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Srinivasarao DA, Shah S, Famta P, Vambhurkar G, Jain N, Pindiprolu SKSS, Sharma A, Kumar R, Padhy HP, Kumari M, Madan J, Srivastava S. Unravelling the role of tumor microenvironment responsive nanobiomaterials in spatiotemporal controlled drug delivery for lung cancer therapy. Drug Deliv Transl Res 2025; 15:407-435. [PMID: 39037533 DOI: 10.1007/s13346-024-01673-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2024] [Indexed: 07/23/2024]
Abstract
Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.
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Affiliation(s)
- Dadi A Srinivasarao
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India.
| | - Saurabh Shah
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Paras Famta
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Ganesh Vambhurkar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Naitik Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Sai Kiran S S Pindiprolu
- Aditya Pharmacy College, Surampalem, 533 437, Andhra Pradesh, India
- Jawaharlal Nehru Technological University, Kakinada, 533 003, Andhra Pradesh, India
| | - Anamika Sharma
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Rahul Kumar
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Hara Prasad Padhy
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Meenu Kumari
- Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Jitender Madan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India.
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Zheng Y, Tian Q, Yang H, Cai Y, Zhang J, Wu Y, Zhu S, Qiu Z, Lin Y, Hong J, Zhang Y, Dockrell D, Ma S. Identification of Nicotinic Acetylcholine Receptor for N-Acetylcysteine to Rescue Nicotine-induced Injury Using Beating Cilia in Primary Tissue Derived Airway Organoids. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407054. [PMID: 39582278 PMCID: PMC11714201 DOI: 10.1002/advs.202407054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/10/2024] [Indexed: 11/26/2024]
Abstract
Smoking is one of the major contributors to airway injuries. N-acetylcysteine (NAC) has been proposed as a treatment or preventive measure for such injuries. However, the exact nature of the smoking-induced injury and the protective mechanism of NAC are not yet fully understood. Here, patient tissue-derived airway organoids for modeling smoking-induced injury, therapeutic investigation, and mechanism studies are developed. Airway organoids consist mainly of ciliated cells, together with basal cells, goblet cells, and myofibroblast-like cells. The organoids display apical-out and basal-in polarity and are enriched in beating cilia, which are sensitive to smoking challenge and NAC treatment. An algorithm is developed to measure ciliary beating activity by analyzing the altered beating pattern of cilia in response to nicotine challenge and NAC treatment. Nicotinic acetylcholine receptors (nAChRs) expressed by airway organoids are involved in the mechanisms of nicotine-induced injury through the nicotine-nAChR pathway. In contrast to the common understanding that NAC has an antioxidative effect that mitigates airway damage, it is elucidated that NAC binding to nicotine can abolish the binding capacity of nicotine to nAChRs and thus prevent nicotine-induced injury. This study focuses on the advances and potential of humanized organoids in understanding biological processes, mechanisms, and identifying therapeutic targets.
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Affiliation(s)
- Yichao Zheng
- Institute of Biopharmaceutical and Health EngineeringTsinghua Shenzhen International Graduate School (SIGS)Tsinghua UniversityShenzhen518055China
- Precision Medicine and Healthcare Research CentreTsinghua‐Berkeley Shenzhen Institute (TBSI)Tsinghua UniversityShenzhen518055China
| | - Qinyong Tian
- Department of Cardiothoracic SurgeryZhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhou363000China
| | - Haowei Yang
- Institute of Biopharmaceutical and Health EngineeringTsinghua Shenzhen International Graduate School (SIGS)Tsinghua UniversityShenzhen518055China
| | - Yongde Cai
- Institute of Biopharmaceutical and Health EngineeringState Key Laboratory of Chemical OncogenomicsShenzhen International Graduate SchoolTsinghua UniversityShenzhen518055China
| | - Jiaxin Zhang
- Institute of Biopharmaceutical and Health EngineeringState Key Laboratory of Chemical OncogenomicsShenzhen International Graduate SchoolTsinghua UniversityShenzhen518055China
| | - Yifen Wu
- Department of Internal MedicineZhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhou363000China
| | - Shuo Zhu
- Key Laboratory of Rubber‐PlasticsMinistry of Education/Shandong Provincial Key Laboratory of Rubber and PlasticsQingdao University of Science and TechnologyQingdao266042China
| | - Zuocheng Qiu
- Guangdong Provincial Key Laboratory of Speed Capability ResearchJinan UniversityGuangzhou510632China
| | - Yimin Lin
- Department of Cardiothoracic SurgeryZhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhou363000China
| | - Jiangquan Hong
- Department of Cardiothoracic SurgeryZhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhou363000China
| | - Yi Zhang
- Department of Cardiothoracic SurgeryZhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhou363000China
| | - David Dockrell
- Department of Respiratory Medicine and MRC Centre for Inflammation ResearchUniversity of EdinburghEdinburghEH16 4TJUK
| | - Shaohua Ma
- Institute of Biopharmaceutical and Health EngineeringTsinghua Shenzhen International Graduate School (SIGS)Tsinghua UniversityShenzhen518055China
- Precision Medicine and Healthcare Research CentreTsinghua‐Berkeley Shenzhen Institute (TBSI)Tsinghua UniversityShenzhen518055China
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Hone AJ, Santiago U, Harvey PJ, Tekarli B, Gajewiak J, Craik DJ, Camacho CJ, McIntosh JM. Design, Synthesis, and Structure-Activity Relationships of Novel Peptide Derivatives of the Severe Acute Respiratory Syndrome-Coronavirus-2 Spike-Protein that Potently Inhibit Nicotinic Acetylcholine Receptors. J Med Chem 2024; 67:9587-9598. [PMID: 38814877 PMCID: PMC11444331 DOI: 10.1021/acs.jmedchem.4c00735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence (682RRARS686) that forms a cleavage site for the enzyme furin. Strikingly, the structure of the spike-protein loop containing the furin cleavage site bears substantial similarity to neurotoxin peptides found in the venoms of certain snakes and marine cone snails. Leveraging this relationship, we designed and synthesized disulfide-constrained peptides with amino-acid sequences corresponding to the furin cleavage-sites of wild-type (B.1 variant) SARS-CoV-2 or the Alpha, Delta, and Omicron variants. Remarkably, some of these peptides potently inhibited α7 and α9α10 nicotinic acetylcholine receptors (nAChR) with nM affinity and showed SARS-CoV-2 variant and nAChR subtype-dependent potencies. Nuclear magnetic resonance spectroscopy and molecular dynamics were used to rationalize structure-activity relationships between peptides and their cognate receptors. These findings delineate nAChR subtypes that can serve as high-affinity spike-protein targets in tissues central to COVID-19 pathophysiology and identify ligands and target receptors to inform the development of novel SARS-CoV-2 therapeutics.
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Affiliation(s)
- Arik J Hone
- School of Biological Sciences, University of Utah, Salt Lake City, Utah 84112, United States
- MIRECC, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah 84148, United States
| | - Ulises Santiago
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
| | - Peta J Harvey
- Institute for Molecular Bioscience, ARC Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Bassel Tekarli
- School of Biological Sciences, University of Utah, Salt Lake City, Utah 84112, United States
| | - Joanna Gajewiak
- School of Biological Sciences, University of Utah, Salt Lake City, Utah 84112, United States
| | - David J Craik
- Institute for Molecular Bioscience, ARC Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Carlos J Camacho
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
| | - J Michael McIntosh
- School of Biological Sciences, University of Utah, Salt Lake City, Utah 84112, United States
- Department of Psychiatry, University of Utah, Salt Lake City, Utah 84112, United States
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah 84148, United States
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Rasmi Y, Shokati A, Hatamkhani S, Farnamian Y, Naderi R, Jalali L. Assessment of the relationship between the dopaminergic pathway and severe acute respiratory syndrome coronavirus 2 infection, with related neuropathological features, and potential therapeutic approaches in COVID-19 infection. Rev Med Virol 2024; 34:e2506. [PMID: 38282395 DOI: 10.1002/rmv.2506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 07/06/2023] [Accepted: 12/17/2023] [Indexed: 01/30/2024]
Abstract
Dopamine is a known catecholamine neurotransmitter involved in several physiological processes, including motor control, motivation, reward, cognition, and immune function. Dopamine receptors are widely distributed throughout the nervous system and in immune cells. Several viruses, including human immunodeficiency virus and Japanese encephalitis virus, can use dopaminergic receptors to replicate in the nervous system and are involved in viral neuropathogenesis. In addition, studies suggest that dopaminergic receptors may play a role in the progression and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. When SARS-CoV-2 binds to angiotensin-converting enzyme 2 receptors on the surface of neuronal cells, the spike protein of the virus can bind to dopaminergic receptors on neighbouring cells to accelerate its life cycle and exacerbate neurological symptoms. In addition, recent research has shown that dopamine is an important regulator of the immune-neuroendocrine system. Most immune cells express dopamine receptors and other dopamine-related proteins, indicating the importance of dopaminergic immune regulation. The increase in dopamine concentration during SARS-CoV2 infection may reduce immunity (innate and adaptive) that promotes viral spread, which could lead to neuronal damage. In addition, dopaminergic signalling in the nervous system may be affected by SARS-CoV-2 infection. COVID -19 can cause various neurological symptoms as it interacts with the immune system. One possible treatment strategy for COVID -19 patients could be the use of dopamine antagonists. To fully understand how to protect the neurological system and immune cells from the virus, we need to study the pathophysiology of the dopamine system in SARS-CoV-2 infection.
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Affiliation(s)
- Yousef Rasmi
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ameneh Shokati
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Shima Hatamkhani
- Experimental and Applied Pharmaceutical Sciences Research Center, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Pharmacy, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Yeganeh Farnamian
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Roya Naderi
- Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ladan Jalali
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Cao Y, Chen H, Yang J. Neuroanatomy of lymphoid organs: Lessons learned from whole-tissue imaging studies. Eur J Immunol 2023; 53:e2250136. [PMID: 37377338 DOI: 10.1002/eji.202250136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/06/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023]
Abstract
Decades of extensive research have documented the presence of neural innervations of sensory, sympathetic, or parasympathetic origin in primary and secondary lymphoid organs. Such neural inputs can release neurotransmitters and neuropeptides to directly modulate the functions of various immune cells, which represents one of the essential aspects of the body's neuroimmune network. Notably, recent studies empowered by state-of-the-art imaging techniques have comprehensively assessed neural distribution patterns in BM, thymus, spleen, and LNs of rodents and humans, helping clarify several controversies lingering in the field. In addition, it has become evident that neural innervations in lymphoid organs are not static but undergo alterations in pathophysiological contexts. This review aims to update the current information on the neuroanatomy of lymphoid organs obtained through whole-tissue 3D imaging and genetic approaches, focusing on anatomical features that may designate the functional modulation of immune responses. Moreover, we discuss several critical questions that call for future research, which will advance our in-depth understanding of the importance and complexity of neural control of lymphoid organs.
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Affiliation(s)
- Ying Cao
- Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Hongjie Chen
- Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Jing Yang
- Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
- Shenzhen Bay Laboratory, Institute of Molecular Physiology, Shenzhen, China
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6
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Roxlau ET, Pak O, Hadzic S, Garcia-Castro CF, Gredic M, Wu CY, Schäffer J, Selvakumar B, Pichl A, Spiegelberg D, Deutscher J, Bednorz M, Schäfer K, Kraut S, Kosanovic D, Zeidan EM, Kojonazarov B, Herold S, Strielkov I, Guenther A, Wilhelm J, Khalifa MMA, Taye A, Brandes RP, Hecker M, Grimminger F, Ghofrani HA, Schermuly RT, Seeger W, Sommer N, Weissmann N. Nicotine promotes e-cigarette vapour-induced lung inflammation and structural alterations. Eur Respir J 2023; 61:2200951. [PMID: 37105573 PMCID: PMC10285110 DOI: 10.1183/13993003.00951-2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 03/19/2023] [Indexed: 04/29/2023]
Abstract
BACKGROUND Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear. RESULTS In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations (e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8 months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8 cells·mL-1; control: 37.0±21.1 cells·mL-1; NF ECV: 198.6±94.9 cells·mL-1) and in lung tissue (ECV: 25.7±3.3 cells·mm-3; control: 4.8±1.1 cells·mm-3; NF ECV: 14.1±2.2 cells·mm-3). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function (e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV. CONCLUSIONS NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations.
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Affiliation(s)
- Elsa T Roxlau
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Joint first authors
| | - Oleg Pak
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Joint first authors
| | - Stefan Hadzic
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Claudia F Garcia-Castro
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Marija Gredic
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Cheng-Yu Wu
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Julia Schäffer
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Balachandar Selvakumar
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Sharjah Institute of Medical Research (SIMR), College of Medicine - University of Sharjah (UoS), Sharjah, United Arab Emirates
| | - Alexandra Pichl
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - David Spiegelberg
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Janik Deutscher
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Mariola Bednorz
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Katharina Schäfer
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Simone Kraut
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Djuro Kosanovic
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Esraa M Zeidan
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Baktybek Kojonazarov
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Giessen, Germany
| | - Susanne Herold
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Ievgen Strielkov
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Andreas Guenther
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Jochen Wilhelm
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Giessen, Germany
| | - Mohamed M A Khalifa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Ashraf Taye
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena, Egypt
| | - Ralf P Brandes
- Institute for Cardiovascular Physiology, Goethe University, Cardio-Pulmonary Institute (CPI), Frankfurt, Germany
| | - Matthias Hecker
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Friedrich Grimminger
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Hossein A Ghofrani
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Department of Medicine, Imperial College London, London, UK
| | - Ralph T Schermuly
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Werner Seeger
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Natascha Sommer
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Norbert Weissmann
- Justus Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
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7
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Kuebler WM. (V)aperçu on the harm of nicotine e-cigarettes. Eur Respir J 2023; 61:2300886. [PMID: 37348900 DOI: 10.1183/13993003.00886-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 05/30/2023] [Indexed: 06/24/2023]
Affiliation(s)
- Wolfgang M Kuebler
- Institute of Physiology, Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner site Berlin, Germany
- German Center for Lung Research (DZL), Partner site Berlin, Germany
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada
- Departments of Physiology and Surgery, University of Toronto, Toronto, ON, Canada
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8
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Richter K, Grau V. Signaling of nicotinic acetylcholine receptors in mononuclear phagocytes. Pharmacol Res 2023; 191:106727. [PMID: 36966897 DOI: 10.1016/j.phrs.2023.106727] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/07/2023] [Accepted: 03/10/2023] [Indexed: 03/28/2023]
Abstract
Nicotinic acetylcholine receptors are not only expressed by the nervous system and at the neuro-muscular junction but also by mononuclear phagocytes, which belong to the innate immune system. Mononuclear phagocyte is an umbrella term for monocytes, macrophages, and dendritic cells. These cells play pivotal roles in host defense against infection but also in numerous often debilitating diseases that are characterized by exuberant inflammation. Nicotinic acetylcholine receptors of the neuronal type dominate in these cells, and their stimulation is mainly associated with anti-inflammatory effects. Although the cholinergic modulation of mononuclear phagocytes is of eminent clinical relevance for the prevention and treatment of inflammatory diseases and neuropathic pain, we are only beginning to understand the underlying mechanisms on the molecular level. The purpose of this review is to report and critically discuss the current knowledge on signal transduction mechanisms elicited by nicotinic acetylcholine receptors in mononuclear phagocytes.
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Affiliation(s)
- Katrin Richter
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Germany
| | - Veronika Grau
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Germany; German Centre for Lung Research (DZL), Giessen, Germany; Cardiopulmonary Institute (CPI), Giessen, Germany.
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9
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Dormoy V, Pons S, Gosset P, Maskos U. [Nicotinic acetylcholine receptor and chronic obstructive pulmonary disease]. Med Sci (Paris) 2022; 38:637-639. [PMID: 36094229 DOI: 10.1051/medsci/2022092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Valérian Dormoy
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France
| | - Stéphanie Pons
- Institut Pasteur de Paris, Université Paris Cité, Neurobiologie intégrative des systèmes cholinergiques, CNRS UMR 3571, Paris, France
| | - Philippe Gosset
- Université de Lille, CNRS UMR8204, Inserm U1019, CHRU Lille, Institut Pasteur Lille, Centre d'infection et d'immunité de Lille, Lille, France
| | - Uwe Maskos
- Institut Pasteur de Paris, Université Paris Cité, Neurobiologie intégrative des systèmes cholinergiques, CNRS UMR 3571, Paris, France
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10
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Español A, Sanchez Y, Salem A, Obregon J, Sales ME. Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells. World J Clin Oncol 2022; 13:505-519. [PMID: 35949430 PMCID: PMC9244968 DOI: 10.5306/wjco.v13.i6.505] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/24/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients’ treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients.
AIM To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells.
METHODS Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers’ blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP “binding cassette” G2 drug transporter (ABCG2) expression and its modulation by the different treatments with Western blot. The effect of the treatments on apoptosis induction was determined by flow cytometry using annexin-V and 7AAD markers.
RESULTS Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells.
CONCLUSION Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.
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Affiliation(s)
- Alejandro Español
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Yamila Sanchez
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Agustina Salem
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Jaqueline Obregon
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Maria Elena Sales
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
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11
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Dormoy V, Perotin JM, Gosset P, Maskos U, Polette M, Deslée G. Nicotinic receptors as SARS-CoV-2 spike co-receptors? Med Hypotheses 2021; 158:110741. [PMID: 34924680 PMCID: PMC8669939 DOI: 10.1016/j.mehy.2021.110741] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 11/16/2021] [Accepted: 12/10/2021] [Indexed: 12/18/2022]
Abstract
Nicotinic acetylcholine receptors (nAChRs) play an important role in homeostasis and respiratory diseases. Controversies regarding the association between COVID-19 hospitalizations and smoking suggest that nAChRs may contribute to SARS-CoV-2 respiratory syndrome. We recently detailed the expression and localization of all nAChR subunits in the human lung. Since virus association with nAChRs has been shown in the past, we hypothesize that nAChR subunits act as SARS-CoV-2 Spike co-receptors. Based on sequence alignment analysis, we report domains of high molecular similarities in nAChRs with the binding domain of hACE2 for SARS-CoV-2 Spike protein. This hypothesis supported by in silico pilot data provides a rational for the modelling and the in vitro experimental validation of the interaction between SARS-CoV-2 and the nAChRs.
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Affiliation(s)
- Valérian Dormoy
- University of Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, SFR CAP-SANTE, 51092 Reims, France
| | - Jeanne-Marie Perotin
- University of Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, SFR CAP-SANTE, 51092 Reims, France.,CHU of Reims, Hôpital Maison Blanche, Department of Respiratory Diseases, 51092 Reims, France
| | - Philippe Gosset
- University of Lille, CNRS UMR8204, Inserm U1019, CHRU Lille, Institut Pasteur Lille, CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Uwe Maskos
- Institut Pasteur Paris, Université de Paris, Integrative Neurobiology of Cholinergic Systems, CNRS, UMR 3571, Paris, France
| | - Myriam Polette
- University of Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, SFR CAP-SANTE, 51092 Reims, France.,CHU Reims, Hôpital Maison Blanche, Department of Biopathology, 51092 Reims, France
| | - Gaëtan Deslée
- University of Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, SFR CAP-SANTE, 51092 Reims, France.,CHU of Reims, Hôpital Maison Blanche, Department of Respiratory Diseases, 51092 Reims, France
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12
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Routhier J, Pons S, Freidja ML, Dalstein V, Cutrona J, Jonquet A, Lalun N, Mérol JC, Lathrop M, Stitzel JA, Kervoaze G, Pichavant M, Gosset P, Tournier JM, Birembaut P, Dormoy V, Maskos U. An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions. Nat Commun 2021; 12:6384. [PMID: 34737286 PMCID: PMC8568944 DOI: 10.1038/s41467-021-26637-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target. Human polymorphisms in nicotinic acetylcholine receptor genes have been linked to both smoking and lung diseases like Chronic Obstructive Pulmonary Disease (COPD) or lung cancer. Here the authors identify a direct role for a human coding polymorphism in COPD-like lesions independent of smoke or nicotine exposure.
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Affiliation(s)
- Julie Routhier
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France
| | - Stéphanie Pons
- Institut Pasteur, Université de Paris, Integrative Neurobiology of Cholinergic Systems, CNRS UMR 3571, Paris, France
| | - Mohamed Lamine Freidja
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France.,Department of Biochemistry and Microbiology, Faculty of Sciences, University of M'sila, M'sila, Algeria
| | - Véronique Dalstein
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France.,Department of Biopathology, CHU of Reims, Reims, France
| | - Jérôme Cutrona
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France
| | - Antoine Jonquet
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France
| | - Nathalie Lalun
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France
| | - Jean-Claude Mérol
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France.,Department of Otorhinolaryngology, CHU of Reims, Reims, France
| | - Mark Lathrop
- McGill University Genome Center, Montréal, QC, Canada
| | - Jerry A Stitzel
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
| | - Gwenola Kervoaze
- University of Lille, CNRS UMR9017, Inserm U1019, CHU Lille, Institut Pasteur de Lille, CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Muriel Pichavant
- University of Lille, CNRS UMR9017, Inserm U1019, CHU Lille, Institut Pasteur de Lille, CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Philippe Gosset
- University of Lille, CNRS UMR9017, Inserm U1019, CHU Lille, Institut Pasteur de Lille, CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Jean-Marie Tournier
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France
| | - Philippe Birembaut
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France.,Department of Biopathology, CHU of Reims, Reims, France
| | - Valérian Dormoy
- Université de Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, Reims, France.
| | - Uwe Maskos
- Institut Pasteur, Université de Paris, Integrative Neurobiology of Cholinergic Systems, CNRS UMR 3571, Paris, France.
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13
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Hollenhorst MI, Krasteva-Christ G. Nicotinic Acetylcholine Receptors in the Respiratory Tract. Molecules 2021; 26:6097. [PMID: 34684676 PMCID: PMC8539672 DOI: 10.3390/molecules26206097] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/01/2021] [Accepted: 10/06/2021] [Indexed: 02/07/2023] Open
Abstract
Nicotinic acetylcholine receptors (nAChR) are widely distributed in neuronal and non-neuronal tissues, where they play diverse physiological roles. In this review, we highlight the recent findings regarding the role of nAChR in the respiratory tract with a special focus on the involvement of nAChR in the regulation of multiple processes in health and disease. We discuss the role of nAChR in mucociliary clearance, inflammation, and infection and in airway diseases such as asthma, chronic obstructive pulmonary disease, and cancer. The subtype diversity of nAChR enables differential regulation, making them a suitable pharmaceutical target in many diseases. The stimulation of the α3β4 nAChR could be beneficial in diseases accompanied by impaired mucociliary clearance, and the anti-inflammatory effect due to an α7 nAChR stimulation could alleviate symptoms in diseases with chronic inflammation such as chronic obstructive pulmonary disease and asthma, while the inhibition of the α5 nAChR could potentially be applied in non-small cell lung cancer treatment. However, while clinical studies targeting nAChR in the airways are still lacking, we suggest that more detailed research into this topic and possible pharmaceutical applications could represent a valuable tool to alleviate the symptoms of diverse airway diseases.
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14
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Zhang L, Bing S, Dong M, Lu X, Xiong Y. Targeting ion channels for the treatment of lung cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188629. [PMID: 34610420 DOI: 10.1016/j.bbcan.2021.188629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/02/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023]
Abstract
Lung cancer is caused by several environmental and genetic variables and is globally associated with elevated morbidity and mortality. Among these variables, membrane-bound ion channels have a key role in regulating multiple signaling pathways in tumor cells and dysregulation of ion channel expression and function is closely related to proliferation, migration, and metastasis of lung cancer. This work reviews and summarizes current knowledge about the role of ion channels in lung cancer, focusing on the changes in the expression and function of various ion channels in lung cancer and how these changes affect lung cancer cell biology both in vitro and in vivo as evidenced by both genetic and pharmacological studies. It can help understand the molecular mechanisms of various ion channels influencing the initiation and progression of lung cancer and shed new insights into their roles in the development and treatment of this deadly disease.
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Affiliation(s)
- Liqin Zhang
- The First Affiliated Hospital of Wannan Medical College，Yijishan Hospital，2 Zheshan West Road, Wuhu 241000，China.
| | - Shuya Bing
- The First Affiliated Hospital of Wannan Medical College，Yijishan Hospital，2 Zheshan West Road, Wuhu 241000，China
| | - Mo Dong
- The First Affiliated Hospital of Wannan Medical College，Yijishan Hospital，2 Zheshan West Road, Wuhu 241000，China
| | - Xiaoqiu Lu
- The First Affiliated Hospital of Wannan Medical College，Yijishan Hospital，2 Zheshan West Road, Wuhu 241000，China
| | - Yuancheng Xiong
- The First Affiliated Hospital of Wannan Medical College，Yijishan Hospital，2 Zheshan West Road, Wuhu 241000，China
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15
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Chr15q25 Genetic Variant rs16969968 Alters Cell Differentiation in Respiratory Epithelia. Int J Mol Sci 2021; 22:ijms22136657. [PMID: 34206324 PMCID: PMC8268843 DOI: 10.3390/ijms22136657] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/11/2021] [Accepted: 06/17/2021] [Indexed: 12/26/2022] Open
Abstract
The gene cluster region, CHRNA3/CHRNA5/CHRNB4, encoding for nicotinic acetylcholine receptor (nAChR) subunits, contains several genetic variants linked to nicotine addiction and brain disorders. The CHRNA5 single-nucleotide polymorphism (SNP) rs16969968 is strongly associated with nicotine dependence and lung diseases. Using immunostaining studies on tissue sections and air-liquid interface airway epithelial cell cultures, in situ hybridisation, transcriptomic and cytokines detection, we analysed rs16969968 contribution to respiratory airway epithelial remodelling and modulation of inflammation. We provide cellular and molecular analyses which support the genetic association of this polymorphism with impaired ciliogenesis and the altered production of inflammatory mediators. This suggests its role in lung disease development.
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16
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Lunardi F, Fortarezza F, Vedovelli L, Pezzuto F, Boscolo A, Rossato M, Vettor R, Cattelan AM, Del Vecchio C, Crisanti A, Navalesi P, Gregori D, Calabrese F. Lower Gene Expression of Angiotensin Converting Enzyme 2 Receptor in Lung Tissues of Smokers with COVID-19 Pneumonia. Biomolecules 2021; 11:796. [PMID: 34073591 PMCID: PMC8226817 DOI: 10.3390/biom11060796] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 01/08/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE-2) is the main cell entry receptor for severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), thus playing a critical role in causing Coronavirus disease 2019 (COVID-19). The role of smoking habit in the susceptibility to infection is still controversial. In this study we correlated lung ACE-2 gene expression with several clinical/pathological data to explore susceptibility to infection. This is a retrospective observational study on 29 consecutive COVID-19 autopsies. SARS-CoV-2 genome and ACE-2 mRNA expression were evaluated by real-time polymerase chain reaction in lung tissue samples and correlated with several data with focus on smoking habit. Smoking was less frequent in high than low ACE-2 expressors (p = 0.014). A Bayesian regression also including age, gender, hypertension, and virus quantity confirmed that smoking was the most probable risk factor associated with low ACE-2 expression in the model. A direct relation was found between viral quantity and ACE-2 expression (p = 0.028). Finally, high ACE-2 expressors more frequently showed a prevalent pattern of vascular injury than low expressors (p = 0.049). In conclusion, ACE-2 levels were decreased in the lung tissue of smokers with severe COVID-19 pneumonia. These results point out complex biological interactions between SARS-CoV-2 and ACE-2 particularly concerning the aspect of smoking habit and need larger prospective case series and translational studies.
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Affiliation(s)
- Francesca Lunardi
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy; (F.L.); (F.F.); (L.V.); (F.P.); (D.G.)
| | - Francesco Fortarezza
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy; (F.L.); (F.F.); (L.V.); (F.P.); (D.G.)
| | - Luca Vedovelli
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy; (F.L.); (F.F.); (L.V.); (F.P.); (D.G.)
| | - Federica Pezzuto
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy; (F.L.); (F.F.); (L.V.); (F.P.); (D.G.)
| | - Annalisa Boscolo
- Department of Medicine, University of Padova Medical School, 35128 Padova, Italy; (A.B.); (M.R.); (R.V.); (A.M.C.); (P.N.)
| | - Marco Rossato
- Department of Medicine, University of Padova Medical School, 35128 Padova, Italy; (A.B.); (M.R.); (R.V.); (A.M.C.); (P.N.)
| | - Roberto Vettor
- Department of Medicine, University of Padova Medical School, 35128 Padova, Italy; (A.B.); (M.R.); (R.V.); (A.M.C.); (P.N.)
| | - Anna Maria Cattelan
- Department of Medicine, University of Padova Medical School, 35128 Padova, Italy; (A.B.); (M.R.); (R.V.); (A.M.C.); (P.N.)
| | - Claudia Del Vecchio
- Department of Molecular Medicine, University of Padova Medical School, 35121 Padova, Italy; (C.D.V.); (A.C.)
| | - Andrea Crisanti
- Department of Molecular Medicine, University of Padova Medical School, 35121 Padova, Italy; (C.D.V.); (A.C.)
| | - Paolo Navalesi
- Department of Medicine, University of Padova Medical School, 35128 Padova, Italy; (A.B.); (M.R.); (R.V.); (A.M.C.); (P.N.)
| | - Dario Gregori
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy; (F.L.); (F.F.); (L.V.); (F.P.); (D.G.)
| | - Fiorella Calabrese
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy; (F.L.); (F.F.); (L.V.); (F.P.); (D.G.)
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