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1.
Molecules ; 27(11)2022 May 26.
Article in English | MEDLINE | ID: covidwho-1866459

ABSTRACT

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.


Subject(s)
Dipyridamole , Idiopathic Pulmonary Fibrosis , Animals , Dipyridamole/pharmacology , Dipyridamole/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity Relationship
2.
Int J Mol Sci ; 22(23)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1542585

ABSTRACT

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1-7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1-7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.


Subject(s)
Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Fibrosis/metabolism , Peptide Fragments/metabolism , /metabolism , Cannabis , Cigarette Smoking , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Inflammation , Lung/pathology , Pandemics , Respiration, Artificial , Respiratory Distress Syndrome , Respiratory Insufficiency/metabolism , Risk Factors , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
3.
Cells ; 10(10)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470800

ABSTRACT

Pulmonary epithelial cells are widely considered to be the first line of defence in the lung and are responsible for coordinating the innate immune response to injury and subsequent repair. Consequently, epithelial cells communicate with multiple cell types including immune cells and fibroblasts to promote acute inflammation and normal wound healing in response to damage. However, aberrant epithelial cell death and damage are hallmarks of pulmonary disease, with necrotic cell death and cellular senescence contributing to disease pathogenesis in numerous respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and coronavirus disease (COVID)-19. In this review, we summarise the literature that demonstrates that epithelial damage plays a pivotal role in the dysregulation of the immune response leading to tissue destruction and abnormal remodelling in several chronic diseases. Specifically, we highlight the role of epithelial-derived damage-associated molecular patterns (DAMPs) and senescence in shaping the immune response and assess their contribution to inflammatory and fibrotic signalling pathways in the lung.


Subject(s)
COVID-19/immunology , Epithelium/immunology , Idiopathic Pulmonary Fibrosis/immunology , Lung/immunology , Alarmins , Animals , Cellular Senescence , Coculture Techniques , Epithelial Cells/cytology , Epithelial Cells/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Fibrosis/metabolism , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Immunity , Inflammation/metabolism , Ligands , Necroptosis , Necrosis/pathology , Pulmonary Disease, Chronic Obstructive , SARS-CoV-2 , Signal Transduction
4.
J Mol Med (Berl) ; 99(10): 1373-1384, 2021 10.
Article in English | MEDLINE | ID: covidwho-1309024

ABSTRACT

Pulmonary fibrosis is a chronic debilitating condition characterized by progressive deposition of connective tissue, leading to a steady restriction of lung elasticity, a decline in lung function, and a median survival of 4.5 years. The leading causes of pulmonary fibrosis are inhalation of foreign particles (such as silicosis and pneumoconiosis), infections (such as post COVID-19), autoimmune diseases (such as systemic autoimmune diseases of the connective tissue), and idiopathic pulmonary fibrosis. The therapeutics currently available for pulmonary fibrosis only modestly slow the progression of the disease. This review is centered on the interplay of damage-associated molecular pattern (DAMP) molecules, Toll-like receptor 4 (TLR4), and inflammatory cytokines (such as TNF-α, IL-1ß, and IL-17) as they contribute to the pathogenesis of pulmonary fibrosis, and the possible avenues to develop effective therapeutics that disrupt this interplay.


Subject(s)
Alarmins/metabolism , Cytokines/metabolism , Idiopathic Pulmonary Fibrosis/metabolism , Inflammation/metabolism , Toll-Like Receptor 4/metabolism , Animals , Humans , Idiopathic Pulmonary Fibrosis/complications , Idiopathic Pulmonary Fibrosis/therapy , Inflammation/complications , Models, Biological
6.
J Pathol Clin Res ; 7(5): 446-458, 2021 09.
Article in English | MEDLINE | ID: covidwho-1224964

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin-converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS-CoV-2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open-access RNA sequencing datasets. Immunohistochemical and single-cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme-linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Familial Primary Pulmonary Hypertension/pathology , Idiopathic Pulmonary Fibrosis/pathology , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Basigin/genetics , Basigin/metabolism , COVID-19/metabolism , COVID-19/virology , Disease Susceptibility , Familial Primary Pulmonary Hypertension/enzymology , Familial Primary Pulmonary Hypertension/virology , Female , Furin/genetics , Furin/metabolism , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/virology , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/virology , Risk Factors , Serine Endopeptidases/genetics , Virus Internalization
7.
J Med Chem ; 64(2): 1170-1179, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1019736

ABSTRACT

Ifenprodil (1) is a potent GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonist that is used as a cerebral vasodilator and has been examined in clinical trials for the treatment of drug addiction, idiopathic pulmonary fibrosis, and COVID-19. To correlate biological data with configuration, all four ifenprodil stereoisomers were prepared by diastereoselective reduction and subsequent separation of enantiomers by chiral HPLC. The absolute configuration of ifenprodil stereoisomers was determined by X-ray crystal structure analysis of (1R,2S)-1a and (1S,2S)-1d. GluN2B affinity, ion channel inhibitory activity, and selectivity over α, σ, and 5-HT receptors were evaluated. (1R,2R)-Ifenprodil ((1R,2R)-1c) showed the highest affinity toward GluN2B-NMDA receptors (Ki = 5.8 nM) and high inhibition of ion flux in two-electrode voltage clamp experiments (IC50 = 223 nM). Whereas the configuration did not influence considerably the GluN2B-NMDA receptor binding, (1R)-configuration is crucial for elevated inhibitory activity. (1R,2R)-Configured ifenprodil (1R,2R)-1c exhibited high selectivity for GluN2B-NMDA receptors over adrenergic, serotonergic, and σ1 receptors.


Subject(s)
Antifibrinolytic Agents/chemistry , Antifibrinolytic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Antifibrinolytic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , COVID-19/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Models, Molecular , Molecular Structure , Piperidines/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Stereoisomerism , Structure-Activity Relationship
8.
Cells ; 9(9)2020 08 24.
Article in English | MEDLINE | ID: covidwho-727401

ABSTRACT

The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris. This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy-lysosome pathway. These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19). Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease. Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases. In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease. Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.


Subject(s)
Autophagy/immunology , Betacoronavirus , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Disease Progression , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Acute Lung Injury/immunology , Acute Lung Injury/metabolism , COVID-19 , Coronavirus Infections/virology , Cystic Fibrosis/immunology , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Homeostasis , Humans , Idiopathic Pulmonary Fibrosis/immunology , Idiopathic Pulmonary Fibrosis/metabolism , Lysosomes/metabolism , Pandemics , Pneumonia, Viral/virology , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , SARS-CoV-2
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