scholarly journals Enhanced apoptosis as a possible mechanism to self-limit SARS-CoV-2 replication in porcine primary respiratory epithelial cells in contrast to human cells

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Rahul K. Nelli ◽  
Kruttika-S Phadke ◽  
Gino Castillo ◽  
Lu Yen ◽  
Amy Saunders ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Animal Health ◽  
Clinical Signs ◽  
In Vivo Studies ◽  
Specific Cell ◽  
Dependent Manner ◽  
Respiratory Epithelial Cells ◽  
Virus Dose ◽  
Respiratory Epithelial ◽  
Dose Dependent

AbstractThe ability of SARS-CoV to infect different species, including humans, dogs, cats, minks, ferrets, hamsters, tigers, and deer, pose a continuous threat to human and animal health. Pigs, though closely related to humans, seem to be less susceptible to SARS-CoV-2. Former in vivo studies failed to demonstrate clinical signs and transmission between pigs, while later attempts using a higher infectious dose reported viral shedding and seroconversion. This study investigated species-specific cell susceptibility, virus dose-dependent infectivity, and infection kinetics, using primary human (HRECs) and porcine (PRECs) respiratory epithelial cells. Despite higher ACE2 expression in HRECs compared to PRECs, SARS-CoV-2 infected, and replicated in both PRECs and HRECs in a dose-dependent manner. Cytopathic effect was particularly more evident in PRECs than HRECs, showing the hallmark morphological signs of apoptosis. Further analysis confirmed an early and enhanced apoptotic mechanism driven through caspase 3/7 activation, limiting SARS-CoV-2 propagation in PRECs compared to HRECs. Our findings shed light on a possible mechanism of resistance of pigs to SARS-CoV-2 infection, and it may hold therapeutic value for the treatment of COVID-19.

Intranasal Toxicity of BMS-181885, A Novel 5-HT1 Agonist

1999 ◽  
Vol 18 (5) ◽  
pp. 285-296
Author(s):  
Gene E. Schulze ◽  
Jim E. Proctor ◽  
Mark A. Dominick ◽  
Amy E. Weiss ◽  
Oliver P. Flint ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Nasal Mucosa ◽  
Olfactory Epithelium ◽  
Mucosal Injury ◽  
Separate Experiment ◽  
Toxic Metabolite ◽  
Respiratory Epithelial Cells ◽  
Nasal Injury ◽  
Respiratory Epithelial ◽  
Dose Dependent

One-month intranasal toxicity studies were conducted with BMS-181885 at doses of 1.5, 9, or 15 mg/animal/day in rats and 4, 24, or 40 mg/animal/day in monkeys. A 1-month intermittent intranasal toxicity study was also conducted in monkeys at doses of 3, 6, and 12 mg/animal 3 days per week. BMS-181885 was generally well tolerated in rats but resulted in dose-dependent nasal mucosal injury, primarily characterized by subacute inflammation of the nasal mucosa, and degeneration, single-cell necrosis, and/or erosion of the olfactory epithelium and, to a lesser extent, the respiratory epithelium. In monkeys, daily BMS-181885 administration was well tolerated and produced similar dose-dependent nasal injury primarily characterized by subacute inflammation of the nasal mucosa with degeneration and erosion of the olfactory epithelium. In a separate experiment, intermittent administration also resulted in dose-dependent nasal injury. In cultured rat nasal mucosal cells, BMS-181885 was toxic to olfactory epithelial cells with a range of mean IC50s between 44 and 291 μM. In contrast, BMS-181885 had no effect on respiratory epithelial cells up to its maximum solubility. Cytochrome P450 inhibition had no effect on the toxicity of BMS-181885 in olfactory epithelial cells but produced dose-dependent toxicity in respiratory epithelial cells, which was not present previously. The in vitro data suggest that parent drug, rather than a toxic metabolite, caused the drug-associated nasal mucosal injury.

scholarly journals Chemical Adducts of Reactive Flavor Aldehydes Formed in E-Cigarette Liquids Are Cytotoxic and Inhibit Mitochondrial Function in Respiratory Epithelial Cells

2020 ◽  
Vol 22 (Supplement_1) ◽  
pp. S25-S34
Author(s):  
Sairam V Jabba ◽  
Alexandra N Diaz ◽  
Hanno C Erythropel ◽  
Julie B Zimmerman ◽  
Sven-Eric Jordt
Keyword(s):  
Epithelial Cells ◽  
Mitochondrial Function ◽  
Dead Cell ◽  
Inhalation Toxicity ◽  
Dependent Manner ◽  
Respiratory Epithelial Cells ◽  
In Vivo Models ◽  
Ethyl Vanillin ◽  
Toxicological Studies ◽  
Respiratory Epithelial

Abstract Introduction Flavor aldehydes in e-cigarettes, including vanillin, ethyl vanillin (vanilla), and benzaldehyde (berry/fruit), rapidly undergo chemical reactions with the e-liquid solvents, propylene glycol, and vegetable glycerol (PG/VG), to form chemical adducts named flavor aldehyde PG/VG acetals that can efficiently transfer to e-cigarette aerosol. The objective of this study was to compare the cytotoxic and metabolic toxic effects of acetals and their parent aldehydes in respiratory epithelial cells. Aims and Methods Cell metabolic assays were carried out in bronchial (BEAS-2B) and alveolar (A549) epithelial cells assessing the effects of benzaldehyde, vanillin, ethyl vanillin, and their corresponding PG acetals on key bioenergetic parameters of mitochondrial function. The potential cytotoxic effects of benzaldehyde and vanillin and their corresponding PG acetals were analyzed using the LIVE/DEAD cell assay in BEAS-2B cells and primary human nasal epithelial cells (HNEpC). Cytostatic effects of vanillin and vanillin PG acetal were compared using Click-iT EDU cell proliferation assay in BEAS-2B cells. Results Compared with their parent aldehydes, PG acetals diminished key parameters of cellular energy metabolic functions, including basal respiration, adenosine triphosphate production, and spare respiratory capacity. Benzaldehyde PG acetal (1–10 mM) increased cell mortality in BEAS-2B and HNEpC, compared with benzaldehyde. Vanillin PG acetal was more cytotoxic than vanillin at the highest concentration tested while both diminished cellular proliferation in a concentration-dependent manner. Conclusions Reaction products formed in e-liquids between flavor aldehydes and solvent chemicals have differential toxicological properties from their parent flavor aldehydes and may contribute to the health effects of e-cigarette aerosol in the respiratory system of e-cigarette users. Implications With no inhalation toxicity studies available for acetals, data from this study will provide a basis for further toxicological studies using in vitro and in vivo models. This study suggests that manufacturers’ disclosure of e-liquid ingredients at time of production may be insufficient to inform a comprehensive risk assessment of e-liquids and electronic nicotine delivery systems use, due to the chemical instability of e-liquids over time and the formation of new compounds.

scholarly journals Early Bacterial Colonization Induces Toll-Like Receptor-Dependent Transforming Growth Factor β Signaling in the Epithelium

2009 ◽  
Vol 77 (5) ◽  
pp. 2212-2220 ◽  
Author(s):  
Christoph Beisswenger ◽  
Elena S. Lysenko ◽  
Jeffrey N. Weiser
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Epithelial Barrier ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Respiratory Epithelial Cells ◽  
Mucosal Barrier Function ◽  
Respiratory Epithelial

ABSTRACT Colonization of the upper respiratory tract is an initial step that may lead to disease for many pathogens. To prevent compromise of the epithelial barrier, the host must monitor and tightly control bacterial levels on the mucosa. Here we show that innate immune functions of respiratory epithelial cells control colonization by Streptococcus pneumoniae and Haemophilus influenzae in a Toll-like receptor (TLR)-dependent manner. Activation of inflammatory pathways, including mitogen-activated protein kinase signaling, in respiratory epithelial cells was accompanied by the induction of the transforming growth factor β signaling cascade during early colonization. Thus, colonization resulted in upregulation of factors involved in a proinflammatory response (e.g., interleukin-6) as well as factors known to modulate the epithelial barrier (e.g., Snail-1). These in vivo data provided a link between inflammation control and maintenance of the mucosal barrier function during infection and emphasized the importance of TLR-dependent inflammatory responses of the respiratory epithelium.

scholarly journals Microarray Analysis Reveals Induction of Lipoprotein Genes in Mucoid Pseudomonas aeruginosa: Implications for Inflammation in Cystic Fibrosis

2004 ◽  
Vol 72 (9) ◽  
pp. 5012-5018 ◽  
Author(s):  
Aaron M. Firoved ◽  
Wojciech Ornatowski ◽  
Vojo Deretic
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Microarray Analysis ◽  
High Morbidity ◽  
Dependent Manner ◽  
Respiratory Epithelial Cells ◽  
Therapeutic Benefits ◽  
Human Respiratory Epithelial Cells ◽  
Respiratory Epithelial

ABSTRACT The main cause of the high morbidity and mortality of cystic fibrosis (CF) is the progressive lung inflammation associated with Pseudomonas aeruginosa colonization. During the course of chronic CF infections, P. aeruginosa undergoes a conversion to a mucoid phenotype. The emergence of mucoid P. aeruginosa in CF is associated with increased inflammation, respiratory decline, and a poor prognosis. Here we show, by the use of microarray analysis, that upon P. aeruginosa conversion to mucoidy, there is a massive and preferential induction of genes encoding bacterial lipoproteins. Bacterial lipoproteins are potent agonists of Toll-like receptor 2 (TLR2) signaling. The expression of TLR2 in human respiratory epithelial cells was ascertained by Western blot analysis. Human respiratory epithelial cells responded in a TLR2-dependent manner to bacterial lipopeptides derived from Pseudomonas lipoproteins induced in mucoid strains. The TLR2 proinflammatory response was further augmented in CF cells. Thus, the excessive inflammation in CF is the result of a global induction in mucoid P. aeruginosa of lipoproteins that act as proinflammatory toxins (here termed lipotoxins) superimposed on the hyperexcitability of CF cells. Blocking the signaling cascade responding to bacterial lipotoxins may provide therapeutic benefits for CF patients.

scholarly journals SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation

2021 ◽  
Vol 6 (58) ◽  
pp. eabg0833
Author(s):  
Bingyu Yan ◽  
Tilo Freiwald ◽  
Daniel Chauss ◽  
Luopin Wang ◽  
Erin West ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Clinical Manifestations ◽  
Lung Epithelial Cells ◽  
Complement Factor ◽  
Respiratory Epithelial Cells ◽  
Signature Genes ◽  
Wide Range ◽  
Lung Epithelial ◽  
Gene Transcripts ◽  
Respiratory Epithelial

Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-κB as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines, but did not affect NF-κB-regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-κB-signaling could potentially have clinical application for severe COVID-19.

Sign in / Sign up

Export Citation Format

Share Document