of cell growth and apoptosis, whereas the effect of neutral sphingomyelinase was time limited. The involvement of acidic sphingomyelinase in TNF alpha action was demonstrated by the partial prevention of ceramide generation, apoptosis, and reduced cell growth by the inhibitor of the acidic sphingomyelinase-generating pathway, D609, whereas the involvement of ceramide was proved by complete prevention of TNF alpha-induced effects by treatment with okadaic acid at concentrations inhibiting ceramide-dependent protein phosphatase. The present data indicate that TNF alpha, through activation of ceramide-generating pathways, is able to affect GT1-7 cell viability, suggesting an additional effect that may contribute to the global action of this cytokine on neuroendocrine activities.

Glia mediates the neuroprotective action of estradiol on beta-amyloid-induced neuronal death.

17beta-Estradiol (17beta-E(2)) is known to exert neuroprotective activity against beta-amyloid, but its exact target and mechanism of action in this effect have not been elucidated. The involvement of astroglia in neuroprotection of 17beta-E(2) against the beta-amyloid fragment [betaAP((25-35))] has been evaluated using an experimental paradigm in which medium conditioned from rat astroglia pretreated with 17beta-E2 was transferred to pure rat cortical neurons challenged with 25 microm betaAP((25-35)) for 24 h. The toxicity of betaAP((25-35)) was assessed by flow cytometry, evaluating the ability of the peptide to induce an aberrant mitotic cell cycle in neurons. The results obtained indicate that conditioned medium from astrocytes preexposed to 17beta-E(2) for 4 h increased the viability of cortical neurons treated with betaAP((25-35)). This effect was not modified by treatment with the estrogen receptor antagonist ICI 182,780, added directly to neurons, nor was it mimicked by direct addition of 17beta-E(2) to neuronal cultures during exposure to betaAP((25-35)). A soluble factor stimulated by 17beta-E(2) seemed to be involved, and accordingly, the intracellular and released levels of TGF-beta1 were increased by 17beta-E(2) treatment, as established by Western blot analysis. In addition, the intracellular content of TGF-beta1 in immunopositive cells, as detected by flow cytometry, was reduced, suggesting that 17beta-E(2) stimulated mainly the release of the cytokine. In support of a role for TGF-beta1 in astrocyte-mediated 17beta-E(2) neuroprotective activity, incubation with a neutralizing anti-TGF-beta1 antibody significantly modified the reduction of neuronal death induced by 17beta-E(2)-treated astrocyte-conditioned medium.

Nuclear factor-kappaB activation in human monocytes stimulated with lipopolysaccharide is inhibited by fibroblast conditioned medium and exogenous PGE2.

The nuclear factor kappaB (NF-kappaB) is thought to be crucially involved in the gene activation of several cytokines, including tumor necrosis factor alpha (TNF). Previously, we showed that fibroblast conditioned medium (FCM) is able to inhibit both TNF mRNA accumulation and protein release in peripheral blood-derived human monocytes (PBM) stimulated with lipopolysaccharide (LPS). In this study we have investigated the effect of FCM on the LPS-induced DNA-binding activity of NF-kappaB, by means of electrophoretic shift assay (EMSA). We provide evidence that FCM strongly inhibits the LPS-induced NF-kappaB activation in PBM. Furthermore, we show that exogenous PGE2 mimics the NF-kappaB inhibitory effect of FCM. On the other hand, FCM produced in the presence of indomethacin does not inhibit NF-kappaB activation by LPS. Our results lend further support to the hypothesis that inflammatory and immune responses of monocytes/macrophages may be modulated at the molecular level by signals originating from tissue structural cells such as fibroblasts.

Novel neuronal targets for the acetylcholinesterase inhibitor donepezil.

The effects of the acetylcholinesterase inhibitor donepezil on cell viability and proliferation events have been analysed in SH-SY5Y human neuroblastoma cells. Short- (48 h) or long-term (7 days) exposure of SH-SY5Y cells to donepezil (100 nM-10 microM) induced a concentration-dependent inhibition of cell proliferation that was not modified by muscarinic and nicotinic receptor antagonists, or mimicked by galantamine, and was not related to induction of apoptosis. By analysing the distribution profile of cell populations within the cell cycle following treatment with 10 microM donepezil, a reduction of cells in the S-G2/M phases of the cycle and a parallel increase of the G0/G1 population were observed. In addition, the expression of two cyclins of the G1/S and G2/M transitions, cyclin E and cyclin B, was significantly reduced in donepezil-treated cells. In contrast, the expression of the cell cycle inhibitor p21 rapidly (6 h) increased following exposure to the drug. Finally, donepezil increased the expression of the neuronal marker MAP-2 in selected subpopulations of SH-SY5Y cells, suggesting that the effect on cell proliferation by donepezil may correlate to a trend to neuronal differentiation.

Pulmonary tuberous sclerosis in a woman of child-bearing age with no mental retardation.

Tuberous sclerosis is a rare disease characterized by epilepsy, mental retardation and adenoma sebaceum. We describe the case of a 29-year-old woman with a clinical history of tuberous sclerosis who also had severe hypoxaemia, multifocal hamartoma-like lesions of various extrapulmonary organs, massive hypersplenism and coagulation defects. This case emphasizes the value of high resolution computed tomography (HRCT) in patients with pulmonary tuberous sclerosis.

The long-term antimicrobial prophylaxis of chronic bronchitis exacerbations.

Infectious exacerbations are the major cause of mortality in patients with chronic bronchitis, particularly in elderly subjects. Considering that the preventive use of antibiotics has provided no clear-cut evidence of real efficacy, it has become quite common to use treatments potentially able to stimulate the immune system for prevention of exacerbations of chronic bronchitis. This treatment, based on the oral administration of bacterial extracts, should, at least in theory, stimulate the immune defenses and reduce the incidence of recurring respiratory tract infections. Although during the last few years a good effort to define better the real efficacy and role played by bacterial extracts in chronic bronchitis has been made, their clinical effectiveness is still the subject of debate and the results of some clinical trials are controversial. Particularly, its mechanism of action remains poorly understood, although a huge effort has been made in this direction.

Influence of asthmatic and rhinitic symptomatology duration on bronchial responsiveness to histamine.

Our Study aimed to investigate the influence of the time in years elapsed from the onset of symptoms on bronchial nonspecific responsiveness in rhinitic and asthmatic patients. The study was performed on 83 asthmatic patients and on 46 patients with allergic rhinopathy. The beginning of the symptoms and years of asthmatic or rhinitic history were particularly investigated. A histamine challenge was performed. The dose of histamine producing at 20% change in FEV1 (forced expiratory volume in one second) was calculated from the individual semilogarithmic dose-response curve (PD20). Bronchial responsiveness to histamine showed wide variability in subjects of two groups, and an overlap of the distribution curves was observed between asthmatic and rhinitic patients. A significant relationship (p less than 0.01) between the years elapsed from the onset of symptoms and bronchial responsiveness to histamine was observed in each group of patients. We noticed that the number of the years passed heightened the bronchial responsiveness to histamine in both groups of patients.

[Mast cell mediator release after endobronchial challenge with adenosine 5'-monophosphate in asthmatic subjects]. / Liberazione di mediatori mastocitari dopo challenge endobronchiale con adenosina 5'-monofosfato in soggetti asmatici.

Mediator release from activated mast cells is also likely to take place in the asthmatic airways in vivo during adenosine-induced bronchoconstriction. To test this hypothesis, we evaluated mast cell mediator release directly into the airways of 9 asthmatic subjects after endobronchial challenge with adenosine by bronchoalveolar lavage (BAL). The mediators measured were histamine, tryptase, and PGD2. When compared to the saline-challenged segment, the response to AMP instillation was characterized by a prompt reduction in airway calibre paralleled by a significant 4.2-fold increase in PGD2 levels in the BAL fluid (p = 0.004). There were also increases in median histamine (from 200.1 to 433.6 pg/mL) and tryptase levels (from 0.31 to 0.46 ng/mL) recovered after AMP challenge, although they were not significant. These findings support the view that acute bronchospastic response to AMP in asthmatic airways is paralleled by the local release of mast cells derived products, particularly PGD2.

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.