Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.

Inflammation and vascular dysfunction: The negative synergistic combination of diabetes and COVID-19.

AIMS: Several reports indicate that diabetes determines an increased mortality risk in patients with coronavirus disease 19 (COVID-19) and a good glycaemic control appears to be associated with more favourable outcomes. Evidence also supports that COVID-19 pneumonia only accounts for a part of COVID-19 related deaths. This disease is indeed characterised by abnormal inflammatory response and vascular dysfunction, leading to the involvement and failure of different systems, including severe acute respiratory distress syndrome, coagulopathy, myocardial damage and renal failure. Inflammation and vascular dysfunction are also well-known features of hyperglycemia and diabetes, making up the ground for a detrimental synergistic combination that could explain the increased mortality observed in hyperglycaemic patients. MATERIALS AND METHODS: In this work, we conduct a narrative review on this intriguing connection. Together with this, we also present the clinical characteristics, outcomes, laboratory and histopathological findings related to this topic of a cohort of nearly 1000 subjects with COVID-19 admitted to a third-level Hospital in Milan. RESULTS: We found an increased mortality in subjects with COVID-19 and diabetes, together with an altered inflammatory profile. CONCLUSIONS: This may support the hypothesis that diabetes and COVID-19 meet at the crossroads of inflammation and vascular dysfunction. (ClinicalTrials.gov NCT04463849 and NCT04382794).

Pancreatic islet of Langerhans' cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus.

While a number of structural and cellular abnormalities occur in the islet of Langerhans in diabetes, and in particular in type 2 diabetes, the focus has been mostly on the insulin producing ß-cells and only more recently on glucagon producing α- and δ-cells. There is ample evidence that in type 2 diabetes mellitus (T2DM), in addition to a progressive decline in ß-cell function and associated insulin resistance in a number of insulin-sensitive tissues, alterations in glucagon secretion are also present and may play an important role in the pathogenesis of hyperglycemia both in the fasting and in the postprandial state. Recently, a number of studies have showed that there are also functional and structural alterations in glucagon-producing α-cells and somatostatin-producing δ-cells. Thus, it is becoming increasingly clear that multiple cellular alterations of multiple cell types occur, which adds even more complexity to our understanding of the pathophysiology of this common and severe disease. We believe that persistent efforts to increase the understanding of the pathophysiology of hormone secretion in the islets of Langerhans will also improve our capability to better prevent and treat diabetes mellitus.

Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates.

In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a ß-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.

Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas).

AIMS/HYPOTHESIS: The cellular composition of the islet of Langerhans is essential to ensure its physiological function. Morphophysiological islet abnormalities are present in type 2 diabetes but the relationship between fasting plasma glucose (FPG) and islet cell composition, particularly the role of delta cells, is unknown. We explored these questions in pancreases from baboons (Papio hamadryas) with FPG ranging from normal to type 2 diabetic values. METHODS: We measured the volumes of alpha, beta and delta cells and amyloid in pancreatic islets of 40 baboons (Group 1 [G1]: FPG < 4.44 mmol/l [n = 10]; G2: FPG = 4.44-5.26 mmol/l [n = 9]; G3: FPG = 5.27-6.94 mmol/l [n = 9]; G4: FPG > 6.94 mmol/l [n = 12]) and correlated islet composition with metabolic and hormonal variables. We also performed confocal microscopy including TUNEL, caspase-3, and anti-caspase cleavage product of cytokeratin 18 (M30) immunostaining, electron microscopy, and immuno-electron microscopy with anti-somatostatin antibodies in baboon pancreases. RESULTS: Amyloidosis preceded the decrease in beta cell volume. Alpha cell volume increased ∼ 50% in G3 and G4 (p < 0.05), while delta cell volume decreased in these groups by 31% and 39%, respectively (p < 0.05). In G4, glucagon levels were higher, while insulin and HOMA index of beta cell function were lower than in the other groups. Immunostaining of G4 pancreatic sections with TUNEL, caspase-3 and M30 showed apoptosis of beta and delta cells, which was also confirmed by immuno-electron microscopy with anti-somatostatin antibodies. CONCLUSIONS/INTERPRETATION: In diabetic baboons, changes in islet composition correlate with amyloid deposition, with increased alpha cell and decreased beta and delta cell volume and number due to apoptosis. These data argue for an important role of delta cells in type 2 diabetes.

Role of podocyte B7-1 in diabetic nephropathy.

Podocyte injury and resulting albuminuria are hallmarks of diabetic nephropathy, but targeted therapies to halt or prevent these complications are currently not available. Here, we show that the immune-related molecule B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic nephropathy. We report the induction of podocyte B7-1 in kidney biopsy specimens from patients with type 2 diabetes. Genetic and epidemiologic studies revealed the association of two single nucleotide polymorphisms at the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of the soluble isoform of the B7-1 ligand CD28 correlated with the progression to ESRD in individuals with type 2 diabetes. In vitro, high glucose conditions prompted the phosphatidylinositol 3 kinase-dependent upregulation of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was also induced in vivo in two murine models of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion and improved kidney pathology in these animals. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of diabetic nephropathy.

Mixed pituitary adenoma/craniopharyngioma: clinical, morphological, immunohistochemical and ultrastructural study of a case, review of the literature, and pathogenetic and nosological considerations.

Mixed pituitary adenoma/craniopharyngiomas are very rare tumors. Their pathogenesis is still unclear and it is not known whether they are collision tumors derived from independent stem cells or whether they originate from a single stem cell undergoing divergent differentiation. The latter hypothesis is supported by the close commixture between the two tumor components with transition areas that has been previously described. However, "hybrid" cells with both pituitary adenoma and craniopharyngioma features have never been described. In this paper we report a case of mixed pituitary adenoma/craniopharyngioma observed in a 75-year-old woman presenting with diplopia and slight increase of serum prolactin, who underwent endoscopic endonasal trans-sphenoidal tumor resection. Histologically, the tumor was composed of a typical pituitary silent subtype 2 ACTH cell adenoma admixed with islands of adamantinomatous craniopharyngioma. Electron microscopy showed that, in addition to distinct silent subtype 2 ACTH and craniopharyngioma cells, there were "hybrid" cells, showing characteristics of both pituitary adenoma and craniopharyngioma, consisting of small dense secretory granules, bundles of cytoplasmic filaments, and desmosomes. This ultrastructural finding was also confirmed by the presence of cells showing nuclear p40 expression and chromogranin A immunoreactivity. The close commixture between the two components and the ultrastructural and immunohistochemical findings demonstrate a common histogenesis of the two components and support the classification of the neoplasm as a mixed tumor. The patient completely recovered and, 10 months after surgery, head MR confirmed the complete resection of the lesion.

Renal cell carcinoma metastatic to a pituitary FSH/LH adenoma: case report and review of the literature.

Abstract Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe. A few cases of metastatic carcinoma to a pituitary adenoma have been described so far. Here, the authors present an additional case of a clear cell renal cell carcinoma (CCRCC) metastatic to a FSH/LH/α-subunit pituitary adenoma and systematically review the literature. Immunohistochemistry and electron microscopy were performed to characterize both neoplastic components at the morphological level. Moreover, it was hypothesized that expression of VEGF and of the corresponding receptor VEGFR1 could be implicated in the development of the carcinomatous metastasis within the adenoma.

A chromEM-staining protocol optimized for cardiac tissue.

Three-dimensional (3D) chromatin organization has a key role in defining the transcription program of cells during development. Its alteration is the cause of gene expression changes responsible for several diseases. Thus, we need new tools to study this aspect of gene expression regulation. To this end, ChromEM was recently developed: this is an electron-microscopy staining technique that selectively marks nuclear DNA without altering its structure and, thus, allows better visualization of 3D chromatin conformation. However, despite increasingly frequent application of this staining technique on cells, it has not yet been applied to visualize chromatin ultrastructure in tissues. Here, we provide a protocol to carry out ChromEM on myocardial tissue harvested from the left ventricles of C57BL/6J mice and use this in combination with transmission electron microscopy (TEM) to measure some morphological parameters of peripheral heterochromatin in cardiomyocytes. This protocol could also be used, in combination with electron tomography, to study 3D chromatin organization in cardiomyocytes in different aspects of heart pathobiology (e.g., heart development, cardiac aging, and heart failure) as well as help to set-up ChromEM in other tissues.

Gastric Amphicrine Carcinoma Showing Neuroendocrine and Pancreatic Acinar Cell Differentiation. Lesson from a Challenging Case Opening New Perspectives in the Diagnostic Work-Up of Gastric Neuroendocrine Neoplasms.

Amphicrine carcinomas are epithelial neoplasms composed of cells with co-existing exocrine-neuroendocrine phenotype and are challenging lesions from both diagnostic and therapeutic perspectives.Here, we report the case of a 63-year-old male patient with a gastric nodule that was endoscopically biopsied, revealing histological features of a type 3 well-differentiated gastric neuroendocrine tumor (NET). At imaging, the lesion was single and limited to the stomach, but did not present In-111Octreotide uptake, despite SSTR2A immunohistochemical expression. The patient underwent a wedge resection of the gastric wall, with a final pathological diagnosis of amphicrine carcinoma with pancreatic acinar cell and neuroendocrine features (pT1b). Predictive immunohistochemistry showed microsatellite stability and negative HER2 status. Hotspot targeted deep sequencing of 57 genes showed no somatic mutation, in agreement with the low mutational burden reported for gastric amphicrine carcinomas. Due to a low stage of the tumor and the poor performance status of the patient, no additional oncological treatment was administered. The patient was disease-free after 18 months.This unusual case highlights the importance of considering amphicrine carcinoma in the diagnostic work-up of gastric type 3 NET. This can be done by including in the immunohistochemical panel non-neuroendocrine markers, such as the pancreatic acinar cell and glandular ones. Correct pathological diagnosis is pivotal to determine the appropriate staging (NET vs exocrine one) for surgical and oncological management.

Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity.

Cell fate transitions observed in embryonic development involve changes in three-dimensional genomic organization that provide proper lineage specification. Whether similar events occur within tumor cells and contribute to cancer evolution remains largely unexplored. We modeled this process in the pediatric cancer Ewing sarcoma and investigated high-resolution looping and large-scale nuclear conformation changes associated with the oncogenic fusion protein EWS-FLI1. We show that chromatin interactions in tumor cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, which directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Conversely, EWS-FLI1 depletion led to the disassembly of these looping networks and a widespread nuclear reorganization through the establishment of new looping patterns and large-scale compartment configuration matching those observed in mesenchymal stem cells, a candidate Ewing sarcoma progenitor. Our data demonstrate that major architectural features of nuclear organization in cancer cells can depend on single oncogenes and are readily reversed to reestablish latent differentiation programs.

The glial glutamate transporter 1 (GLT1) is expressed by pancreatic beta-cells and prevents glutamate-induced beta-cell death.

Glutamate is the major excitatory neurotransmitter of the central nervous system (CNS) and may induce cytotoxicity through persistent activation of glutamate receptors and oxidative stress. Its extracellular concentration is maintained at physiological concentrations by high affinity glutamate transporters of the solute carrier 1 family (SLC1). Glutamate is also present in islet of Langerhans where it is secreted by the α-cells and acts as a signaling molecule to modulate hormone secretion. Whether glutamate plays a role in islet cell viability is presently unknown. We demonstrate that chronic exposure to glutamate exerts a cytotoxic effect in clonal ß-cell lines and human islet ß-cells but not in α-cells. In human islets, glutamate-induced ß-cell cytotoxicity was associated with increased oxidative stress and led to apoptosis and autophagy. We also provide evidence that the key regulator of extracellular islet glutamate concentration is the glial glutamate transporter 1 (GLT1). GLT1 localizes to the plasma membrane of ß-cells, modulates hormone secretion, and prevents glutamate-induced cytotoxicity as shown by the fact that its down-regulation induced ß-cell death, whereas GLT1 up-regulation promoted ß-cell survival. In conclusion, the present study identifies GLT1 as a new player in glutamate homeostasis and signaling in the islet of Langerhans and demonstrates that ß-cells critically depend on its activity to control extracellular glutamate levels and cellular integrity.

Genetic heterogeneity in HER2 testing may influence therapy eligibility.

Prospective studies have demonstrated that approximately 20% of HER2 testing may be inaccurate. When carefully validated testing is conducted, available data do not clearly demonstrate the superiority of either IHC or fluorescence in situ hybridization (FISH) as a predictor of benefit from anti-HER2 therapy. In addition, the interpretation of the findings of HER2 tests according to international guidelines is not uniform. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) recently published practice guidelines for a definition of HER2 amplification heterogeneity that can give rise to discrepant results between IHC and FISH assays for HER2. In this article, we compare the HER2 status of 291 non consecutive breast cancers. The status is determined by both IHC and FISH approaches, using a specific FISH strategy to investigate genetic heterogeneity. Our data demonstrate that HER2 amplified cells may be found as diffuse, clustered in a specific area or section, intermingled with non-amplified cells or confined to metastatic nodules. The correct evaluation of ratio value in the presence of genetic heterogeneity and of polysomy contributes to the accurate assessment of HER2 status and potentially affects the selection of appropriate anti-HER2 therapy. By taking into account the presence of different genetic cell populations, the immunotherapy eligibility criteria for HER2 FISH scoring proposed in the CAP (2009) and SIGU guidelines identify an additional subset of cases for trastuzumab or lapatinib therapy compared to the ASCO/CAP (2007) guidelines.

SEL1L, an UPR response protein, a potential marker of colonic cell transformation.

BACKGROUND: SEL1L gene product is implicated in the endoplasmic reticulum (ER)-associated protein degradation and Unfolded Protein Response pathways. This gene and associated miRNAs have been indicated as predictive and prognostic markers of pancreatic cancer. AIM: Explore the role of SEL1L in colorectal cancer (CRC) progression. METHODS: SEL1L expression was analysed immunohistochemically in 153 adenomas and 71 CRCs from African American and North Italian patients. The distribution of stained cells was determined by computing median and inter quartile range. The receiver operating characteristics plot was used as discriminate power of SEL1L expression, CRC diagnosis and the effects on patient survival. RESULTS: SEL1L was low in normal mucosa and confined to few scattered cells at the base crypt of the villi and in the foveolar glandular compartment. The highest levels were in Paneth cells within the lysosomes. The enterocytic progenitor cells and mature enterocytes showed less cytoplasmic staining. In CRCs, SEL1L expression significantly correlated with the progression from adenoma to carcinoma (P = 0.0001) being stronger in well-to-moderately differentiated cancers. No correlation was found with other clinicopathological characteristics or ethnicity. CONCLUSIONS: SEL1L expression is a potential CRC tissue biomarker since its expression is significantly higher in adenoma cells with respect to normal mucosa. The levels of expression decrease sensibly in undifferentiated CRC cancers. Interestingly, Paneth cells contain high levels of SEL1L protein that could indicate pre-neoplastic mucosa undergoing neoplastic transformation. Since SEL1L's major function lies within ER stress and active ERAD response, it may identify CRCs with differentiated secretory phenotype and acute cellular stress.

Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons.

beta-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r = 0.662, P < 0.001) and HbA1c (r = 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative beta-cell volume, and increased relative alpha-cell volume and hyperglucagonemia. These results strongly support the concept that IA and beta-cell apoptosis in concert with alpha-cell proliferation and hypertrophy are key determinants of islets of Langerhans "dysfunctional remodeling" and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R(2) = 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.

Pancreatic PEComa: a case report with ultrastructural localization of HMB-45 within melanosomes.

PEComas (perivascular epithelioid cell tumors) represent a group of mesenchymal neoplasms showing characteristic morphologic, immunohistochemical, ultrastructural, and genetic features. These neoplasms are usually considered benign, being often well circumscribed by a thin capsule and showing scarce atypia. However, in some cases, they show local invasion and multiple metastases and cause the patient's death. PEComas have been found in many locations, but only 7 cases have been described in the pancreas to date. Here, the authors report an additional case of this rare neoplasm and demonstrate the HMB-45 immunoreactivity of melanosomes or premelanosomes at the ultrastructural level.

Indirect and Direct Effects of SARS-CoV-2 on Human Pancreatic Islets.

Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti-interleukin-1ß (IL-1ß), anti-IL-6, and anti-tumor necrosis factor α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-19 revealed mild lymphocytic infiltration of pancreatic islets and pancreatic lymph nodes. Moreover, SARS-CoV-2-specific viral RNA, along with the presence of several immature insulin granules or proinsulin, was detected in postmortem pancreatic tissues, suggestive of ß-cell-altered proinsulin processing, as well as ß-cell degeneration and hyperstimulation. These data demonstrate that SARS-CoV-2 may negatively affect human pancreatic islet function and survival by creating inflammatory conditions, possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patients with COVID-19.

EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma.

Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

An integrated air quality forecast system for a metropolitan area.

Air quality forecasting is an important issue in environmental research, due to the effects that air pollutants have on population health. To deal with this topic, in this work an integrated modelling system has been developed to forecast daily maximum eight hours ozone concentrations and daily mean PM10 concentrations, up to two days in advance, over an urban area. The presented approach involves two steps. In the first step, artificial neural networks are identified and applied to get point-wise forecasting. In the second step, the forecasts obtained at the monitoring station locations are spatially interpolated all over the domain using the cokriging technique, which allows to improve the spatial interpolation in the absence of densely sampled data. The integrated modelling system has been then applied to a case study over Northern Italy, performing a validation over space and time for the year 2004 and analyzing if the limit values for the protection of human health set by the European Commission are respected. The presented approach represents a fast and reliable way to provide decision makers and the general public with air quality forecasting, and to support prevention and precautionary measures.

Minimizing external indirect health costs due to aerosol population exposure: a case study from Northern Italy.

Environmental Agencies require Decision Support Systems, in order to plan Air Quality Policies considering the cost of emission reduction measures and the human health effects (with related social costs). The use of Decision Support Systems is also useful to spread information to general public, explaining the effectiveness of proposed air quality plans. In this paper, a multi-objective approach to control PM10 concentration at a regional level is presented. The problem considers both the internal costs (due to the implementation of emission reduction measures) and the external costs (due to population exposure to high PM10 concentrations). To model PM10 concentrations, a single surrogate model is used for the entire domain, allowing the implementation of a very efficient optimization procedure. The surrogate model is derived through a set of 10 simulations, performed using a Chemistry Transport Model fed with different emission reduction scenarios. The methodology is applied to Northern Italy, a region affected by very high PM10 concentrations that exceed the limit values specified by the EU legislation.