Giuseppe Spaziano | Università della Campania Luigi Vanvitelli (original) (raw)

Papers by Giuseppe Spaziano

Research paper thumbnail of A Multiple Synergic Treatment for Non-Healing Ulcer Management in a Patient with Klippel–Trenaunay Syndrome

Reports, Jul 20, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Design and synthesis of functionalized 4-aryl-Catechol derivatives as new antiinflammtory agents with in vivo efficacy

European journal of medicinal chemistry, Dec 1, 2022

Research paper thumbnail of Oxygen–Ozone Therapy in Cervicobrachial Pain: A Real-Life Experience

Journal of Clinical Medicine, Dec 29, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of 肺間葉系幹細胞は,気腫の動物モデルにおけるエラスターゼ誘発損傷を改善する【JST・京大機械翻訳】

Research paper thumbnail of Panitumumab Induced Forearm Panniculitis in Two Women With Metastatic Colon Cancer

Current Drug Safety, Sep 17, 2019

Background: Panitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal canc... more Background: Panitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal cancer (mCRC), even if its use is related to skin toxicity. Case Presentation: We report the development of forearm panniculitis in two women during the treatment with Panitumumab (6 mg/Kg intravenous every 2 weeks) + FOLFOX-6 (leucovorin, 5fluorouracil, and oxaliplatin at higher dosage) for the treatment of mCRC. Results: In both patients, clinical, laboratory and radiological evaluation documented the presence of a local panniculitis, probably related to panitumumab (Naranjo score: 6). Panatimumab discontinuation and antimicrobial + corticosteroid treatment induced a remission of skin manifestations. Conclusion: We reported for the first time the development of panniculitis during Panitumumab treatment, and we documented that the treatment with beta-lactams to either fluoroquinolones or oxazolidinone in the presence of corticosteroid improves clinical symptoms in young patients with mCRC, without the development of adverse drug reactions or drug-drug interactions.

Research paper thumbnail of Distinct Lung MicroRNA (miRNA) Signatures in Non-Small Cell Lung Cancer (NSCLC) and Chronic Obstructive Pulmonary Disease (COPD)

C69. PRECLINICAL COPD MODELS: IN VITRO, EX VIVO, IN VIVO

Research paper thumbnail of Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand?

Biomedicines

The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is n... more The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants of concern. In fact, the recent emergence of variants has pointed out how the SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting the need to find new targets as therapeutic tools. However, cocktail therapy is useful to reduce drug resistance and maximize vaccination efficacy. Natural products and metal-drug-based treatments have also shown interesting antiviral activity, representing a valid contribution to counter COVID-19 outbreak. This report summarizes the available evidence which supports the use of approved drugs and further focuses on significant clinical trials that have investigated the safety and efficacy of repurposing drugs and new molecules in different COVID-19 phenotypes. To date, there are many individuals vulner...

Research paper thumbnail of Similar Programmed Death Ligand 1 expression profile in COPD and NSCLC structural and immune cells

05.01 - Airway pharmacology and treatment

Research paper thumbnail of Design and Synthesis of Functionalized4-Aryl-Catechol Derivatives as New Anti-Inflammatory Agents with In Vivo Efficacy PART I

Research paper thumbnail of Increased Programmed Death Ligand 1 (PD-L1) Expression Profile in Structural and Immune Cells from Mild COPD Patients and Lung Cancer

B14. OLD DOGS NEW TRICKS: LATE-BREAKING ABSTRACTS IN OBSTRUCTIVE LUNG DISEASE

Research paper thumbnail of Proceedings of the Merck & Elsevier Young Chemists Symposium (MEYCS 2018)

Research paper thumbnail of Association between Sex-Related ALOX5 Gene Polymorphisms and Lung Atopy Risk

Journal of Clinical Medicine

Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnor... more Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnormalities of the leukotrienes (LTs) pathway play a crucial role. Recent studies have described sex as a key variable in LT biosynthesis, partly explaining why treatment with anti-LT drugs in atopic subjects leads to better control of symptoms in women. In addition, variability in LT production is often associated with single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase (ALOX5) gene, which encodes the leukotriene-synthesizing enzyme machinery, 5-lipoxygenase (5-LO). This study aimed to investigate whether two SNPs of ALOX5 are implicated in sex differences in allergic diseases in a prospective cohort of 150 age- and sex-matched atopic and healthy subjects. Rs2029253 and rs2115819 were genotyped using allele-specific RT-PCR, and serum levels of 5-LO and LTB4 were measured by ELISA. Both polymorphisms are significantly more common in women than in men, and their influen...

Research paper thumbnail of Lung microRNAs Expression in Lung Cancer and COPD: A Preliminary Study

Biomedicines

Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an i... more Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an impending burden on the healthcare system. Despite increasing attention, the mechanisms underlying tumorigenesis in cancer-related diseases such as COPD remain unclear, making novel biomarkers necessary to improve lung cancer early diagnosis. MicroRNAs (miRNAs) are short non-coding RNA that interfere with several pathways and can act as oncogenes or tumor suppressors. This study aimed to compare miRNA lung expression between subjects with NSCLC and COPD and healthy controls to obtain the miRNA expression profile by analyzing shared pathways. Lung specimens were collected from a prospective cohort of 21 sex-matched subjects to determine the tissue miRNA expression of hsa-miR-34a-5p, 33a-5p, 149-3p, 197-3p, 199-5p, and 320a-3p by RT-PCR. In addition, an in silico prediction of miRNA target genes linked to cancer was performed. We found a specific trend for has-miR-149-3p, 197-3p, and 34a-5p...

Research paper thumbnail of The Role of MMPs in the Era of CFTR Modulators: An Additional Target for Cystic Fibrosis Patients?

Biomolecules

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, r... more Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs t...

Research paper thumbnail of Circulating MicroRNAs Expression Profile in Lung Inflammation: A Preliminary Study

Journal of Clinical Medicine, Sep 16, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Formulation of Solid Lipid Nanoparticles Loaded with Nociceptin/Orphanin FQ (N/OFQ) and Characterization in a Murine Model of Airway Hyperresponsiveness

Pharmaceuticals

Asthma is characterized by chronic inflammation and a variable degree of airway hyperresponsivene... more Asthma is characterized by chronic inflammation and a variable degree of airway hyperresponsiveness (AHR). Our previous papers documented a role for Nociceptin/Orphanin FQ (N/OFQ) and its receptor N/OFQ peptide (NOP) in AHR. Therefore, the aim of this study was to improve the bioavailability of N/OFQ by developing solid lipid nanoparticles (SLNs). N/OFQ-loaded SLNs were prepared by the Quasi Emulsion Solvent Diffusion (QESD) technique and then characterized. Brown Norway rats were sensitized to ovalbumin (OVA) and treated with an intratracheal administration of saline solution or N/OFQ-SLN. Then, 24 h after the last challenge, functional histological and molecular evaluations were performed. SLNs showed a mean diameter of 233 ± 0.03 nm, a polydispersity index (PDI) value around 0.28 ± 0.02 and a drug release percentage of 84.3. The in vitro release of N/OFQ from SLNs showed that the release of the peptide starts already after two hours of incubation. Animals receiving N/OFQ-SLN show...

Research paper thumbnail of Similar Programmed Death Ligand 1 (PD-L1) expression profile in patients with mild COPD and lung cancer

Rationale: Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance... more Rationale: Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear.Methods: In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression: 1) via cutting-edge digital spatial proteomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n=19); and 2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n = 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract.Results: PD-L1 expression was increased in the bronchiolar wall,...

Research paper thumbnail of Sphingosine‐1‐phosphate/TGF‐β axis drives epithelial mesenchymal transition in asthma‐like disease

British Journal of Pharmacology, 2021

BACKGROUND AND PURPOSE Airway remodelling is a critical feature of chronic lung diseases. Epithel... more BACKGROUND AND PURPOSE Airway remodelling is a critical feature of chronic lung diseases. Epithelial-mesenchymal transition (EMT) represents an important source of myofibroblasts, contributing to airway remodelling. Here, we investigated the sphingosine-1-phosphate (S1P) role in EMT and its involvement in asthma-related airway dysfunction. EXPERIMENTAL APPROACH A549 were used to assess the S1P effect on EMT and its interaction with TGF-β signaling. To assess S1P role in vivo and its impact on lung function two experimental models of asthma were used by exposing BALB/c mice to subcutaneous administration of either S1P or ovalbumin (OVA). KEY RESULTS Following incubation with TGF-β or S1P, A549 acquire a fibroblast-like morphology associated with an increase of mesenchymal markers and downregulation of the epithelial. These effects are reversed by treatment with TGF-β receptor antagonist LY2109761. Systemic administration of S1P to BALB/c mice induces asthma-like disease characterized by mucous cell metaplasia and increased levels of TGF-β, IL-33 and FGF-2 within the lung. The bronchi harvested from S1P-treated mice display bronchial hyperresponsiveness associated with overexpression of the mesenchymal and fibrosis markers and reduction of the epithelial. S1P-induced switch from the epithelial toward the mesenchymal pattern correlates to a significant increase of lung resistance and fibroblast activation. TGF-β blockade, in S1P-treated mice, abrogates these effects. Finally, inhibition of sphingosine kinases by SK1-II in OVA-sensitized mice, abrogates EMT, pulmonary TGF-β upregulation, fibroblasts recruitment and airway hyperresponsiveness. CONCLUSION AND IMPLICATIONS Targeting S1P/TGF-β axis may hold promise as a feasible therapeutic target to control airway dysfunction in asthma.

Research paper thumbnail of Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach

Drug Design, Development and Therapy, 2017

Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle... more Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug.

Research paper thumbnail of New Role of Adult Lung c-kit+ Cells in a Mouse Model of Airway Hyperresponsiveness

Mediators of Inflammation, 2016

Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Em... more Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the ind...

Research paper thumbnail of A Multiple Synergic Treatment for Non-Healing Ulcer Management in a Patient with Klippel–Trenaunay Syndrome

Reports, Jul 20, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Design and synthesis of functionalized 4-aryl-Catechol derivatives as new antiinflammtory agents with in vivo efficacy

European journal of medicinal chemistry, Dec 1, 2022

Research paper thumbnail of Oxygen–Ozone Therapy in Cervicobrachial Pain: A Real-Life Experience

Journal of Clinical Medicine, Dec 29, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of 肺間葉系幹細胞は,気腫の動物モデルにおけるエラスターゼ誘発損傷を改善する【JST・京大機械翻訳】

Research paper thumbnail of Panitumumab Induced Forearm Panniculitis in Two Women With Metastatic Colon Cancer

Current Drug Safety, Sep 17, 2019

Background: Panitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal canc... more Background: Panitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal cancer (mCRC), even if its use is related to skin toxicity. Case Presentation: We report the development of forearm panniculitis in two women during the treatment with Panitumumab (6 mg/Kg intravenous every 2 weeks) + FOLFOX-6 (leucovorin, 5fluorouracil, and oxaliplatin at higher dosage) for the treatment of mCRC. Results: In both patients, clinical, laboratory and radiological evaluation documented the presence of a local panniculitis, probably related to panitumumab (Naranjo score: 6). Panatimumab discontinuation and antimicrobial + corticosteroid treatment induced a remission of skin manifestations. Conclusion: We reported for the first time the development of panniculitis during Panitumumab treatment, and we documented that the treatment with beta-lactams to either fluoroquinolones or oxazolidinone in the presence of corticosteroid improves clinical symptoms in young patients with mCRC, without the development of adverse drug reactions or drug-drug interactions.

Research paper thumbnail of Distinct Lung MicroRNA (miRNA) Signatures in Non-Small Cell Lung Cancer (NSCLC) and Chronic Obstructive Pulmonary Disease (COPD)

C69. PRECLINICAL COPD MODELS: IN VITRO, EX VIVO, IN VIVO

Research paper thumbnail of Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand?

Biomedicines

The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is n... more The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants of concern. In fact, the recent emergence of variants has pointed out how the SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting the need to find new targets as therapeutic tools. However, cocktail therapy is useful to reduce drug resistance and maximize vaccination efficacy. Natural products and metal-drug-based treatments have also shown interesting antiviral activity, representing a valid contribution to counter COVID-19 outbreak. This report summarizes the available evidence which supports the use of approved drugs and further focuses on significant clinical trials that have investigated the safety and efficacy of repurposing drugs and new molecules in different COVID-19 phenotypes. To date, there are many individuals vulner...

Research paper thumbnail of Similar Programmed Death Ligand 1 expression profile in COPD and NSCLC structural and immune cells

05.01 - Airway pharmacology and treatment

Research paper thumbnail of Design and Synthesis of Functionalized4-Aryl-Catechol Derivatives as New Anti-Inflammatory Agents with In Vivo Efficacy PART I

Research paper thumbnail of Increased Programmed Death Ligand 1 (PD-L1) Expression Profile in Structural and Immune Cells from Mild COPD Patients and Lung Cancer

B14. OLD DOGS NEW TRICKS: LATE-BREAKING ABSTRACTS IN OBSTRUCTIVE LUNG DISEASE

Research paper thumbnail of Proceedings of the Merck & Elsevier Young Chemists Symposium (MEYCS 2018)

Research paper thumbnail of Association between Sex-Related ALOX5 Gene Polymorphisms and Lung Atopy Risk

Journal of Clinical Medicine

Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnor... more Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnormalities of the leukotrienes (LTs) pathway play a crucial role. Recent studies have described sex as a key variable in LT biosynthesis, partly explaining why treatment with anti-LT drugs in atopic subjects leads to better control of symptoms in women. In addition, variability in LT production is often associated with single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase (ALOX5) gene, which encodes the leukotriene-synthesizing enzyme machinery, 5-lipoxygenase (5-LO). This study aimed to investigate whether two SNPs of ALOX5 are implicated in sex differences in allergic diseases in a prospective cohort of 150 age- and sex-matched atopic and healthy subjects. Rs2029253 and rs2115819 were genotyped using allele-specific RT-PCR, and serum levels of 5-LO and LTB4 were measured by ELISA. Both polymorphisms are significantly more common in women than in men, and their influen...

Research paper thumbnail of Lung microRNAs Expression in Lung Cancer and COPD: A Preliminary Study

Biomedicines

Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an i... more Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an impending burden on the healthcare system. Despite increasing attention, the mechanisms underlying tumorigenesis in cancer-related diseases such as COPD remain unclear, making novel biomarkers necessary to improve lung cancer early diagnosis. MicroRNAs (miRNAs) are short non-coding RNA that interfere with several pathways and can act as oncogenes or tumor suppressors. This study aimed to compare miRNA lung expression between subjects with NSCLC and COPD and healthy controls to obtain the miRNA expression profile by analyzing shared pathways. Lung specimens were collected from a prospective cohort of 21 sex-matched subjects to determine the tissue miRNA expression of hsa-miR-34a-5p, 33a-5p, 149-3p, 197-3p, 199-5p, and 320a-3p by RT-PCR. In addition, an in silico prediction of miRNA target genes linked to cancer was performed. We found a specific trend for has-miR-149-3p, 197-3p, and 34a-5p...

Research paper thumbnail of The Role of MMPs in the Era of CFTR Modulators: An Additional Target for Cystic Fibrosis Patients?

Biomolecules

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, r... more Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs t...

Research paper thumbnail of Circulating MicroRNAs Expression Profile in Lung Inflammation: A Preliminary Study

Journal of Clinical Medicine, Sep 16, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Formulation of Solid Lipid Nanoparticles Loaded with Nociceptin/Orphanin FQ (N/OFQ) and Characterization in a Murine Model of Airway Hyperresponsiveness

Pharmaceuticals

Asthma is characterized by chronic inflammation and a variable degree of airway hyperresponsivene... more Asthma is characterized by chronic inflammation and a variable degree of airway hyperresponsiveness (AHR). Our previous papers documented a role for Nociceptin/Orphanin FQ (N/OFQ) and its receptor N/OFQ peptide (NOP) in AHR. Therefore, the aim of this study was to improve the bioavailability of N/OFQ by developing solid lipid nanoparticles (SLNs). N/OFQ-loaded SLNs were prepared by the Quasi Emulsion Solvent Diffusion (QESD) technique and then characterized. Brown Norway rats were sensitized to ovalbumin (OVA) and treated with an intratracheal administration of saline solution or N/OFQ-SLN. Then, 24 h after the last challenge, functional histological and molecular evaluations were performed. SLNs showed a mean diameter of 233 ± 0.03 nm, a polydispersity index (PDI) value around 0.28 ± 0.02 and a drug release percentage of 84.3. The in vitro release of N/OFQ from SLNs showed that the release of the peptide starts already after two hours of incubation. Animals receiving N/OFQ-SLN show...

Research paper thumbnail of Similar Programmed Death Ligand 1 (PD-L1) expression profile in patients with mild COPD and lung cancer

Rationale: Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance... more Rationale: Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear.Methods: In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression: 1) via cutting-edge digital spatial proteomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n=19); and 2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n = 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract.Results: PD-L1 expression was increased in the bronchiolar wall,...

Research paper thumbnail of Sphingosine‐1‐phosphate/TGF‐β axis drives epithelial mesenchymal transition in asthma‐like disease

British Journal of Pharmacology, 2021

BACKGROUND AND PURPOSE Airway remodelling is a critical feature of chronic lung diseases. Epithel... more BACKGROUND AND PURPOSE Airway remodelling is a critical feature of chronic lung diseases. Epithelial-mesenchymal transition (EMT) represents an important source of myofibroblasts, contributing to airway remodelling. Here, we investigated the sphingosine-1-phosphate (S1P) role in EMT and its involvement in asthma-related airway dysfunction. EXPERIMENTAL APPROACH A549 were used to assess the S1P effect on EMT and its interaction with TGF-β signaling. To assess S1P role in vivo and its impact on lung function two experimental models of asthma were used by exposing BALB/c mice to subcutaneous administration of either S1P or ovalbumin (OVA). KEY RESULTS Following incubation with TGF-β or S1P, A549 acquire a fibroblast-like morphology associated with an increase of mesenchymal markers and downregulation of the epithelial. These effects are reversed by treatment with TGF-β receptor antagonist LY2109761. Systemic administration of S1P to BALB/c mice induces asthma-like disease characterized by mucous cell metaplasia and increased levels of TGF-β, IL-33 and FGF-2 within the lung. The bronchi harvested from S1P-treated mice display bronchial hyperresponsiveness associated with overexpression of the mesenchymal and fibrosis markers and reduction of the epithelial. S1P-induced switch from the epithelial toward the mesenchymal pattern correlates to a significant increase of lung resistance and fibroblast activation. TGF-β blockade, in S1P-treated mice, abrogates these effects. Finally, inhibition of sphingosine kinases by SK1-II in OVA-sensitized mice, abrogates EMT, pulmonary TGF-β upregulation, fibroblasts recruitment and airway hyperresponsiveness. CONCLUSION AND IMPLICATIONS Targeting S1P/TGF-β axis may hold promise as a feasible therapeutic target to control airway dysfunction in asthma.

Research paper thumbnail of Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach

Drug Design, Development and Therapy, 2017

Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle... more Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug.

Research paper thumbnail of New Role of Adult Lung c-kit+ Cells in a Mouse Model of Airway Hyperresponsiveness

Mediators of Inflammation, 2016

Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Em... more Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the ind...