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BACKGROUND: Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID-19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID-19, we examined circulating levels of mediators involved in various aspects of these processes in COVID-19 patients. METHODS: Serial blood samples were obtained from two cohorts of hospitalised COVID-19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3-month follow-up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60-day total mortality and pulmonary pathology after 3-months. We also evaluated the direct effect of inactivated SARS-CoV-2 on the release of the different ECM mediators in relevant cell lines. RESULTS: Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium-binding protein A12 and YKL-40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3-months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS-CoV-2 suggesting a direct link between these mediators and the causal agent of COVID-19. CONCLUSION: Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19.
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COVID-19 , Neumonía , Humanos , COVID-19/metabolismo , Proteína 1 Similar a Quitinasa-3 , SARS-CoV-2 , Matriz ExtracelularRESUMEN
BACKGROUND: Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients. METHODS: Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. RESULTS: A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up. CONCLUSIONS: Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19. CLINICAL TRIALS REGISTRATION: NCT04321616 and NCT04381819.
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COVID-19 , Humanos , Quimiocina CCL19 , Quimiocina CCL21 , Quimiocinas , Inflamación , Gravedad del Paciente , Receptores CCR7 , SARS-CoV-2RESUMEN
BACKGROUND: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. METHODS: Plasma was collected during hospital admission and after 3 months from the NOR-Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene. RESULTS: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low-grade inflammation and respiratory dysfunction after 3 months. CONCLUSION: Respiratory dysfunction after COVID-19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.
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COVID-19 , Microbioma Gastrointestinal , COVID-19/complicaciones , Ensayos Clínicos como Asunto , Humanos , Inflamación , ARN Ribosómico 16S/genética , SARS-CoV-2 , Síndrome Post Agudo de COVID-19RESUMEN
Thromboembolic events are frequent and associated with poor outcome in severe COVID-19 disease. Anti-PF4/polyanion antibodies are related to heparin-induced thrombocytopenia (HIT) and thrombus formation, but data on these antibodies in unselected COVID-19 populations are scarce. We assessed the presence of anti-PF4/polyanion antibodies in prospectively collected serum from an unselected cohort of hospitalized COVID-19 patients and evaluated if elevated levels could give prognostic information on ICU admission and respiratory failure (RF), were associated with markers of inflammation, endothelial activation, platelet activation, coagulation and fibrosis and were associated with long-term pulmonary CT changes. Five out of 65 patients had anti-PF4/polyanion reactivity with OD ≥0.200. These patients had more severe disease as reflected by ICU admission without any evidence of HIT. They also had signs of enhanced inflammation and fibrinogenesis as reflected by elevated ferritin and osteopontin, respectively, during the first 10 days of hospitalization. Increased ferritin and osteopontin persisted in these patients at 3 months follow-up, concomitant with pulmonary CT pathology. Our finding shows that the presence of anti-PF4/polyanion antibodies in unselected hospitalized COVID-19 patients was not related to HIT, but was associated with disease severity, inflammation, and pulmonary pathology after 3 months.
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COVID-19 , Trombocitopenia , Anticoagulantes/efectos adversos , Ferritinas/efectos adversos , Heparina/efectos adversos , Humanos , Inflamación , Osteopontina/efectos adversos , Factor Plaquetario 4 , Índice de Severidad de la Enfermedad , Trombocitopenia/diagnósticoRESUMEN
BACKGROUND: Long-term noninvasive ventilation (NIV) can increase or maintain health-related quality of life (HRQoL) for patients with chronic hypercapnic respiratory failure (CHRF). Evidence from studies systematically assessing how NIV-specific factors influence HRQoL is limited. OBJECTIVES: The objective of this study was to describe HRQoL measured by the Severe Respiratory Insufficiency Questionnaire (SRI) in patients with CHRF treated with long-term NIV and to analyze the associations between HRQoL and hypoxemia, hypercapnia, and respiratory events such as apneas, hypopneas (AHI), and patient ventilator asynchrony (PVA) occurring during long-term NIV. METHODS: We included sixty-seven stable patients with established long-term NIV due to neuromuscular disease or thoracic cage disorders in a prospective cross-sectional study at Oslo University Hospital. Patients answered the SRI and underwent daytime arterial blood gases, nocturnal pulse oximetry, sleep polygraphy, and nocturnal transcutaneous CO2. RESULTS: The mean global SRI for 62 patients was 64.8 ± 14.5, with the highest score in SRI Social Relationships (79.5 ± 15.6). There were no differences in HRQoL between the different patient groups. Compliant patients had a significantly higher score in SRI Attendant and Sleep. Residual nocturnal hypoxemia affected both the subscale SRI "Respiratory Complaints" and SRI "Attendant Symptoms and Sleep." Persisting daytime hypercapnia, nocturnal hypoventilation, and high AHI affected the subscale SRI "Anxiety" negatively, while frequent PVA was associated with a lower score in SRI "Physical Function." CONCLUSION: In a group of patients with long-term NIV, undesired respiratory events during NIV are associated with lower HRQoL in several of the SRI subscales. We suggest designing interventional studies to confirm the possible relationship between HRQoL and respiratory events during long-term NIV.
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Ventilación no Invasiva , Enfermedad Pulmonar Obstructiva Crónica , Insuficiencia Respiratoria , Humanos , Calidad de Vida , Hipercapnia/etiología , Hipercapnia/terapia , Estudios Prospectivos , Estudios Transversales , Hipoventilación/terapia , Hipoxia/complicacionesRESUMEN
The long-term pulmonary outcomes of coronavirus disease 2019 (COVID-19) are unknown. We aimed to describe self-reported dyspnoea, quality of life, pulmonary function and chest computed tomography (CT) findings 3â months following hospital admission for COVID-19. We hypothesised outcomes to be inferior for patients admitted to intensive care units (ICUs), compared with non-ICU patients.Discharged COVID-19 patients from six Norwegian hospitals were enrolled consecutively in a prospective cohort study. The current report describes the first 103 participants, including 15 ICU patients. The modified Medical Research Council (mMRC) dyspnoea scale, the EuroQol Group's questionnaire, spirometry, diffusing capacity of the lung for carbon monoxide (D LCO), 6-min walk test, pulse oximetry and low-dose CT scan were performed 3â months after discharge.mMRC score was >0 in 54% and >1 in 19% of the participants. The median (25th-75th percentile) forced vital capacity and forced expiratory volume in 1â s were 94% (76-121%) and 92% (84-106%) of predicted, respectively. D LCO was below the lower limit of normal in 24% of participants. Ground-glass opacities (GGO) with >10% distribution in at least one of four pulmonary zones were present in 25% of participants, while 19% had parenchymal bands on chest CT. ICU survivors had similar dyspnoea scores and pulmonary function as non-ICU patients, but higher prevalence of GGO (adjusted OR 4.2, 95% CI 1.1-15.6) and lower performance in usual activities.3â months after admission for COVID-19, one-fourth of the participants had chest CT opacities and reduced diffusing capacity. Admission to ICU was associated with pathological CT findings. This was not reflected in increased dyspnoea or impaired lung function.
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COVID-19 , Calidad de Vida , Disnea , Hospitales , Humanos , Pulmón/diagnóstico por imagen , Estudios Prospectivos , SARS-CoV-2 , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Diffuse large B-cell lymphoma is an aggressive non-Hodgkin lymphoma. The patients are often critically ill with a variety of symptoms, but the disease is potentially curable. CASE PRESENTATION: A previously healthy man in his forties was admitted to the local hospital feeling unwell, with dyspnoea, cough, fever and weight loss. The clinical examination was normal. Lactate dehydrogenase and sedimentation rate were elevated. Blood smear and bone marrow biopsy were normal. In the weeks that followed, the patient became critically ill with respiratory failure, exhaustion and continuous fever. Computed tomography (CT) scan revealed diffuse lung infiltrates in addition to hepatosplenomegaly. High levels of ferritin, triglycerides and soluble interleukin-2 receptor were also found. Haemophagocytic lymphohistiocytosis was suspected, and the patient was admitted to the intensive care unit. Biopsies confirmed diffuse large B-cell lymphoma, and treatment was started immediately. INTERPRETATION: The clinical manifestations of lymphoma are diverse. In this case report the suspicion of haemophagocytic lymphohistiocytosis led to a thorough search for a malignant disease, primarily lymphoma. Patients with diffuse large B-cell lymphoma are often critically ill, deteriorating rapidly. Histological verification of the diagnosis and immediate start of treatment are essential for the outcome.
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Linfohistiocitosis Hemofagocítica , Linfoma de Células B Grandes Difuso , Biopsia , Disnea/etiología , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Masculino , Tomografía Computarizada por Rayos XRESUMEN
Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxia-induced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1ß, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC(-/-), and NLRP3(-/-) mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC(-/-) mice was significantly lower than in WT exposed to hypoxia (40.8 ± 1.5 mmHg vs. 55.8 ± 2.4 mmHg, P < 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3(-/-) mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1ß in WT and NLRP3(-/-) mice, this response was absent in ASC(-/-) mice. Moreover, ASC(-/-) mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.
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Proteínas Reguladoras de la Apoptosis/genética , Hipertensión Pulmonar/metabolismo , Inflamasomas/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Arterias/patología , Proteínas Adaptadoras de Señalización CARD , Hipoxia de la Célula , Colágeno/metabolismo , Expresión Génica , Hipertrofia Ventricular Derecha/metabolismo , Interleucina-18/sangre , Leucocitos/inmunología , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/patología , Remodelación VentricularRESUMEN
OBJECTIVES: To investigate changes in chest CT between 3 and 12 months and associations with disease severity in patients hospitalized for COVID-19 during the first wave in 2020. MATERIALS AND METHODS: Longitudinal cohort study of patients hospitalized for COVID-19 in 2020. Chest CT was performed 3 and 12 months after admission. CT images were evaluated using a CT severity score (CSS) (0-12 scale) and recoded to an abbreviated version (0-3 scale). We analyzed determinants of the abbreviated CSS with multivariable mixed effects ordinal regression. RESULTS: 242 patients completed CT at 3 months, and 124 (mean age 62.3±13.3, 78 men) also at 12 months. Between 3 and 12 months (n = 124) CSS (0-12 scale) for ground-glass opacities (GGO) decreased from median 3 (25th-75th percentile: 0-12) at 3 months to 0.5 (0-12) at 12 months (p<0.001), but increased for parenchymal bands (p<0.001). In multivariable analysis of GGO, the odds ratio for more severe abbreviated CSS (0-3 scale) at 12 months was 0.11 (95%CI 0.11 0.05 to 0.21, p<0.001) compared to 3 months, for WHO severity category 5-7 (high-flow oxygen/non-invasive ventilation/ventilator) versus 3 (non-oxygen use) 37.16 (1.18 to 43.47, p = 0.032), and for age ≥60 compared to <60 years 4.8 (1.33 to 17.6, p = 0.016). Mosaicism was reduced at 12 compared to 3 months, OR 0.33 (95%CI 0.16 to 0.66, p = 0.002). CONCLUSIONS: GGO and mosaicism decreased, while parenchymal bands increased from 3 to 12 months. Persistent GGO were associated with initial COVID-19 severity and age ≥60 years.
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COVID-19 , Hospitalización , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Humanos , COVID-19/diagnóstico por imagen , COVID-19/epidemiología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Estudios Prospectivos , SARS-CoV-2/aislamiento & purificación , Estudios Longitudinales , Pulmón/diagnóstico por imagen , Pulmón/patologíaRESUMEN
Inflammation through activation of caspase-1, seems to play a role in pulmonary hypertension induced by alveolar hypoxia. Whether alveolar hypoxia induces caspase-1-mediated inflammation and influx of leukocytes in other organs than the lungs, is not known. Our aim was to explore sites of caspase-1-related inflammation in alveolar hypoxia. Wild type (WT) mice were exposed to environmental hypoxia or room-air, and organs were analyzed. Right heart catheterization was performed after 14 days of alveolar hypoxia in WT mice and mice transplanted with WT or caspase-1-/- bone marrow. Hypoxia induced leukocyte accumulation and increased caspase-1 protein in the lungs, not in other organs. WT mice transplanted with WT or caspase-1-/- bone marrow showed no difference in pulmonary leukocyte accumulation or development of pulmonary hypertension after alveolar hypoxia. Caspase-1 and IL-18 were detected in bronchial epithelium in WT mice, and hypoxia induced IL-18 secretion from bronchial epithelial cells. IL-18 stimulation generated IL-6 mRNA in monocytes. Phosphorylated STAT3 was increased in hypoxic lungs, not in other organs. Alveolar hypoxia induces caspase-1 activation and leukocyte accumulation specific to the lungs, not in other organs. Caspase-1 activation and IL-18 secretion from bronchial epithelial cells might initiate hypoxia-induced inflammation, leading to pulmonary hypertension.
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Caspasa 1 , Hipoxia , Inflamasomas , Interleucina-18 , Pulmón , Ratones Endogámicos C57BL , Animales , Masculino , Inflamasomas/metabolismo , Ratones , Caspasa 1/metabolismo , Caspasa 1/genética , Pulmón/metabolismo , Pulmón/patología , Interleucina-18/metabolismo , Interleucina-18/genética , Hipoxia/metabolismo , Inflamación/metabolismo , Inflamación/patología , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Ratones Noqueados , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patologíaRESUMEN
Background: Several studies have examined parameters of increased thrombogenicity in COVID-19, but studies examining their association with long-term outcome and potential effects of antiviral agents in hospitalized patients with COVID-19 are scarce. Objectives: To evaluate plasma levels of hemostatic proteins during hospitalization in relation to disease severity, treatment modalities, and persistent pulmonary pathology after 3 months. Methods: In 165 patients with COVID-19 recruited into the NOR-Solidarity trial (NCT04321616) and randomized to treatment with hydroxychloroquine, remdesivir, or standard of care, we analyzed plasma levels of hemostatic proteins during the first 10 days of hospitalization (n = 160) and at 3 months of follow-up (n = 100) by enzyme immunoassay. Results: Our main findings were as follows: (i) tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) were increased in patients with severe disease (ie, the combined endpoint of respiratory failure [Po2-to-FiO2 ratio, <26.6 kPa] or need for treatment at an intensive care unit) during hospitalization. Compared to patients without severe disease, tPA levels were a median of 42% (P < .001), 29% (P = .002), and 36% (P = .015) higher at baseline, 3 to 5 days, and 7 to 10 days, respectively. For TFPI, median levels were 37% (P = .003), 25% (P < .001), and 10% (P = .13) higher in patients with severe disease at these time points, respectively. No changes in thrombin-antithrombin complex; alpha 2-antiplasmin; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; or antithrombin were observed in relation to severe disease. (ii) Patients treated with remdesivir had lower levels of TFPI than those in patients treated with standard of care alone. (iii) TFPI levels during hospitalization, but not at 3 months of follow-up, were higher in those with persistent pathology on chest computed tomography imaging 3 months after hospital admission than in those without such pathology. No consistent changes in thrombin-antithrombin complex, alpha 2-antiplasmin, ADAMTS-13, tPA, or antithrombin were observed in relation to pulmonary pathology at 3 months of follow-up. Conclusion: TFPI and tPA are associated with severe disease in hospitalized patients with COVID-19. For TFPI, high levels measured during the first 10 days of hospitalization were also associated with persistent pulmonary pathology even 3 months after hospital admittance.
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COVID-19 primarily affects the respiratory system. We aimed to evaluate how pulmonary outcomes develop after COVID-19 by assessing participants from the first pandemic wave prospectively 3 and 12â months following hospital discharge. Pulmonary outcomes included self-reported dyspnoea assessed with the modified Medical Research Council dyspnoea scale, 6-min walk distance (6MWD), spirometry, diffusing capacity of the lung for carbon monoxide (D LCO), body plethysmography and chest computed tomography (CT). Chest CT was repeated at 12â months in participants with pathological findings at 3â months. The World Health Organization (WHO) ordinal scale for clinical improvement defined disease severity in the acute phase. Of 262 included COVID-19 patients, 245 (94%) and 222 (90%) participants attended the 3- and 12-month follow-up, respectively. Self-reported dyspnoea and 6MWD remained unchanged between the two time points, while D LCO and total lung capacity improved (0.28â mmol·min-1·kPa-1, 95% CI 0.12-0.44, and 0.13â L, 95% CI 0.02-0.24, respectively). The prevalence of fibrotic-like findings on chest CT at 3 and 12â months in those with follow-up chest CT was unaltered. Those with more severe disease had worse dyspnoea, D LCO and total lung capacity values than those with mild disease. There was an overall positive development of pulmonary outcomes from 3 to 12â months after hospital discharge. The discrepancy between the unaltered prevalence of self-reported dyspnoea and the improvement in pulmonary function underscores the complexity of dyspnoea as a prominent factor of long-COVID. The lack of increase in fibrotic-like findings from 3 to 12â months suggests that SARS-CoV-2 does not induce a progressive fibrotic process in the lungs.
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Interleukin (IL)-18 is a pro-inflammatory cytokine suggested to be involved in the development of pulmonary emphysema and inflammation. Studies involving immunology and cancer have revealed that IL-18 can have synergistic effects with IL-12. We have studied the presence of IL-18 and IL-12 receptors (IL-18R/IL-12R) in the lungs and whether IL-18 and IL-12, alone or in combination, have the ability to initiate the induction of mediators related to the development of emphysema and inflammation. The expression of the IL-18R was abundant in lungs compared to other organs (heart, liver, and spleen), and the IL-12R was also expressed in lung tissue. Mice treated with i.p. injection of recombinant murine IL-18 or IL-12 expressed significantly higher pulmonary mRNA levels of the matrix degrading enzymes metalloproteinase (MMP) 12 and cathepsin S, in addition to interferon-γ, tumor necrosis factor-α, and CXC chemokine ligand 9 (CXCL9) (all P < .05) than controls (received PBS). Treatment with IL-18 and IL-12 in combination showed an even more pronounced induction of these mediators, as well as a significant increase in MMP-9, IL-6, IL-1ß, and transforming growth factor-ß (P < .05). Furthermore, cellular apoptosis in lung tissue was induced. Immunohistochemical analysis revealed T-cell infiltration in pulmonary vessels following co-stimulation. In summary, IL-18 and IL-12 exert a synergistic effect on the lungs by inducing MMPs, cathepsins S, and pro-inflammatory cytokines, which may promote pulmonary emphysema and inflammation. The synergy between IL-18 and IL-12 involves infiltration of T-cells in the lungs, possibly induced by the T-cell chemoattractant CXCL9.
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Catepsinas/biosíntesis , Interleucina-12/farmacología , Interleucina-18/farmacología , Pulmón/efectos de los fármacos , Metaloproteinasa 12 de la Matriz/biosíntesis , Animales , Apoptosis/efectos de los fármacos , Catepsinas/genética , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Metaloproteinasa 12 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Receptores de Interleucina-12/metabolismo , Receptores de Interleucina-18/metabolismo , Proteínas Recombinantes/farmacología , Linfocitos T/metabolismo , Linfocitos T/patología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: The lungs are the organ most likely to sustain serious injury from coronavirus disease 2019 (COVID-19). However, the mechanisms for long-term complications are not clear. Patients with severe COVID-19 have shorter telomere lengths and higher levels of cellular senescence, and we hypothesized that circulating levels of the telomere-associated senescence markers chitotriosidase, ß-galactosidase, cathelicidin antimicrobial peptide and stathmin 1 (STMN1) were elevated in hospitalized COVID-19 patients compared to controls and could be associated with pulmonary sequelae following hospitalization. METHODS: Ninety-seven hospitalized patients with COVID-19 who underwent assessment for pulmonary sequelae at three-month follow-up were included in the study. ß-Galactosidase and chitotriosidase were analysed by fluorescence; stathmin 1 and cathelicidin antimicrobial peptide were analysed by enzyme immuno-assay in plasma samples from the acute phase and after three-months. In addition, the classical senescence markers cyclin-dependent kinase inhibitor 1A and 2A were analysed by enzyme immuno-assay in peripheral blood mononuclear cell lysate after three months. RESULTS: We found elevated plasma levels of the senescence markers chitotriosidase and stathmin 1 in patients three months after hospitalization with COVID-19, and these markers in addition to protein levels of cyclin-dependent kinase inhibitor 2A in cell lysate, were associated with pulmonary pathology. The elevated levels of these markers seem to reflect both age-dependent (chitotriosidase) and age-independent (stathmin 1, cyclin-dependent kinase inhibitor 2A) processes. CONCLUSIONS: We suggest that accelerated ageing or senescence could be important for long-term pulmonary complications of COVID-19, and our findings may be relevant for future research exploring the pathophysiology and management of these patients.
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COVID-19 , Humanos , COVID-19/complicaciones , Estatmina , Leucocitos Mononucleares/metabolismo , Senescencia Celular/fisiología , beta-Galactosidasa/metabolismo , Biomarcadores , Progresión de la Enfermedad , Quinasas Ciclina-DependientesRESUMEN
The chemokine receptor CCR7 regulates lymphocyte trafficking, and CCR7 deficiency induces infiltration of T and B cells adjacent to vessels in mouse lungs. Perivascular infiltration of T and B cells has also been found in human pulmonary arterial hypertension, and downregulation of the CCR7 receptor in circulating leukocytes of such patients has been observed. To investigate whether changes in the CCR7 system contribute to the pathogenesis of pulmonary hypertension, we utilized mice deficient of the CCR7 receptor. The cardiopulmonary and inflammatory responses of CCR7 depletion were evaluated in CCR7-deficient and wild-type mice. Measurements of cytokines upregulated in the animal model were also performed in patients with pulmonary hypertension and controls and in vascular smooth muscle cells. We found that mice lacking CCR7 had increased right ventricular systolic pressure, reduced pulmonary artery acceleration time, increased right ventricular/tibial length ratio, Rho kinase-mediated pulmonary vasoconstriction, and increased muscularization of distal arteries, indicating pulmonary hypertension. These mice also showed increased perivascular infiltration of leukocytes, consisting mainly of T and B cells, and increased mRNA levels of the inflammatory cytokines interleukin-12 and CX3CL1 within pulmonary tissue. Increased serum levels of interleukin-12 and CX3CL1 were also observed in patients with pulmonary hypertension, particularly in those with pulmonary hypertension associated with connective tissue disorder. In smooth muscle cells, interleukin-12 induced secretion of the angiogenic cytokine interleukin-8. We conclude that these results suggest a role for CCR7 in the development of pulmonary arterial hypertension, at least in some subgroups, possibly via pulmonary infiltration of lymphocytes and secretion of interleukin-12 and CX3CL1.
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Movimiento Celular , Leucocitos/patología , Neumonía/complicaciones , Neumonía/patología , Receptores CCR7/deficiencia , Adulto , Animales , Quimiocina CX3CL1/sangre , Hipertensión Pulmonar Primaria Familiar , Femenino , Regulación de la Expresión Génica , Hemodinámica , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Interleucina-12/sangre , Interleucina-8/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Tamaño de los Órganos , Neumonía/sangre , Neumonía/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CCR7/metabolismoRESUMEN
PURPOSE: To evaluate the ability of a novel ultrasound (US) device, DiaMon, to monitor diaphragm movement via its proxy liver movement, and compare it with the respired flow measured with a flowmeter, in awake and healthy volunteers. We wanted to (1) establish the optimal anatomical position for attaching the DiaMon device to the abdominal wall, and (2) evaluate the accuracy of continuous monitoring of respiratory frequency. METHODS: Thirty healthy subjects were recruited. The DiaMon probe was applied subcostally in four different positions with the subjects in five different postures. The subjects breathed tidal volumes into a spirometer for 30-60 s with the DiaMon recording simultaneously. RESULTS: The device detected a readable signal in 83-100% of the position/posture-combinations. The technical correlation between the two signals was highest in the anterior axillary-supine position (mean ± SD: 0.95 ± 0.03), followed by paramidline-supine (0.90 ± 0.09) and midclavicular-supine (0.89 ± 0.12). The frequency measurements yielded a mean difference of 0.03 (95% limits of agreement - 0.11, 0.16) breaths per minute in the anterior axillary-supine position. CONCLUSION: The DiaMon device is able to detect liver movement in most subjects, and it measures breathing frequency accurately.
Asunto(s)
Diafragma , Adulto , Anciano , Diafragma/diagnóstico por imagen , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Movimiento , Postura , Respiración , Adulto JovenRESUMEN
The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.