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1.
PLoS Pathog ; 18(1): e1010171, 2022 01.
Article in English | MEDLINE | ID: covidwho-2327858

ABSTRACT

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , Lung/virology , SARS-CoV-2/physiology , Virus Internalization , Adult , Animals , Antiviral Agents/pharmacology , COVID-19/immunology , COVID-19/pathology , Cells, Cultured , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drugs, Investigational/pharmacology , Drugs, Investigational/therapeutic use , HEK293 Cells , Host-Pathogen Interactions/drug effects , Humans , Inflammation/pathology , Inflammation/therapy , Inflammation/virology , Lung/pathology , SARS-CoV-2/drug effects , Vero Cells , Virus Internalization/drug effects
2.
Clin Exp Rheumatol ; 41(2): 199-213, 2023 Mar.
Article in English | MEDLINE | ID: covidwho-2314200

ABSTRACT

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of disorders in which chronic inflammation of the skeletal muscle, leading to muscle weakness, is a common feature. Different phenotypes have been identified within the IIM spectrum based on extra-muscular manifestations, immunology, muscle histology, responsiveness to therapy, and prognosis. The pathogenesis, classification, treatment, and prognosis of the different IIM subtypes are subject to active discussion and research. This review highlights the most relevant literature published on this topic over the last year.


Subject(s)
Myositis , Humans , Muscle, Skeletal/pathology , Prognosis , Inflammation/pathology
3.
Cardiovasc Pathol ; 64: 107524, 2023.
Article in English | MEDLINE | ID: covidwho-2305846

ABSTRACT

BACKGROUND: Histopathological studies have shown inflammation, cardiomyocyte injury, and microvascular thrombosis in the ventricular myocardium of patients with coronavirus disease 2019 (COVID-19). However, although atrial dysfunction is common in COVID-19, little is known about histopathological changes in the atria of the heart. We therefore analyzed inflammation, cardiomyocyte injury, and microvascular thrombogenicity in the atria of deceased patients with COVID-19. METHODS: Atrial tissue was obtained from autopsied COVID-19 (n=16) patients and control patients (n=10) and analyzed using immunohistochemistry. The infiltration of CD45+ leukocytes, CD3+ T lymphocytes, CD68+ macrophages, MPO+ neutrophils, and Tryptase+ mast cells were quantified as well as cardiomyocyte damage and microvascular thrombosis. In addition, Tissue Factor (TF) and Factor XII (FXII) were quantified as markers of microvascular thrombogenicity. RESULTS: The numbers of lymphocytes, macrophages, and neutrophils were significantly increased in the atrial myocardium and epicardial atrial adipose tissue of COVID-19 patients compared with the control group. This was accompanied by dispersed cardiomyocyte injury, the occasional presence of microvascular thrombosis, and an increased presence of TF and FXII in the microvascular endothelium. CONCLUSIONS: Severe COVID-19 induces inflammation, cardiomyocyte injury, and microvascular thrombosis in the atria of the heart.


Subject(s)
Atrial Fibrillation , COVID-19 , Thrombosis , Humans , COVID-19/complications , COVID-19/pathology , Inflammation/pathology , Heart Atria/pathology , Thrombosis/etiology , Thrombosis/pathology
4.
Pathol Res Pract ; 245: 154471, 2023 May.
Article in English | MEDLINE | ID: covidwho-2299736

ABSTRACT

The impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on lung tissue in patients on respiratory support is of significant scientific interest in predicting mortality. This study aimed to analyze post-mortem histological changes in the lung tissue of COVID-19 patients on respiratory support using vital radiology semiotics. A total of 41 autopsies were performed on patients who died of SARS-CoV-2 and had confirmed COVID-19 by polymerase chain reaction (PCR) and radiological evidence of lung tissue consolidation and ground glass opacity. The results showed that the duration of COVID-19 in patients on respiratory support was significantly associated with the development of all stages of diffuse alveolar damage, acute fibrous organizing pneumonia, pulmonary capillary congestion, fibrin thrombi, perivascular inflammation, alveolar hemorrhage, proliferating interstitial fibroblasts, and pulmonary embolism. The prediction model for lethal outcomes based on the duration of total respiratory support had a sensitivity of 68.3% and a specificity of 87.5%. In conclusion, for COVID-19 patients on long-term respiratory support with radiological signs of ground glass opacity and lung consolidation, post-mortem morphological features included various stages of diffuse alveolar lung damage, pulmonary capillary congestion, fibrin clots, and perivascular inflammation.


Subject(s)
COVID-19 , Thrombosis , Humans , COVID-19/pathology , SARS-CoV-2 , Lung/pathology , Thrombosis/pathology , Inflammation/pathology , Fibrin
5.
BMC Neurol ; 23(1): 57, 2023 Feb 03.
Article in English | MEDLINE | ID: covidwho-2256347

ABSTRACT

BACKGROUND: Small vessel childhood primary angiitis of the central nervous system (SV-cPACNS) is a rare disease characterized by inflammation within small vessels such as arterioles or capillaries. CASE PRESENTATION: We report a case of SV-cPACNS in an 8-year-old boy confirmed by brain biopsy. This patient was also incidentally found to have anti-glial fibrillary acidic protein (GFAP) antibodies in the cerebrospinal fluid (CSF) but had no evidence of antibody-mediated disease on brain biopsy. A literature review highlighted the rarity of SV-cPACNS and found no prior reports of CSF GFAP-associated SV-cPACNS in the pediatric age group. CONCLUSION: We present the first case of biopsy proven SV-cPACNS vasculitis associated with an incidental finding of CSF GFAP antibodies. The GFAP antibodies are likely a clinically insignificant bystander in this case and possibly in other diseases with CNS inflammation. Further research is needed to determine the clinical significance of newer CSF autoantibodies such as anti-GFAP before they are used for medical decision-making in pediatrics.


Subject(s)
Vasculitis, Central Nervous System , Male , Humans , Child , Vasculitis, Central Nervous System/diagnosis , Autoantibodies , Inflammation/pathology
6.
BMC Infect Dis ; 23(1): 195, 2023 Mar 31.
Article in English | MEDLINE | ID: covidwho-2255104

ABSTRACT

BACKGROUND: Lung ultrasound (LUS) is an increasingly popular imaging method in clinical practice. It became particularly important during the COVID-19 pandemic due to its mobility and ease of use compared to high-resolution computed tomography (HRCT). The objective of this study was to assess the value of LUS in quantifying the degree of lung involvement and in discrimination of lesion types in the course of COVID-19 pneumonia as compared to HRCT analyzed by the artificial intelligence (AI). METHODS: This was a prospective observational study including adult patients hospitalized due to COVID-19 in whom initial HRCT and LUS were performed with an interval < 72 h. HRCT assessment was performed automatically by AI. We evaluated the correlations between the inflammation volume assessed both in LUS and HRCT, between LUS results and the HRCT structure of inflammation, and between LUS and the laboratory markers of inflammation. Additionally we compared the LUS results in subgroups depending on the respiratory failure throughout the hospitalization. RESULTS: Study group comprised 65 patients, median 63 years old. For both lungs, the median LUS score was 19 (IQR-interquartile range 11-24) and the median CT score was 22 (IQR 16-26). Strong correlations were found between LUS and CT scores (for both lungs r = 0.75), and between LUS score and percentage inflammation volume (PIV) (r = 0.69). The correlations remained significant, if weakened, for individual lung lobes. The correlations between LUS score and the value of the percentage consolidation volume (PCV) divided by percentage ground glass volume (PGV), were weak or not significant. We found significant correlation between LUS score and C-reactive protein (r = 0.55), and between LUS score and interleukin 6 (r = 0.39). LUS score was significantly higher in subgroups with more severe respiratory failure. CONCLUSIONS: LUS can be regarded as an accurate method to evaluate the extent of COVID-19 pneumonia and as a promising tool to estimate its clinical severity. Evaluation of LUS in the assessment of the structure of inflammation, requires further studies in the course of the disease. TRIAL REGISTRATION: The study has been preregistered 13 Aug 2020 on clinicaltrials.gov with the number NCT04513210.


Subject(s)
COVID-19 , Respiratory Insufficiency , Adult , Humans , Middle Aged , COVID-19/diagnostic imaging , COVID-19/pathology , Artificial Intelligence , Pandemics , SARS-CoV-2 , Lung/diagnostic imaging , Lung/pathology , Inflammation/pathology , Tomography, X-Ray Computed/methods , Tomography , Ultrasonography/methods
7.
Vet Pathol ; 60(2): 214-225, 2023 03.
Article in English | MEDLINE | ID: covidwho-2262480

ABSTRACT

Bronchopneumonia with interstitial pneumonia (BIP) has been considered a variant of acute interstitial pneumonia (AIP) rather than a distinct disease. This study compared 18 BIP, 24 bronchopneumonia (BP), and 13 AIP cases in feedlot beef cattle. Grossly, BIP cases typically had cranioventral lung lesions of similar morphology and extent as BP cases, but the caudodorsal lung appeared overinflated, bulged on section, and had interlobular edema and emphysema. Gross diagnosis of BIP had 83% sensitivity and 73% specificity relative to histopathology. Histologic lesions of BIP in cranioventral areas were of chronic BP, while caudodorsal lesions included alveolar and bronchiolar damage and inflammation, interstitial hypercellularity, and multifocal hemorrhages. In BIP cases, cranioventral lung lesions were more chronic than caudodorsal lesions. Histologic scores and microbiology data were comparable in cranioventral lung of BIP versus BP cases and caudodorsal lung of BIP versus AIP cases, with differences reflecting a more chronic disease involving less virulent bacteria in BIP versus BP. Mycoplasma bovis infection was similarly frequent among groups, and a viral cause of BIP was not identified. Lesion morphology and similar blood cytokine concentrations among groups argued against sepsis as a cause of lung injury. Surfactant dysfunction was identified in BIP and BP, and was only partially the result of protein exudation. These and other findings establish BIP as a distinct condition in which chronic cranioventral BP precedes acute caudodorsal interstitial lung disease, supporting a role of chronic inflammation in heightened sensitivity to 3-methylindole or another lung toxicant.


Subject(s)
Bronchopneumonia , Cattle Diseases , Lung Diseases, Interstitial , Cattle , Animals , Bronchopneumonia/microbiology , Bronchopneumonia/pathology , Bronchopneumonia/veterinary , Cattle Diseases/pathology , Lung Diseases, Interstitial/pathology , Lung Diseases, Interstitial/veterinary , Lung/pathology , Inflammation/pathology , Inflammation/veterinary
8.
Arch Virol ; 168(3): 96, 2023 Feb 26.
Article in English | MEDLINE | ID: covidwho-2258642

ABSTRACT

There is an urgent need to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions involved in virus spread and pathogenesis, which might contribute to the identification of new therapeutic targets. In this study, we investigated the presence of SARS-CoV-2 in postmortem lung, kidney, and liver samples of patients who died with coronavirus disease (COVID-19) and its relationship with host factors involved in virus spread and pathogenesis, using microscopy-based methods. The cases analyzed showed advanced stages of diffuse acute alveolar damage and fibrosis. We identified the SARS-CoV-2 nucleocapsid (NC) in a variety of cells, colocalizing with mitochondrial proteins, lipid droplets (LDs), and key host proteins that have been implicated in inflammation, tissue repair, and the SARS-CoV-2 life cycle (vimentin, NLRP3, fibronectin, LC3B, DDX3X, and PPARγ), pointing to vimentin and LDs as platforms involved not only in the viral life cycle but also in inflammation and pathogenesis. SARS-CoV-2 isolated from a patient´s nasal swab was grown in cell culture and used to infect hamsters. Target cells identified in human tissue samples included lung epithelial and endothelial cells; lipogenic fibroblast-like cells (FLCs) showing features of lipofibroblasts such as activated PPARγ signaling and LDs; lung FLCs expressing fibronectin and vimentin and macrophages, both with evidence of NLRP3- and IL1ß-induced responses; regulatory cells expressing immune-checkpoint proteins involved in lung repair responses and contributing to inflammatory responses in the lung; CD34+ liver endothelial cells and hepatocytes expressing vimentin; renal interstitial cells; and the juxtaglomerular apparatus. This suggests that SARS-CoV-2 may directly interfere with critical lung, renal, and liver functions involved in COVID-19-pathogenesis.


Subject(s)
COVID-19 , Humans , COVID-19/pathology , Fibronectins , Vimentin , SARS-CoV-2 , Endothelial Cells , NLR Family, Pyrin Domain-Containing 3 Protein , PPAR gamma , Lung , Inflammation/pathology , Kidney , Liver
9.
BJOG ; 130(8): 949-958, 2023 07.
Article in English | MEDLINE | ID: covidwho-2272214

ABSTRACT

OBJECTIVE: To study whether the occurrence and type of placental lesions vary according to the time of onset of COVID-19 in pregnant women. DESIGN: Case-control study. SETTING: Departments of Gynaecology-Obstetrics and Pathology, Strasbourg University Hospital, France. POPULATION: Cases were 49 placentas of women with COVID-19. Controls were 50 placentas from women who had a past history of molar pregnancy. COVID-19 placentas were categorised based on whether birth occurred at more or less than 14 days post-infection. METHODS: Comparison between case and controls. MAIN OUTCOME MEASURES: Maternal and neonatal outcomes were recorded. Macroscopic and microscopic examination of the placentas was performed. RESULTS: The rate of vascular complications was higher in the COVID groups than in the controls (8 [16.3%] versus 1 [2%], p = 0.02). Signs of fetal (22[44.9%] versus 13 [26%], p = 0.05) and maternal (44 [89.8%] versus 36 [72.0%], p = 0.02) vascular malperfusion and signs of inflammation (11 [22.4%] versus 3 [6.0%], p = 0.019) were significantly more common in the COVID-19 groups than in the control group. Fetal malperfusion lesions (9 [39.1%] versus 13 [50.0%], p = 0.45) and placental inflammation (4 [17.4%] versus 7 [26.9%], p = 0.42) rates were not significantly different between the two COVID-19 groups. Chronic villitis was significantly more common when the delivery occurred >14 days after infection than in the group that delivered <14 days after infection (7 [26.9%] versus 1 [4.4%], p = 0.05). CONCLUSIONS: Our study suggests that SARS-COV-2 induces placental lesions that evolve after disease recovery, especially with the development of inflammatory lesions, such as chronic villitis.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Uterine Neoplasms , Infant, Newborn , Pregnancy , Female , Humans , Placenta/blood supply , Case-Control Studies , SARS-CoV-2 , Inflammation/pathology , Parturition , Uterine Neoplasms/pathology , Pregnancy Complications, Infectious/epidemiology
10.
Pril (Makedon Akad Nauk Umet Odd Med Nauki) ; 44(1): 7-16, 2023 Mar 01.
Article in English | MEDLINE | ID: covidwho-2288398

ABSTRACT

Background: COVID-19 is a disease in several stages starting with virus replication to dysregulation in immune system response, organ failure and recovery/death. Our aim was to determine the effect of Ganoderma lucidum, lycopene, sulforaphane, royal jelly and resveratrol extract on markers of oxidative stress, inflammation, routine laboratory analyses and duration of symptoms in COVID-19 patients. Methods: The oxidative stress parameters and interleukines 6 and 8 (IL-6, IL-8), tumor necrosis factor alpha (TNF-α) were determined in order to estimate the antioxidant and the anti-inflammatory effect of the product using a spectrophotometric and a magnetic bead-based multiplex assay in serum of 30 patients with mild form of COVID-19. Results: Statistically significant differences were obtained for all investigated parameters between the treated patients and the control group. Moreover, significant differences were observed for leukocytes, neutrophil to leukocyte ratio and iron. The average duration of the symptoms was 9.4±0.487 days versus 13.1±0.483 days in the treatment and the control group, respectively (p=0.0003). Conclusion: Our results demonstrated the promising effect of Ge132+NaturalTM on reducing the oxidative stress and the IL-6, IL-8 and TNF-α levels, and symptoms duration in COVID-19 patients. The evidence presented herein suggest that the combination of Ganoderma lucidum extract, lycopene, sulforaphane, royal jelly and resveratrol could be used as a potent an adjuvant therapy in diseases accompanied by increased oxidative stress and inflammation.


Subject(s)
Antioxidants , COVID-19 , Humans , Antioxidants/adverse effects , Resveratrol/therapeutic use , Resveratrol/pharmacology , Lycopene/therapeutic use , Lycopene/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6 , Interleukin-8/pharmacology , Oxidative Stress/physiology , Inflammation/pathology
11.
Annu Rev Immunol ; 41: 277-300, 2023 04 26.
Article in English | MEDLINE | ID: covidwho-2286486

ABSTRACT

Emerging and re-emerging respiratory viral infections pose a tremendous threat to human society, as exemplified by the ongoing COVID-19 pandemic. Upon viral invasion of the respiratory tract, the host initiates coordinated innate and adaptive immune responses to defend against the virus and to promote repair of the damaged tissue. However, dysregulated host immunity can also cause acute morbidity, hamper lung regeneration, and/or lead to chronic tissue sequelae. Here, we review our current knowledge of the immune mechanisms regulating antiviral protection, host pathogenesis, inflammation resolution, and lung regeneration following respiratory viral infections, mainly using influenza virus and SARS-CoV-2 infections as examples. We hope that this review sheds light on future research directions to elucidate the cellular and molecular cross talk regulating host recovery and to pave the way to the development of pro-repair therapeutics to augment lung regeneration following viral injury.


Subject(s)
COVID-19 , Humans , Animals , Immunity, Innate , Pandemics , SARS-CoV-2 , Inflammation/pathology
12.
Can J Physiol Pharmacol ; 101(4): 180-184, 2023 Apr 01.
Article in English | MEDLINE | ID: covidwho-2231083

ABSTRACT

In patients with COVID-19-induced pneumonia, shear wave elasticity (SWE) was used to assess liver stiffness. This study included 48 cases of COVID-19-induced pneumonia and 48 cases of normal physical examination. Basic and clinical data, including aspartate aminotransferase (AST), were evaluated. Color ultrasonography was used to test the liver's SWE. A biopsy of the liver was also performed. In patients with COVID-19-induced pneumonia, AST and alanine aminotransferase (ALT) levels were higher than those in the control group. Liver SWE showed that liver stiffness is hard (8.745 ± 0.2104) compared with the control group (7.386 ± 0.1521) (P < 0.0001). Pathological biopsy showed that liver inflammation accounted for 89.58%, steatosis accounted for 81.25%, necrosis accounted for 10.42%, and fibrosis accounted for 33.33% in patients with COVID-19-induced pneumonia. ROC curve analysis showed that the SWE is highly sensitive and specific for the diagnosis of liver inflammation and steatosis. The sensitivity was 88.76% and the specificity was 77.01% for the evaluation of liver inflammation. For steatosis, the sensitivity was 90.20%, and the specificity was 78.40%. The SWE of liver is useful to assess liver function and pathological status in COVID-19 patients.


Subject(s)
COVID-19 , Elasticity Imaging Techniques , Fatty Liver , Humans , Liver Cirrhosis/pathology , Ultrasonics , COVID-19/diagnostic imaging , COVID-19/pathology , Liver/diagnostic imaging , Liver/pathology , Fatty Liver/pathology , Inflammation/pathology
13.
World J Gastroenterol ; 28(48): 6875-6887, 2022 Dec 28.
Article in English | MEDLINE | ID: covidwho-2234644

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hepatic involvement is common in SARS-CoV-2-infected individuals. It is currently accepted that the direct and indirect hepatic effects of SARS-CoV-2 infection play a significant role in COVID-19. In individuals with pre-existing infectious and non-infectious liver disease, who are at a remarkably higher risk of developing severe COVID-19 and death, this pathology is most medically relevant. This review emphasizes the current pathways regarded as contributing to the gastrointestinal and hepatic ailments linked to COVID-19-infected patients due to an imbalanced interaction among the liver, systemic inflammation, disrupted coagulation, and the lung.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/pathology , Liver/pathology , Inflammation/pathology , Tropism
14.
Microvasc Res ; 147: 104500, 2023 05.
Article in English | MEDLINE | ID: covidwho-2221183

ABSTRACT

INTRODUCTION: We conducted this study to detect possible changes in posterior segment structures using the optical coherence tomography angiography (OCTA) in individuals vaccinated with the Pfizer-BioNTech vaccine. MATERIALS AND METHODS: The study included healthcare professionals who presented to the Ophthalmology Clinic of Health Sciences University Antalya Training and Research Hospital, who were scheduled to receive the first dose of the Pfizer-BioNTech vaccine. The exclusion criteria were any eye pathology (e.g., glaucoma, uveitis, diabetic retinopathy, amblyopia), myopia with the absolute value of refractive error >6, axial length >26 mm, history of eye surgery, and presence of systemic disease.OCTA was performed to 40 healthcare professionals before vaccination and on the third day after vaccination. RESULTS: After Pfizer-BioNTech vaccination, there was a statistically significant decrease in the total vascular, foveal vascular, parafoveal vascular and perifoveal vascular density of the superficial capillary plexus and the perifoveal vascular density of the deep capillary plexus and a statistically significant increase in the retinal foveal thickness and total retinal parafoveal thickness compared to the pre-vaccination values (p < 0.0001, p = 0.009, p < 0.0001, p = 0.001, p = 0.04, p = 0.03, and p = 0.05, respectively). CONCLUSION: We consider that the decrease in the retinal vascular density may be due to vascular endothelial damage and inflammation in vaccinated people. It can be suggested that increased inflammation plays a role in the retinal thickness in vaccinated people similar to patients with a history of COVID-19. We also consider that spike protein may be effective in these processes.


Subject(s)
COVID-19 , Optic Disk , Humans , Retinal Vessels , Inflammation/pathology , Vaccination , Tomography, Optical Coherence/methods , Fluorescein Angiography/methods
15.
Matrix Biol ; 116: 49-66, 2023 02.
Article in English | MEDLINE | ID: covidwho-2221114

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as the cause of a global pandemic. Infection with SARS-CoV-2 can result in COVID-19 with both acute and chronic disease manifestations that continue to impact many patients long after the resolution of viral replication. There is therefore great interest in understanding the host factors that contribute to COVID-19 pathogenesis. In this review, we address the role of hyaluronan (HA), an extracellular matrix polymer with roles in inflammation and cellular metabolism, in COVID-19 and critically evaluate the hypothesis that HA promotes COVID-19 pathogenesis. We first provide a brief overview of COVID-19 infection. Then we briefly summarize the known roles of HA in airway inflammation and immunity. We then address what is known about HA and the pathogenesis of COVID-19 acute respiratory distress syndrome (COVID-19 ARDS). Next, we examine potential roles for HA in post-acute SARS-CoV-2 infection (PASC), also known as "long COVID" as well as in COVID-associated fibrosis. Finally, we discuss the potential therapeutics that target HA as a means to treat COVID-19, including the repurposed drug hymecromone (4-methylumbelliferone). We conclude that HA is a promising potential therapeutic target for the treatment of COVID-19.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Hyaluronic Acid , Inflammation/pathology , Post-Acute COVID-19 Syndrome
16.
Int J Mol Sci ; 23(24)2022 Dec 13.
Article in English | MEDLINE | ID: covidwho-2200321

ABSTRACT

Acute respiratory distress syndrome (ARDS) and sepsis are risk factors contributing to mortality in patients with pneumonia. In ARDS, also termed acute lung injury (ALI), pulmonary immune responses lead to excessive pro-inflammatory cytokine release and aberrant alveolar neutrophil infiltration. Systemic spread of cytokines is associated with systemic complications including sepsis, multi-organ failure, and death. Thus, dampening pro-inflammatory cytokine release is a viable strategy to improve outcome. Activation of cannabinoid type II receptor (CB2) has been shown to reduce cytokine release in various in vivo and in vitro studies. Herein, we investigated the effect of HU-308, a specific CB2 agonist, on systemic and pulmonary inflammation in a model of pneumonia-induced ALI. C57Bl/6 mice received intranasal endotoxin or saline, followed by intravenous HU-308, dexamethasone, or vehicle. ALI was scored by histology and plasma levels of select inflammatory mediators were assessed by Luminex assay. Intravital microscopy (IVM) was performed to assess leukocyte adhesion and capillary perfusion in intestinal and pulmonary microcirculation. HU-308 and dexamethasone attenuated LPS-induced cytokine release and intestinal microcirculatory impairment. HU-308 modestly reduced ALI score, while dexamethasone abolished it. These results suggest administration of HU-308 can reduce systemic inflammation without suppressing pulmonary immune response in pneumonia-induced ALI and systemic inflammation.


Subject(s)
Acute Lung Injury , Cannabinoids , Pneumonia , Respiratory Distress Syndrome , Sepsis , Mice , Animals , Endotoxins/adverse effects , Microcirculation , Pneumonia/drug therapy , Pneumonia/etiology , Pneumonia/pathology , Inflammation/pathology , Lung/pathology , Cannabinoids/adverse effects , Acute Lung Injury/etiology , Acute Lung Injury/chemically induced , Cytokines , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Lipopolysaccharides/toxicity , Dexamethasone/adverse effects , Mice, Inbred C57BL
17.
Acta Neuropathol Commun ; 10(1): 186, 2022 12 17.
Article in English | MEDLINE | ID: covidwho-2196487

ABSTRACT

BACKGROUND: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2. METHODS: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. RESULTS: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient's medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. CONCLUSIONS: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.


Subject(s)
COVID-19 , Encephalitis , Vascular System Injuries , Humans , Male , Female , COVID-19/pathology , SARS-CoV-2 , Autopsy , Critical Illness , Vascular System Injuries/pathology , Brain/pathology , Encephalitis/pathology , Inflammation/pathology , RNA, Viral
18.
PLoS Pathog ; 18(10): e1010734, 2022 10.
Article in English | MEDLINE | ID: covidwho-2154305

ABSTRACT

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS2) affected the geriatric population. Among research models, Golden Syrian hamsters (GSH) are one of the most representative to study SARS2 pathogenesis and host responses. However, animal studies that recapitulate the effects of SARS2 in the human geriatric population are lacking. To address this gap, we inoculated 14 months old GSH with a prototypic ancestral strain of SARS2 and studied the effects on virus pathogenesis, virus shedding, and respiratory and gastrointestinal microbiome changes. SARS2 infection led to high vRNA loads in the nasal turbinates (NT), lungs, and trachea as well as higher pulmonary lesions scores later in infection. Dysbiosis throughout SARS2 disease progression was observed in the pulmonary microbial dynamics with the enrichment of opportunistic pathogens (Haemophilus, Fusobacterium, Streptococcus, Campylobacter, and Johnsonella) and microbes associated with inflammation (Prevotella). Changes in the gut microbial community also reflected an increase in multiple genera previously associated with intestinal inflammation and disease (Helicobacter, Mucispirillum, Streptococcus, unclassified Erysipelotrichaceae, and Spirochaetaceae). Influenza A virus (FLUAV) pre-exposure resulted in slightly more pronounced pathology in the NT and lungs early on (3 dpc), and more notable changes in lungs compared to the gut microbiome dynamics. Similarities among aged GSH and the microbiome in critically ill COVID-19 patients, particularly in the lower respiratory tract, suggest that GSHs are a representative model to investigate microbial changes during SARS2 infection. The relationship between the residential microbiome and other confounding factors, such as SARS2 infection, in a widely used animal model, contributes to a better understanding of the complexities associated with the host responses during viral infections.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , Cricetinae , Animals , Humans , Aged , Infant , SARS-CoV-2 , Mesocricetus , Dysbiosis/pathology , Lung/pathology , Inflammation/pathology
19.
Autoimmun Rev ; 22(2): 103240, 2023 Feb.
Article in English | MEDLINE | ID: covidwho-2149363

ABSTRACT

The overlap between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) including coronary artery aneurysms (CAA) and broadly shared gastrointestinal and mucocutaneous disease is poorly defined. In this perspective, we highlight common age-related extravascular epicardial microanatomical and immunological factors that might culminate in CAA expression in both MIS-C and KD. Specifically, the coronary vasa vasorum originates outside the major coronary arteries. Widespread inflammation in the epicardial interstitial compartment in shared between KD and MIS-C. Age-related changes in the neonatal and immature coronary vasculature including the impact of coronary artery biomechanical factors including coronary vessel calibre, age-related vessel distensibility, flow, and vessel neurovascular innervation may explain the decreasing CAA frequency from neonates to older children and the virtual absence of CAA in young adults with the MIS-C phenotype. Other KD and MIS-C features including mucocutaneous disease with keratinocyte-related immunopathology corroborate that disease phenotypes are centrally influenced by inflammation originating outside vessel walls but a potential role for primary coronary artery vascular wall inflammation cannot be excluded. Hence, common extravascular originating tissue-specific responses to aetiologically diverse triggers including superantigens may lead to widespread interstitial tissue inflammation characteristically manifesting as CAA development, especially in younger subjects. Given that CAA is virtually absent in adults, further studies are needed to ascertain whether epicardial interstitial inflammation may impact on both coronary artery physiology and cardiac conduction tissue and contribute to cardiovascular disease- a hitherto unappreciated consideration.


Subject(s)
Coronary Aneurysm , Mucocutaneous Lymph Node Syndrome , Humans , Mucocutaneous Lymph Node Syndrome/complications , Coronary Vessels/pathology , Coronary Aneurysm/complications , Coronary Aneurysm/pathology , Inflammation/pathology
20.
Int J Mol Sci ; 23(23)2022 Nov 29.
Article in English | MEDLINE | ID: covidwho-2163435

ABSTRACT

Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.


Subject(s)
Pneumonia , Pulmonary Fibrosis , Humans , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/therapy , Pulmonary Fibrosis/metabolism , Prognosis , Lung/pathology , Pneumonia/metabolism , Fibrosis , Inflammation/pathology
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