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The results of research activities performed in two Italian Alpine valleys (Chiese Valley, Trentino; Camonica Valley, Lombardy) are presented. The four intensive field campaigns held during summer 2019 and winter 2020 covered different topics: wintertime black carbon (BC) concentrations, techniques for measuring PM10 and temperature vertical profiles, surface size-resolved aerosol fluxes, aerosol concentrations, and chemical composition. Firstly, the contribution of two significant PM sources (traffic and biomass burning) to wintertime total black carbon concentrations was estimated, and the effect of meteorological factors on BC levels was assessed. In both pilot areas, traffic resulted as the predominant BC source during the daytime, while biomass burning weighed more than 50% at night. Atmospheric mixing and strong winds contributed to the removal of BC from the atmosphere, while wet scavenging was not effective if accompanied by low wind and friction velocities along with a significant increase in emission sources. Other aerosol sources, such as secondary particulate matter formation in the atmosphere, manure, fertilizers, or lithospheric erosion, were instead appointed in both seasons through the chemical speciation of the inorganic aerosol fraction, which had deposited on the filters of a multi-stage Electrical Low-Pressure Impactor (Elpi+, Dekati, FI) during an entire campaign. Results showed that SIA (secondary inorganic aerosol) components were the most abundant inorganic water-soluble ions in the collected samples. Secondly, three techniques for measuring PM10 and temperature vertical distributions were applied and compared. The first method enabled continuous monitoring by positioning 5 battery-powered stations, equipped with low-cost sensors, on the mountain slope overlooking the valleys. These measurements extended up to about 1000 m above the valley floor and were accompanied by drone profiles in summer and tethered balloon soundings in winter, both of them equipped with the same sensors installed in the slope stations. The research aimed at evaluating the effectiveness of the temperature and PM10 slope pseudo-vertical profiles in reproducing soundings measured in the valley centre. Slope stations successfully replicated the vertical profiles, especially in the morning/evening hours, thus representing a good and inexpensive alternative for long-lasting campaigns or even excellent support to traditional methods. Finally, the role of a typical alpine agro-economic ecosystem (pasture/grass field) in the atmosphere-Earth surface aerosol exchange was evaluated, studying aerosol size-segregated fluxes (9 classes, 10 nm ≤ GMD ≤ 0.76 m) with the eddy covariance technique, employing the aforementioned Dekati (FI) Elpi+ multi-stage impactor. Surprisingly, the pasture did not behave as an aerosol sink, favouring aerosol removal from the atmosphere, but rather contributed to the formation of secondary particulate matter through ammonia, NOX, and organic sulphides emissions from soil and vegetation. Deposition phenomena were registered under atmospheric stability or low turbulence conditions, but emission phenomena were very frequent, especially during winter. Thanks to the ion chromatography analysis of the inorganic particulate soluble fraction deposited on the impactor filters, aerosol fluxes were also linked to aerosol chemical composition and sources, thus hypothesizing nucleation, growth, and coagulation processes as responsible for the formation of concentration gradients in the atmosphere and the observation of deposition fluxes in the ultrafine range. The data collected and described in the present thesis had an interesting follow-up within the EU Alpine Space project BB-CLEAN, within which the activities developed. In particular, the experimental data were used by modellists to calibrate a meteorological and dispersion modelling chain that provided 48-hour PM concentration forecasts to a smartphone app, indicating when the activation of biomass burning heating systems might be sustainable. The researchers of the BB-CLEAN project also employed the model to evaluate some scenarios that envisaged the reduction of PM emissions from biomass burning appliances (e.g., through system upgrades, app use, and realization of a district heating network). Simulations showed that some of these scenarios could lead to a significant decrease in PM concentrations. However, no scenario can be elected as an absolute best, as policymakers should consider the characteristics of their respective municipalities when faced with the need to decide which scenario to implement.

No / Background  Interleukin (IL)-33 is a member of the IL-1 family and has been implicated in Th2-driven allergic diseases such as atopic dermatitis (AD) and asthma. The principal Th2 cytokine IL-4, found highly expressed in acute allergic eczema, is known to downregulate human β-defensin 2 (hBD2) expression in human keratinocytes and this is associated with superinfection in patients with AD. Objectives  To investigate the effect of IL-33 on the expression of hBD2 in human keratinocytes. Methods  hBD2 production by stimulated keratinocytes was measured by enzyme-linked immunosorbent assay. Results  Our results showed that serum is a very potent inducer of hBD2 and 2·5% human serum was much more potent in inducing hBD2 than 20 ng mL−1 of tumour necrosis factor-α. Interestingly, serum from patients with AD showed an impaired ability to induce hBD2 in normal keratinocytes. IL-33 significantly downregulated serum-induced hBD2. The downregulatory capacity of IL-33 was found to be 1·5- to 2-fold weaker compared with IL-4. Conclusions  Our data suggest that IL-33 can significantly contribute to the decreased expression of hBD2 in acute eczematous reaction clinically characterized by spongiosis and oozing – thus indicative for contact of the epidermis with serum components.

The Alpine region is a sensitive area to air pollution, as it presents specific characteristics, which expose it to a greater environmental burden with respect to flat areas. During the last decades, the scientific community has developed many different modeling tools to tackle the problem of air pollution. This issue demands at least three distinct procedures: the modeling of the meteorological fields, the modeling of the transport and dispersion of the pollutants and the modeling of the emitting sources. Each of these procedures performs differently across different space and time scales and carries its own strengths and weaknesses, which affect results in terms of pollutant dispersion patterns. The present work focuses on testing and improving different modeling tools at a local scale, over very complex topography, where most of them are brought to work at the limit of their applicability, but they are still the best available tools to face the problem. Different case studies are used in this research in order to evaluate strengths and deficiencies of the models and, where possible, to improve their performance. The experimental datasets used for this purpose come from both previously performed field campaigns and specifically designed campaigns, including meteorological and air quality observations. The performance of Land Surface Models within the Weather Research and Forecasting Model is evaluated and improved, focusing on their ability in reproducing near-ground variables, with specific attention to the frequent ground thermal inversion occurring in the mountainous areas. The performance of dispersion models recommended for applications over complex terrain is also tested and their results are compared with unique measurements (PM10 vertical profiles and tracer gas ground concentration), under challenging wintertime conditions. Atmospheric turbulence parameterizations are also analyzed, in order to understand their role and effects in a modeling chain for dispersion assessment purposes.

A terapia endodôntica visa o selamento biológico do complexo sistema apical, contribuindo para isso, as substâncias usadas no tratamento e a resposta imune do paciente. A LILT tem mostrado atividade antiinflamatória, favorecendo o processo reparacional. Sendo assim, este trabalho objetivou analisar o efeito da LILT na atividade secretória de macrófagos, previamente ativados por IFN-? e LPS de E.coli, e estimulados por substâncias liberadas de três tipos de cimentos endodônticos, um a base de óxido de zinco e eugenol, outro a base de hidróxido de cálcio e um terceiro resinoso. A citotoxicidade dessas substâncias foi avaliada usando a técnica de análise do MTT. Macrófagos ativados foram estimulados por essas substâncias ou não (controle) e então, irradiados ou não (controle) e a secreção de proteínas próinflamatórias (interleucina-1 b, fator de necrose tumoral-a e metaloproteinase da matriz-1) foram analisadas pelo teste ELISA. As irradiações foram realizadas com um laser GaAlAs (780 nm, 70 mW, ponta da fibra de 4 mm2, 1.67 seg, 3 J/cm2). Foram usadas duas aplicações de irradiação com intervalo de 6 h. Os dados obtidos foram tratados por Análise de Variância, quando de distribuição normal, ou teste de Friedman, quando de distribuição não normal, com nível de significância de 5 % (p = 0,05). A viabilidade dos controles e células tratados pelos cimentos endodônticos foi similar. Produção de IL-1 b e TNF-a foram observadas. Houve alta produção de MMP-1. Entretanto, sem diferenças estatísticas entre os grupos experimentais. Os grupos irradiados apresentaram resultados similares aos não irradiados. Substâncias liberadas pelos cimentos endodônticos testados não se mostraram citotóxicas nas condições deste experimento. Essas substâncias, bem como a LILT, no parâmetro utilizado, não causam alteração na atividade de secreção de MMP-1, IL-1 b e TNF-a por macrófagos ativados. / The endodontic therapy seeks the dental root canal biological sealing, depending on substances used in this process and patient’s defense immune factors. LILT has shown an anti-inflammatory activity, improving the periapical repair process. This in vitro study aimed to analyze the effect of LILT at the secretory activity of macrophages previously activated by interferon-gamma and lypopolisaccharide from E.coli, and stimulated by substances leached from three endodontic sealers (zinc oxide-eugenol based, resinous and calcium hydroxide-based). Cytotoxicity of these substances was assessed by the MTT test. Activated macrophages were stimulated by the substances or not (control) and then, irradiated or not (control) and the secretion of pro-inflammatory proteins (interleukin-1 b, tumor necrosis factor-a and matrix metalloproteinase-1) was analyzed by ELISA test. The LILT was performed using a GaAlAs laser (780 nm, 70 mW, focal spot of 4.0 mm2, 1.67 sec, 3 J/cm2). Two irradiations with 6 h-intervals were done. The data was compared by either ANOVA test or Friedman’s test. The cell viabilities of controls and cells treated by the sealers were similar. Production of IL -1 b and TNF-a were observed. There was a high production of MMP-1. However, statistical differences were not observed amongst the groups. The irradiated groups presented results similar to those of non irradiated groups. Substances leached from the endodontic sealers are non cytotoxic at these experiments conditions . These substances, as well as the LILT, at the parameter used, were not able to change the secretion of MMP-1, IL-1 b e TNF-a by activated macrophages.

Allergic asthma is an immunological disease, mediated by CD4+ Th2 cells, and its prevalence has increased over recent decades. Features of allergic asthma include airway hyperresponsiveness (AHR), airway eosinophilia, excessive airway mucus production, and increased IgE and Th2 cytokine levels. Airway remodeling with pulmonary fibrosis is noted in the progress of asthma. In this thesis, a murine model of allergic asthma was used to investigate the effect of cyclophosphamide (CY) on asthma and the involvement of regulatory T cells (Treg), and the role of Granulocyte-macrophage colony stimulating-factor (GM-CSF) in allergic asthma by using GM-CSF knockout mice. CY is a cytotoxic agent, which paradoxically augments several immune responses. The first part of this thesis was aimed to study the effects of CY in a murine model of allergic airway inflammation. BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14, and challenged with aerosolized OVA from days 21 to 27. Some mice additionally received CY on days -2 and 12. In the CY-treated animals, pronounced worsening of inflammatory features was noted, including increases in eosinophil infiltration, epithelial thickness, mucus occlusion and eosinophil numbers in bronchoalveolar lavage fluid (BALF). Increased total and OVA-specific serum IgE were also noted in the CY-treated animals. In cell cultures from peritracheal lymph nodes, the Th2 cytokines IL-4 and IL-5 were elevated in animals treated with CY. It was hypothesized that the effects of CY could be caused by reduced immunosuppression mediated by Treg. mRNA expression of the immunosuppressive cytokines IL-10 and TGF-beta was reduced in the lungs of CY-treated mice. The expression of FoxP3, a marker of naturally occurring Treg, was significantly reduced in spleens, thymuses and peritracheal lymph nodes after the second injection of CY, and in the lung tissue after allergen challenge in CY-treated mice. Furthermore, lung IL-10-producing CD4+ T cells and CTLA-4+-bearing CD4+ T cells were reduced after allergen aerosol challenge in CY-treated mice. Thus CY worsened the features of allergic pulmonary inflammation in this model, in association with increased production of IgE and Th2 cytokines. The reduction in expression of FoxP3 and immunosuppressive cytokines by CY suggests that toxicity to Treg may contribute to the increased inflammation. GM-CSF plays a role in the growth, development, and maturation of bone marrow hemopoietic cells into mature blood cells, and has been proposed to be involved in potentiating the function of inflammatory cells in allergic inflammation. In the second part of this thesis, GM-CSF knockout (KO) mice were used to investigate the role of GM-CSF. In allergic KO mice, airway eosinophils were only shown in the perivascular, but not peribronchial areas in the lung, compared to the allergic wild-type (WT) mice in which eosinophil infiltration appeared in both areas. Eosinophil numbers were drastically reduced in the bronchoalveolar lavage fluid (BALF) of KO mice. IL-5 production in the lung tissue and BALF in allergic KO mice was reduced; similar results were also found in peritracheal draining lymph nodes after in vitro stimulation assays. However, IL-4 and IL-13 production, airway hyperresponsiveness (AHR), and serum IgE production were not affected in allergic KO mice. Surprisingly, lung IFN-gamma mRNA and BALF levels were increased in allergic KO mice. Lung mRNA levels of CCR3, a key chemokine receptor on eosinophils, were significantly reduced in allergic KO mice, whereas expression of the chemokines eotaxin and RANTES were at similar levels in allergic KO and WT mice. Lung mRNA levels of the IFN-gamma-inducible chemokines Mig (CXCL9) and IP-10 (CXCL10), which are antagonists of CCR3, and their receptor CXCR3 were increased in allergic KO mice, compared with allergic WT mice. Data obtained from flow cytometry showed more eosinophils survived in the lung of WT mice than KO mice. Another allergy model, a peritoneal allergy model was performed to investigate inflammation in a different model. Leukocyte subpopulations such as neutrophils, eosinophils, macrophages, and lymphocytes were reduced in the peritoneal lavage fluid of allergic KO mice. The findings revealed that GM-CSF is essential for IL-5 production, pulmonary airway eosinophilia and eosinophil survival. In the absence of GM-CSF, over-production of IFN-???? may induce chemokines, including Mig and IP-10, which are antagonists for CCR3 and may reduce airway eosinophil infiltration. In this thesis, a murine model of allergic asthma has been used to obtain novel findings on the regulation of allergic inflammation. The results with CY are relevant to the treatment of asthma patients with CY and other cytotoxic agents. The findings in the GM-CSF KO mice suggest that GM-CSF is a potential therapeutic target in asthma, and that in assessment of new therapeutic agents for asthma, effects on GM-CSF should be considered.

Inflammatory processes in, or in close vicinity of, the skeleton often lead to loss of bone tissue. Different cytokines have been shown to be involved as stimulators of inflammatory induced osteoclastic bone resorption. During inflammatory processes also the kallikrein-kinin system is activated, leading to production of kinins that can cause pain, vasodilation and increased permeability of vessels. Kinins can also induce bone resorption in vitro. All cytokines and kinins that stimulate bone resorption stimulate in parallell prostaglandin synthesis, and prostaglandins, per se, have also been shown to induce bone resorption. The aim of this project was to increase the knowledge about the mechanisms involved in the interactions between different inflammatory mediators (i.e. kinins, cytokines and prostaglandins) suggested to be involved in the pathogenesis of inflammatory bone resorbing diseases. Human osteoblasts (MG-63) are equipped with both kinin B1 and B2 receptors linked to prostaglandin release and the stimulation of prostaglandin release are likely mediated via separate molecular mechanisms (Paper I). Activation of B1 or B2 receptors causes synergistic stimulation of PGE2 synthesis induced by either interleukin-1b (IL-1b) or tumour necrosis factor-a (TNF-a) (Paper II). The molecular mechanism involves increased expression of cyclooxygenase-2 (COX-2) and results in synergistic potentiation of receptor activator of NF-kB ligand (RANKL) protein expression. The synergistic interaction is dependent on the activation of NF-kB and the mitogen-activated protein kinases (MAPK) p38 and JNK (Paper II). The synergistic increase in RANKL expression might be an explanation why kinins potentiate IL-1b induced bone resorption, a mechanism likely to be important in inflammation induced bone resorption in diseases such as periodontal disease and rheumatoid arthritis. The synergism between kinins and IL-1b or TNF-a might also be dependent on regulation of kinin receptors, since both IL-1b and TNF-a markedly upregulated B1 and B2 receptors, both at the mRNA level and protein level (Paper III). This upregulation is not further potentiated by the kinins, and different kinin receptor agonists do not regulate the receptors for IL-1b or TNF-a, in MG-63 cells. No other cytokines known to stimulate bone resorption regulates the expressions of B1 and B2 receptors. The IL-1b- or TNF-a-induced enhancements of B1 and B2 receptor expressions involve activation of NF-kB and MAPK. The enhancement of kinin receptors may also be an important mechanism in the synergistic interactions between the two pro-inflammatory cytokines and kinins (paper III). IL-4 and IL-13 are two cytokines that have been shown to inhibit bone resorption. We have shown that COX-2 and both B1 and B2 receptors are down-regulated by IL-4 and IL-13, via a ‘signal transducer and activator of transcription6’ (STAT6) dependent pathway, which might be an important regulatory mechanism in inflammation induced bone resorption (paper IV). In conclusion, the mechanisms behind the synergistic potentiation of prostaglandin formation and increased bone resorption caused by co-stimulation with kinins and IL-1b or TNF-a seem to involve both potentiation of COX-2 and subsequently increased levels of RANKL, as well as upregulation of B1 and B2 kinin receptors. Interestingly, IL-4 and IL-13 decreased the expressions of COX-2 and both B1 and B2 receptors. These events might be important in the regulation of inflammation induced bone resorption in diseases such as periodontitis and rheumatoid arthritis.

Le thymus est un organe permettant le développement des lymphocytes T, partie intégrante du système immunitaire. Ces cellules sont communément associées au système immunitaire adaptatif, bien que certaines populations, dont les lymphocytes iNKT et Tγδ, soient associées au système immunitaire inné. De manière générale, ces lymphocytes " innés " sont capables de répondre très rapidement à différents signaux d'activation, par la production rapide et massive d'IL-4, d'IFN-γ et d'IL-17. Notre laboratoire a mis en évidence l'existence de deux sous-populations de lymphocytes iNKT, iNKT conventionnels et iNKT17, ayant deux voies de différenciation thymique bien distinctes, mais dont les mécanismes de détermination sont encore inconnus. Il a été montré que " SLAM-associated protein " (SAP) est indispensable au développement des lymphocytes iNKT, puisqu'ils sont absents chez les souris déficientes en SAP. D'autre part, ces mêmes souris montrent également une déficience de la réponse Th2. Nous avons alors émis l'hypothèse que SAP pourrait être impliqué dans la production d'IL-4 par les lymphocytes iNKT, et dans la détermination des deux sous-populations de lymphocytes iNKT conventionnel ou producteur d'IL-17. Dans une première partie, nous avons utilisé des souris triple mutantes Sap-/- Vα14Tg-ROR(γt)-Egfp, permettant l'étude des sous-populations de lymphocytes iNKT malgré la déficience en SAP. Nous avons ainsi montré que SAP est indispensable à l'acquisition thymique de la capacité de production d'IL-4 par les lymphocytes iNKT conventionnels. Chez ces souris déficientes en SAP, nous avons observé une augmentation de la fréquence des lymphocytes iNKT17 RORγtpos producteurs d'IL-17, ce qui montre clairement que SAP n'est pas nécessaire pour l'acquisition des propriétés fonctionnelles des lymphocytes iNKT17. Nous avons ainsi mis en évidence une nouvelle fonction de SAP dans le développement thymique des cellules iNKT productrices d'IL-4. De plus, nos résultats montrent que SAP est un point de contrôle obligatoire déterminant l'orientation de la différenciation thymique des cellules iNKT vers les cellules iNKT17 ou vers les cellules iNKT conventionnelles. En parallèle des lymphocytes iNKT17 présents dans le thymus, nous avons également analysé une autre population T particulière : des thymocytes TCRαβposCD4pos matures et producteurs d'IL-17, les lymphocytes Th17 naturels. Nous avons mis en évidence que ces lymphocytes expriment le facteur de transcription RORγt. Ces lymphocytes T CD4posCD8negCD44hiRORγtpos sont capables de produire rapidement et massivement de l'IL-17, mais requièrent l'IL-23 pour co-produire l'IL-22. De plus, ils se distinguent des lymphocytes Th17 induits, ou conventionnels, par l'expression du facteur de transcription PLZF et par leur capacité à répondre très rapidement à des stimuli pro-inflammatoires, nommément l'IL-23 associé à l'IL-1β et un agoniste TLR4. Les résultats obtenus durant cette thèse ouvrent donc de nombreuses perspectives de recherches fondamentale et thérapeutique, domaine dans lequel l'IL-17 est devenu une cible privilégiée pour le traitement des maladies auto-immunes.

Allergic asthma is an immunological disease, mediated by CD4+ Th2 cells, and its prevalence has increased over recent decades. Features of allergic asthma include airway hyperresponsiveness (AHR), airway eosinophilia, excessive airway mucus production, and increased IgE and Th2 cytokine levels. Airway remodeling with pulmonary fibrosis is noted in the progress of asthma. In this thesis, a murine model of allergic asthma was used to investigate the effect of cyclophosphamide (CY) on asthma and the involvement of regulatory T cells (Treg), and the role of Granulocyte-macrophage colony stimulating-factor (GM-CSF) in allergic asthma by using GM-CSF knockout mice. CY is a cytotoxic agent, which paradoxically augments several immune responses. The first part of this thesis was aimed to study the effects of CY in a murine model of allergic airway inflammation. BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14, and challenged with aerosolized OVA from days 21 to 27. Some mice additionally received CY on days -2 and 12. In the CY-treated animals, pronounced worsening of inflammatory features was noted, including increases in eosinophil infiltration, epithelial thickness, mucus occlusion and eosinophil numbers in bronchoalveolar lavage fluid (BALF). Increased total and OVA-specific serum IgE were also noted in the CY-treated animals. In cell cultures from peritracheal lymph nodes, the Th2 cytokines IL-4 and IL-5 were elevated in animals treated with CY. It was hypothesized that the effects of CY could be caused by reduced immunosuppression mediated by Treg. mRNA expression of the immunosuppressive cytokines IL-10 and TGF-beta was reduced in the lungs of CY-treated mice. The expression of FoxP3, a marker of naturally occurring Treg, was significantly reduced in spleens, thymuses and peritracheal lymph nodes after the second injection of CY, and in the lung tissue after allergen challenge in CY-treated mice. Furthermore, lung IL-10-producing CD4+ T cells and CTLA-4+-bearing CD4+ T cells were reduced after allergen aerosol challenge in CY-treated mice. Thus CY worsened the features of allergic pulmonary inflammation in this model, in association with increased production of IgE and Th2 cytokines. The reduction in expression of FoxP3 and immunosuppressive cytokines by CY suggests that toxicity to Treg may contribute to the increased inflammation. GM-CSF plays a role in the growth, development, and maturation of bone marrow hemopoietic cells into mature blood cells, and has been proposed to be involved in potentiating the function of inflammatory cells in allergic inflammation. In the second part of this thesis, GM-CSF knockout (KO) mice were used to investigate the role of GM-CSF. In allergic KO mice, airway eosinophils were only shown in the perivascular, but not peribronchial areas in the lung, compared to the allergic wild-type (WT) mice in which eosinophil infiltration appeared in both areas. Eosinophil numbers were drastically reduced in the bronchoalveolar lavage fluid (BALF) of KO mice. IL-5 production in the lung tissue and BALF in allergic KO mice was reduced; similar results were also found in peritracheal draining lymph nodes after in vitro stimulation assays. However, IL-4 and IL-13 production, airway hyperresponsiveness (AHR), and serum IgE production were not affected in allergic KO mice. Surprisingly, lung IFN-gamma mRNA and BALF levels were increased in allergic KO mice. Lung mRNA levels of CCR3, a key chemokine receptor on eosinophils, were significantly reduced in allergic KO mice, whereas expression of the chemokines eotaxin and RANTES were at similar levels in allergic KO and WT mice. Lung mRNA levels of the IFN-gamma-inducible chemokines Mig (CXCL9) and IP-10 (CXCL10), which are antagonists of CCR3, and their receptor CXCR3 were increased in allergic KO mice, compared with allergic WT mice. Data obtained from flow cytometry showed more eosinophils survived in the lung of WT mice than KO mice. Another allergy model, a peritoneal allergy model was performed to investigate inflammation in a different model. Leukocyte subpopulations such as neutrophils, eosinophils, macrophages, and lymphocytes were reduced in the peritoneal lavage fluid of allergic KO mice. The findings revealed that GM-CSF is essential for IL-5 production, pulmonary airway eosinophilia and eosinophil survival. In the absence of GM-CSF, over-production of IFN-???? may induce chemokines, including Mig and IP-10, which are antagonists for CCR3 and may reduce airway eosinophil infiltration. In this thesis, a murine model of allergic asthma has been used to obtain novel findings on the regulation of allergic inflammation. The results with CY are relevant to the treatment of asthma patients with CY and other cytotoxic agents. The findings in the GM-CSF KO mice suggest that GM-CSF is a potential therapeutic target in asthma, and that in assessment of new therapeutic agents for asthma, effects on GM-CSF should be considered.