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1.
PLoS One ; 16(11): e0259822, 2021.
Article in English | MEDLINE | ID: covidwho-1706372

ABSTRACT

BACKGROUND: Clinical outcomes among COVID-19 patients vary greatly with age and underlying comorbidities. We aimed to determine the demographic and clinical factors, particularly baseline chronic conditions, associated with an increased risk of severity in COVID-19 patients from a population-based perspective and using data from electronic health records (EHR). METHODS: Retrospective, observational study in an open cohort analyzing all 68,913 individuals (mean age 44.4 years, 53.2% women) with SARS-CoV-2 infection between 15 June and 19 December 2020 using exhaustive electronic health registries. Patients were followed for 30 days from inclusion or until the date of death within that period. We performed multivariate logistic regression to analyze the association between each chronic disease and severe infection, based on hospitalization and all-cause mortality. RESULTS: 5885 (8.5%) individuals showed severe infection and old age was the most influencing factor. Congestive heart failure (odds ratio -OR- men: 1.28, OR women: 1.39), diabetes (1.37, 1.24), chronic renal failure (1.31, 1.22) and obesity (1.21, 1.26) increased the likelihood of severe infection in both sexes. Chronic skin ulcers (1.32), acute cerebrovascular disease (1.34), chronic obstructive pulmonary disease (1.21), urinary incontinence (1.17) and neoplasms (1.26) in men, and infertility (1.87), obstructive sleep apnea (1.43), hepatic steatosis (1.43), rheumatoid arthritis (1.39) and menstrual disorders (1.18) in women were also associated with more severe outcomes. CONCLUSIONS: Age and specific cardiovascular and metabolic diseases increased the risk of severe SARS-CoV-2 infections in men and women, whereas the effects of certain comorbidities are sex specific. Future studies in different settings are encouraged to analyze which profiles of chronic patients are at higher risk of poor prognosis and should therefore be the targets of prevention and shielding strategies.


Subject(s)
COVID-19/epidemiology , Chronic Disease/mortality , Pulmonary Disease, Chronic Obstructive/epidemiology , SARS-CoV-2/pathogenicity , Adult , Aged , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Cohort Studies , Comorbidity , Female , Hospitalization/statistics & numerical data , Humans , Logistic Models , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/pathology , Risk Factors , Spain/epidemiology
2.
BMC Pulm Med ; 21(1): 371, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1526622

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a kind of chronic lung diseases with the characteristics of airway remodeling and airflow obstruction. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating hepatitis. However, whether MgIG can treat other diseases and its action mechanism is still obscure. In this study, we evaluated the anti-inflammatory effect of MgIG in rats with COPD and investigated the underlying mechanisms. METHODS: Rat model of COPD was constructed by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction. Rats were randomly divided into 5 groups: control group, COPD model group, salmeterol fluticasone comparator group, low dose of MgIG group, and high dose of MgIG group. Except for normal control group, the other four groups received sensitization treatment by cigarette smoking and endotracheal-atomization of endotoxin lipopolysaccharide to construct COPD rats model. After model established successfully, the COPD rats in each group received corresponding dose of endotracheal-atomized normal saline, salmeterol fluticasone, and MgIG every day prior to exposure of cigarette smoke from days 30 to 45. Normal control group were treated with normal saline. Finally, All rats were euthanatized. Pulmonary function was measured. Cells in bronchoalveolar lavage fluid were classified, inflammatory factors IL-6 and TNF-α were determined, histopathological analysis was performed by HE staining, and expression of NLRP3 and cleaved caspase-1 in the lung tissue was also determined by Western blotting. RESULTS: It showed that MgIG treatment (0.40 or 0.80 mg/kg/day) could recover the weight and the clinical symptoms of rats with COPD, accompanied with lung inflammation infiltration reduction, airway wall attenuation, bronchial mucus secretion reduction. Additionally, MgIG administration reduced inflammatory cells (white blood cells, neutrophils, lymphocytes and monocytes) accumulation in bronchoalveolar lavage fluid and decreased IL-6 and TNF-α production in the serum of COPD rats. Furthermore, MgIG treatment also reduced the expression level of NLRP3 and cleaved caspase-1. CONCLUSION: It indicate that MgIG might be an alternative for COPD treatment, and its mechanism of action might be related to the suppression of NLRP3 inflammasome.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Saponins/pharmacology , Triterpenes/pharmacology , Animals , China , Inflammation/prevention & control , Lung/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein , Pulmonary Disease, Chronic Obstructive/pathology , Rats , Rats, Wistar , Smoking
3.
PLoS One ; 16(11): e0259822, 2021.
Article in English | MEDLINE | ID: covidwho-1511833

ABSTRACT

BACKGROUND: Clinical outcomes among COVID-19 patients vary greatly with age and underlying comorbidities. We aimed to determine the demographic and clinical factors, particularly baseline chronic conditions, associated with an increased risk of severity in COVID-19 patients from a population-based perspective and using data from electronic health records (EHR). METHODS: Retrospective, observational study in an open cohort analyzing all 68,913 individuals (mean age 44.4 years, 53.2% women) with SARS-CoV-2 infection between 15 June and 19 December 2020 using exhaustive electronic health registries. Patients were followed for 30 days from inclusion or until the date of death within that period. We performed multivariate logistic regression to analyze the association between each chronic disease and severe infection, based on hospitalization and all-cause mortality. RESULTS: 5885 (8.5%) individuals showed severe infection and old age was the most influencing factor. Congestive heart failure (odds ratio -OR- men: 1.28, OR women: 1.39), diabetes (1.37, 1.24), chronic renal failure (1.31, 1.22) and obesity (1.21, 1.26) increased the likelihood of severe infection in both sexes. Chronic skin ulcers (1.32), acute cerebrovascular disease (1.34), chronic obstructive pulmonary disease (1.21), urinary incontinence (1.17) and neoplasms (1.26) in men, and infertility (1.87), obstructive sleep apnea (1.43), hepatic steatosis (1.43), rheumatoid arthritis (1.39) and menstrual disorders (1.18) in women were also associated with more severe outcomes. CONCLUSIONS: Age and specific cardiovascular and metabolic diseases increased the risk of severe SARS-CoV-2 infections in men and women, whereas the effects of certain comorbidities are sex specific. Future studies in different settings are encouraged to analyze which profiles of chronic patients are at higher risk of poor prognosis and should therefore be the targets of prevention and shielding strategies.


Subject(s)
COVID-19/epidemiology , Chronic Disease/mortality , Pulmonary Disease, Chronic Obstructive/epidemiology , SARS-CoV-2/pathogenicity , Adult , Aged , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Cohort Studies , Comorbidity , Female , Hospitalization/statistics & numerical data , Humans , Logistic Models , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/pathology , Risk Factors , Spain/epidemiology
4.
PLoS One ; 16(10): e0258154, 2021.
Article in English | MEDLINE | ID: covidwho-1450731

ABSTRACT

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) has infected 1.9% of the world population by May 2, 2021. Since most previous studies that examined risk factors for mortality and severity were based on hospitalized individuals, population-based cohort studies are called for to provide evidence that can be extrapolated to the general population. Therefore, we aimed to examine the associations of comorbidities with mortality and disease severity in individuals with COVID-19 diagnosed in 2020 in Ontario, Canada. METHODS AND FINDINGS: We conducted a retrospective cohort study of all individuals with COVID-19 in Ontario, Canada diagnosed between January 15 and December 31, 2020. Cases were linked to health administrative databases maintained in the ICES which covers all residents in Ontario. The primary outcome is all-cause 30-day mortality after the first COVID-19 diagnosis, and the secondary outcome is a composite severity index containing death and hospitalization. To examine the risk factors for the outcomes, we employed Cox proportional hazards regression models and logistic regression models to adjust for demographic, socio-economic variables and comorbidities. Results were also stratified by age groups. A total of 167,500 individuals were diagnosed of COVID-19 in 2020 and included in the study. About half (43.8%, n = 73,378) had at least one comorbidity. The median follow-up period were 30 days. The most common comorbidities were hypertension (24%, n = 40,154), asthma (16%, n = 26,814), and diabetes (14.7%, n = 24,662). Individuals with comorbidity had higher risk of mortality compared to those without (HR = 2.80, 95%CI 2.35-3.34; p<0.001), and the risk substantially was elevated from 2.14 (95%CI 1.76-2.60) to 4.81 (95%CI 3.95-5.85) times as the number of comorbidities increased from one to five or more. Significant predictors for mortality included comorbidities such as solid organ transplant (HR = 3.06, 95%CI 2.03-4.63; p<0.001), dementia (HR = 1.46, 95%CI 1.35-1.58; p<0.001), chronic kidney disease (HR = 1.45, 95%CI 1.34-1.57; p<0.001), severe mental illness (HR = 1.42, 95%CI%, 1.12-1.80; p<0.001), cardiovascular disease (CVD) (HR = 1.22, 95%CI, 1.15-1.30), diabetes (HR = 1.19, 95%, 1.12-1.26; p<0.001), chronic obstructive pulmonary disease (COPD) (HR = 1.19, 95%CI 1.12-1.26; p<0.001), cancer (HR = 1.17, 95%CI, 1.09-1.27; p<0.001), hypertension (HR = 1.16, 95%CI, 1.07-1.26; p<0.001). Compared to their effect in older age groups, comorbidities were associated with higher risk of mortality and severity in individuals under 50 years old. Individuals with five or more comorbidities in the below 50 years age group had 395.44 (95%CI, 57.93-2699.44, p<0.001) times higher risk of mortality compared to those without. Limitations include that data were collected during 2020 when the new variants of concern were not predominant, and that the ICES databases do not contain detailed individual-level socioeconomic and racial variables. CONCLUSION: We found that solid organ transplant, dementia, chronic kidney disease, severe mental illness, CVD, hypertension, COPD, cancer, diabetes, rheumatoid arthritis, HIV, and asthma were associated with mortality or severity. Our study highlights that the number of comorbidities was a strong risk factor for deaths and severe outcomes among younger individuals with COVID-19. Our findings suggest that in addition of prioritizing by age, vaccination priority groups should also include younger population with multiple comorbidities.


Subject(s)
COVID-19/mortality , Comorbidity , Severity of Illness Index , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19/pathology , COVID-19/virology , Canada/epidemiology , Cardiovascular Diseases/pathology , Cohort Studies , Female , Humans , Male , Middle Aged , Proportional Hazards Models , Pulmonary Disease, Chronic Obstructive/pathology , Renal Insufficiency, Chronic/pathology , Risk Factors , SARS-CoV-2/isolation & purification , Survival Analysis
5.
Molecules ; 26(17)2021 Sep 02.
Article in English | MEDLINE | ID: covidwho-1390702

ABSTRACT

Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase "super substrates" that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.


Subject(s)
Immunity, Innate , Leukocyte Elastase/metabolism , Methionine/analogs & derivatives , Neutrophils/immunology , Biocatalysis , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Catalytic Domain/genetics , Enzyme Assays , Host-Pathogen Interactions/immunology , Humans , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/genetics , Lung/immunology , Lung/pathology , Lung/virology , Methionine/metabolism , Molecular Dynamics Simulation , Neutrophil Infiltration , Neutrophils/enzymology , Oxidation-Reduction/drug effects , Proteolysis/drug effects , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/immunology , Substrate Specificity/immunology
6.
Eur J Med Chem ; 225: 113818, 2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1385491

ABSTRACT

Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.


Subject(s)
Anti-Inflammatory Agents/chemistry , Cathepsin C/antagonists & inhibitors , Drug Discovery , Protease Inhibitors/chemistry , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cathepsin C/genetics , Cathepsin C/metabolism , Humans , Papillon-Lefevre Disease/genetics , Papillon-Lefevre Disease/pathology , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism
7.
BMC Pulm Med ; 21(1): 278, 2021 Aug 31.
Article in English | MEDLINE | ID: covidwho-1381257

ABSTRACT

BACKGROUND: There are various reasons for delayed positive nasopharyngeal PCR tests for coronavirus disease 2019 (COVID19) in not only asymptomatic but also severely diseased patients. The pathophysiological attributes are not known. We explore this possibility through a case report. CASE PRESENTATION: A 64-year-old male with history of pulmonary fungal infection, asthma and chronic pulmonary obstructive disease (COPD), diabetes, coronary artery disease presented with shortness of breath, fever and chest image of ground opacity, reticular interstitial thickening, highly suspicious for COVID19. However, nasopharyngeal swab tests were discordantly negative for four times in two weeks, and IgG antibody for COVID19 was also negative. However, serum IgE level was elevated. No other pathogens are identified. His symptoms deteriorated despite corticosteroid, antibiotics and bronchodilator treatment. Bronchoalveolar lavage (BAL) and open lung wedge biopsy were performed for etiology diagnosis. They demonstrated COVID19 viral RNA positive fibrosing organizing pneumonia with respiratory tract damage characterized by suspicious viral cytopathic effect, mixed neutrophilic, lymphoplasmacytic, histiocytic and eosinophilic inflammation and fibrosis besides expected asthma and COPD change. One week later, repeated COVID19 nasopharyngeal tests on day 40 and day 49 became positive. CONCLUSION: Our case and literature review indicate that allergic asthma and associated high IgE level together with corticosteroid inhalation might contribute to the delayed positive nasopharyngeal swab in upper airway; COPD related chronic airways obstruction and the addition of fibrosis induced ventilator dependence and poor prognosis in COVID19 pneumonia, and should be therapeutically targeted besides antiviral therapy.


Subject(s)
COVID-19 Nucleic Acid Testing , COVID-19/diagnosis , Delayed Diagnosis , Nasopharynx/virology , SARS-CoV-2/isolation & purification , Administration, Inhalation , Adrenal Cortex Hormones/therapeutic use , Asthma/complications , Asthma/drug therapy , Asthma/pathology , Bronchoalveolar Lavage , COVID-19/complications , COVID-19/therapy , Fatal Outcome , Humans , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/pathology , Reverse Transcriptase Polymerase Chain Reaction
8.
Int J Mol Sci ; 22(17)2021 Aug 24.
Article in English | MEDLINE | ID: covidwho-1374422

ABSTRACT

The lungs play a very important role in the human respiratory system. However, many factors can destroy the structure of the lung, causing several lung diseases and, often, serious damage to people's health. Nerve growth factor (NGF) is a polypeptide which is widely expressed in lung tissues. Under different microenvironments, NGF participates in the occurrence and development of lung diseases by changing protein expression levels and mediating cell function. In this review, we summarize the functions of NGF as well as some potential underlying mechanisms in pulmonary fibrosis (PF), coronavirus disease 2019 (COVID-19), pulmonary hypertension (PH), asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Furthermore, we highlight that anti-NGF may be used in future therapeutic strategies.


Subject(s)
Airway Remodeling/drug effects , Lung/pathology , Nerve Growth Factor/antagonists & inhibitors , Signal Transduction/drug effects , Asthma/drug therapy , Asthma/pathology , COVID-19/drug therapy , COVID-19/pathology , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/pathology , Lung/drug effects , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Molecular Targeted Therapy/methods , Nerve Growth Factor/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology
9.
PLoS One ; 16(8): e0255659, 2021.
Article in English | MEDLINE | ID: covidwho-1339417

ABSTRACT

BACKGROUND: Reports have suggested a reduction in exacerbations of chronic obstructive pulmonary disease (COPD) during the coronavirus disease 2019 (COVID-19) pandemic, particularly hospital admissions for severe exacerbations. However, the magnitude of this reduction varies between studies. METHOD: Electronic databases were searched from January 2020 to May 2021. Two independent reviewers screened titles and abstracts and, when necessary, full text to determine if studies met inclusion criteria. A modified version of the Newcastle-Ottawa Scale was used to assess study quality. A narrative summary of eligible studies was synthesised, and meta-analysis was conducted using a random effect model to pool the rate ratio and 95% confidence intervals (95% CI) for hospital admissions. Exacerbation reduction was compared against the COVID-19 Containment and Health Index. RESULTS: A total of 13 of 745 studies met the inclusion criteria and were included in this review, with data from nine countries. Nine studies could be included in the meta-analysis. The pooled rate ratio of hospital admissions for COPD exacerbations during the pandemic period was 0.50 (95% CI 0.44-0.57). Findings on the rate of community-treated exacerbations were inconclusive. Three studies reported a significant decrease in the incidence of respiratory viral infections compared with the pre-pandemic period. There was not a significant relationship between exacerbation reduction and the COVID-19 Containment and Health Index (rho = 0.20, p = 0.53). CONCLUSION: There was a 50% reduction in admissions for COPD exacerbations during the COVID-19 pandemic period compared to pre-pandemic times, likely associated with a reduction in respiratory viral infections that trigger exacerbations. Future guidelines should consider including recommendations on respiratory virus infection control measures to reduce the burden of COPD exacerbations beyond the pandemic period.


Subject(s)
COVID-19/epidemiology , Hospitalization/statistics & numerical data , Pulmonary Disease, Chronic Obstructive/pathology , COVID-19/pathology , COVID-19/virology , Databases, Factual , Humans , Pandemics , SARS-CoV-2/isolation & purification
10.
Int J Mol Sci ; 22(14)2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1323266

ABSTRACT

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and causes remodeling of the small airways. However, the exact smoke-induced effects on the different types of small airway epithelial cells (SAECs) are poorly understood. Here, using air-liquid interface (ALI) cultures, single-cell RNA-sequencing reveals previously unrecognized transcriptional heterogeneity within the small airway epithelium and cell type-specific effects upon acute and chronic cigarette smoke exposure. Smoke triggers detoxification and inflammatory responses and aberrantly activates and alters basal cell differentiation. This results in an increase of inflammatory basal-to-secretory cell intermediates and, particularly after chronic smoke exposure, a massive expansion of a rare inflammatory and squamous metaplasia associated KRT6A+ basal cell state and an altered secretory cell landscape. ALI cultures originating from healthy non-smokers and COPD smokers show similar responses to cigarette smoke exposure, although an increased pro-inflammatory profile is conserved in the latter. Taken together, the in vitro models provide high-resolution insights into the smoke-induced remodeling of the small airways resembling the pathological processes in COPD airways. The data may also help to better understand other lung diseases including COVID-19, as the data reflect the smoke-dependent variable induction of SARS-CoV-2 entry factors across SAEC populations.


Subject(s)
Airway Remodeling/drug effects , Alveolar Epithelial Cells/drug effects , Cigarette Smoking/adverse effects , Epithelial Cells/metabolism , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Cell Differentiation/drug effects , Cells, Cultured , Cigarette Smoking/metabolism , Epithelial Cells/drug effects , Humans , Neoplasms, Basal Cell/metabolism , Primary Cell Culture , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Smoke , Smoking/adverse effects , Smoking/metabolism
11.
STAR Protoc ; 2(3): 100663, 2021 09 17.
Article in English | MEDLINE | ID: covidwho-1275773

ABSTRACT

Patients with chronic lung disease are vulnerable to getting severe diseases associated with SARS-CoV-2 infection. Here, we describe protocols for subculturing and differentiating primary normal human bronchial epithelial (NHBE) cells of patients with chronic obstructive lung disease. The differentiation of NHBE cells in air-liquid interface mimics an in vivo airway and provides an in vitro model for studying SARS-CoV-2 infection. We also describe a protocol for detecting proteins in the sectioned epithelium for detailing SARS-CoV-2 infection-induced pathobiology with a vertical view.


Subject(s)
Bronchi/metabolism , COVID-19/complications , Coronavirus Nucleocapsid Proteins/analysis , Epithelium/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/isolation & purification , Bronchi/pathology , Bronchi/virology , COVID-19/metabolism , COVID-19/virology , Coronavirus Nucleocapsid Proteins/metabolism , Epithelium/pathology , Epithelium/virology , Humans , Immunohistochemistry , Paraffin Embedding , Phosphoproteins/analysis , Phosphoproteins/metabolism , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/virology , Virus Replication
12.
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
13.
Cells ; 10(4)2021 04 14.
Article in English | MEDLINE | ID: covidwho-1186898

ABSTRACT

Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases.


Subject(s)
Acute Lung Injury/pathology , COVID-19/pathology , Macrophages/pathology , Pneumonia/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Respiratory Distress Syndrome/pathology , Acute Lung Injury/immunology , Animals , Asthma/immunology , Asthma/pathology , COVID-19/immunology , Chronic Disease , Humans , Idiopathic Pulmonary Fibrosis/immunology , Idiopathic Pulmonary Fibrosis/pathology , Lung/immunology , Lung/pathology , Macrophages/immunology , Pneumonia/immunology , Pulmonary Disease, Chronic Obstructive/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology
14.
Am J Physiol Lung Cell Mol Physiol ; 320(1): L152-L157, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1054733

ABSTRACT

The COVID-19 pandemic is associated with severe pneumonia and acute respiratory distress syndrome leading to death in susceptible individuals. For those who recover, post-COVID-19 complications may include development of pulmonary fibrosis. Factors contributing to disease severity or development of complications are not known. Using computational analysis with experimental data, we report that idiopathic pulmonary fibrosis (IPF)- and chronic obstructive pulmonary disease (COPD)-derived lung fibroblasts express higher levels of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 entry and part of the renin-angiotensin system that is antifibrotic and anti-inflammatory. In preclinical models, we found that chronic exposure to cigarette smoke, a risk factor for both COPD and IPF and potentially for SARS-CoV-2 infection, significantly increased pulmonary ACE2 protein expression. Further studies are needed to understand the functional implications of ACE2 on lung fibroblasts, a cell type that thus far has received relatively little attention in the context of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/pathology , Fibroblasts/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Adult , Animals , Female , Gene Expression Regulation/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Receptors, Virus/biosynthesis , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/metabolism , Smoke/adverse effects
15.
Biofactors ; 47(1): 6-18, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-950385

ABSTRACT

Specialized proresolving mediators (SPMs) are endogenous lipid metabolites of long-chain polyunsaturated fatty acids that are involved in promoting the resolution of inflammation. Many disease conditions characterized by excessive inflammation have impaired or altered SPM biosynthesis, which may lead to chronic, unresolved inflammation. Exogenous administration of SPMs in infectious conditions has been shown to be effective at improving infection clearance and survival in preclinical models. SPMs have also shown tremendous promise in the context of inflammatory lung conditions, such as acute respiratory distress syndrome and chronic obstructive pulmonary disease, mostly in preclinical settings. To date, SPMs have not been studied in the context of the novel Coronavirus, severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), however their preclinical efficacy in combatting infections and improving acute respiratory distress suggest they may be a valuable resource in the fight against Coronavirus disease-19 (COVID-19). Overall, while the research on SPMs is still evolving, they may offer a novel therapeutic option for inflammatory conditions.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Docosahexaenoic Acids/therapeutic use , Lipoxins/therapeutic use , Lung Injury/drug therapy , Pulmonary Disease, Chronic Obstructive/drug therapy , Respiratory Distress Syndrome/drug therapy , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Herpes Simplex/drug therapy , Herpes Simplex/metabolism , Herpes Simplex/pathology , Humans , Influenza, Human/drug therapy , Influenza, Human/metabolism , Influenza, Human/pathology , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/virology , Periodontitis/drug therapy , Periodontitis/metabolism , Periodontitis/pathology , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Disease, Chronic Obstructive/virology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Sepsis/drug therapy , Sepsis/metabolism , Sepsis/pathology , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/metabolism , Tuberculosis, Pulmonary/pathology
16.
Am J Physiol Lung Cell Mol Physiol ; 320(1): L158-L163, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-919085

ABSTRACT

Lungs of smokers and chronic obstructive pulmonary disease (COPD) are severely compromised and are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attack. The dangerous combination of enhanced SARS-CoV-2 attachment receptor protein ACE2 along with an increase in endocytic vacuoles will enable viral attachment, entry, and replication. The objective of the study was to identify the presence of SARS-CoV-2 host attachment receptor angiotensin-converting enzyme-2 (ACE2) along with endocytic vacuoles, early endosome antigen-1 (EEA1), late endosome marker RAB7, cathepsin-L, and lysosomal associated membrane protein-1 (LAMP-1) as lysosome markers in the airways of smokers and COPD patients. The study design was cross-sectional and involved lung resections from 39 patients in total, which included 19 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I or GOLD stage II COPD, of which 9 were current smokers with COPD (COPD-CS) and 10 were ex-smokers with COPD (COPD-ES), 10 were normal lung function smokers, and 10 were never-smoking normal controls. Immunostaining for ACE2, EEA1, RAB7, and cathepsin-L was done. A comparative description for ACE2, EEA1, RAB7, and cathepsin-L expression pattern is provided for the patient groups. Furthermore, staining intensity for LAMP-1 lysosomes was measured as the ratio of the LAMP-1-stained areas per total area of epithelium or subepithelium, using Image ProPlus v7.0 software. LAMP-1 expression showed a positive correlation to patient smoking history while in COPD LAMP-1 negatively correlated to lung function. The active presence of ACE2 protein along with endocytic vacuoles such as early/late endosomes and lysosomes in the small airways of smokers and COPD patients provides evidence that these patient groups could be more susceptible to COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Smoking/pathology , Transport Vesicles/metabolism , Cathepsin L/metabolism , Cross-Sectional Studies , Disease Susceptibility , Humans , Lung/pathology , Lysosome-Associated Membrane Glycoproteins/metabolism , SARS-CoV-2 , Smokers , Vesicular Transport Proteins/metabolism , rab GTP-Binding Proteins/metabolism
18.
Diabetes Res Clin Pract ; 169: 108454, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-778739

ABSTRACT

AIMS: To evaluate whether subjects with diabetes hospitalized for Coronavirus disease-19 (Covid-19) represent a subgroup of patients with high-risk clinical features compared to patients with diabetes without Covid-19. METHODS: In this case-control study 79 patients with type 2 diabetes out of 354 adults hospitalized for Covid-19 and 158 controls with type 2 diabetes but without Covid-19, matched for age and gender, were enrolled. Medical history and concomitant therapies were retrieved from medical charts and compared between cases and controls, controlling for confounders. RESULTS: Fully-adjusted multivariate logistic regression model showed that previous CVD history did not differ between patients with and without Covid-19 (odds ratio 1.40, 95% confidence interval [CI]: 0.59-3.32, p = 0.45). A higher prevalence of chronic obstructive pulmonary disease (COPD) (OR 3.72, 95%CI: 1.42-9.72, p = 0.007) and of chronic kidney disease (CKD) (OR 3.08, 95%CI: 1.18-8.06, p = 0.022) and a lower prevalence of ever smokers (OR 0.30, 95%CI: 0.13-0.67, p = 0.003), of users of lipid lowering agents (OR 0.26, 95%CI: 0.12-0.54, p < 0.001), and of anti-hypertensive drugs (OR 0.39, 95%CI: 0.16-0.93, p = 0.033) were found among cases. CONCLUSIONS: CVD prevalence does not differ between people with diabetes with and without Covid-19 requiring hospitalization. An increased prevalence of COPD and of CKD in Covid-19 patients with type 2 diabetes is suggested. These findings aid to clarify the relationship between underlying conditions and SARS-CoV-2 infection in the high-risk group of patients with diabetes.


Subject(s)
COVID-19/complications , Diabetes Mellitus, Type 2/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Renal Insufficiency, Chronic/pathology , SARS-CoV-2/isolation & purification , Aged , Aged, 80 and over , COVID-19/transmission , COVID-19/virology , Case-Control Studies , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/virology , Female , Hospitalization , Humans , Incidence , Italy/epidemiology , Male , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/virology , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/virology
19.
Cytokine Growth Factor Rev ; 54: 32-42, 2020 08.
Article in English | MEDLINE | ID: covidwho-694176

ABSTRACT

The seventh human coronavirus SARS-CoV2 belongs to the cluster of extremely pathogenic coronaviruses including SARS-CoV and MERS-CoV, which can cause fatal lower respiratory tract infection. Likewise, SARS-CoV2 infection can be fatal as the disease advances to pneumonia, followed by acute respiratory distress syndrome (ARDS). The development of lethal clinical symptons is associated with an exaggerated production of inflammatory cytokines, referred to as the cytokine storm, is a consequence of a hyperactivated immune response aginst the infection. In this article, we discuss the pathogenic consequences of the cytokine storm and its relationship with COVID-19 associated risk factors. The increased pro-inflammatory immune status in patients with risk factors (diabetes, hypertension, cardiovascular disease, COPD) exacerbates the Cytokine-storm of COVID-19 into a 'Cytokine Super Cyclone'. We also evaluate the antiviral immune responses provided by BCG vaccination and the potential role of 'trained immunity' in early protection against SARS-CoV2.


Subject(s)
BCG Vaccine/therapeutic use , Coronavirus Infections/prevention & control , Cytokine Release Syndrome/prevention & control , Cytokines/blood , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Antiviral Agents/therapeutic use , Betacoronavirus/immunology , COVID-19 , Cardiovascular Diseases/pathology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Diabetes Mellitus/pathology , Humans , Hypertension/pathology , Middle East Respiratory Syndrome Coronavirus/immunology , Mycobacterium bovis/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pulmonary Disease, Chronic Obstructive/pathology , Risk Factors , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Vaccination
20.
Diabetes Obes Metab ; 22(10): 1915-1924, 2020 10.
Article in English | MEDLINE | ID: covidwho-657128

ABSTRACT

AIM: To estimate the prevalence of both cardiometabolic and other co-morbidities in patients with COVID-19, and to estimate the increased risk of severity of disease and mortality in people with co-morbidities. MATERIALS AND METHODS: Medline, Scopus and the World Health Organization website were searched for global research on COVID-19 conducted from January 2019 up to 23 April 2020. Study inclusion was restricted to English language publications, original articles that reported the prevalence of co-morbidities in individuals with COVID-19, and case series including more than 10 patients. Eighteen studies were selected for inclusion. Data were analysed using random effects meta-analysis models. RESULTS: Eighteen studies with a total of 14 558 individuals were identified. The pooled prevalence for co-morbidities in patients with COVID-19 disease was 22.9% (95% CI: 15.8 to 29.9) for hypertension, 11.5% (9.7 to 13.4) for diabetes, and 9.7% (6.8 to 12.6) for cardiovascular disease (CVD). For chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), cerebrovascular disease and cancer, the pooled prevalences were all less than 4%. With the exception of cerebrovascular disease, all the other co-morbidities presented a significantly increased risk for having severe COVID-19. In addition, the risk of mortality was significantly increased in individuals with CVD, COPD, CKD, cerebrovascular disease and cancer. CONCLUSIONS: In individuals with COVID-19, the presence of co-morbidities (both cardiometabolic and other) is associated with a higher risk of severe COVID-19 and mortality. These findings have important implications for public health with regard to risk stratification and future planning.


Subject(s)
COVID-19/epidemiology , COVID-19/pathology , COVID-19/complications , COVID-19/mortality , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Cardiovascular Diseases/pathology , Comorbidity , Diabetes Complications/mortality , Diabetes Mellitus/epidemiology , Diabetes Mellitus/mortality , Diabetes Mellitus/pathology , Humans , Hypertension/complications , Hypertension/epidemiology , Hypertension/mortality , Mortality , Neoplasms/complications , Neoplasms/epidemiology , Neoplasms/mortality , Pandemics , Prevalence , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/mortality , Pulmonary Disease, Chronic Obstructive/pathology , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/mortality , Risk Factors , SARS-CoV-2/physiology , Severity of Illness Index
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