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1.
Int J Mol Sci ; 23(1)2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1580700

ABSTRACT

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.


Subject(s)
COVID-19/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Actins/metabolism , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Caveolin 1/metabolism , Collagen Type I/metabolism , Collagen Type III/metabolism , Female , Humans , Hyaluronan Receptors/metabolism , Immunohistochemistry , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , Influenza, Human/pathology , Interleukin-4/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Middle Aged , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Retrospective Studies , Transforming Growth Factor beta1/metabolism
2.
Pan Afr Med J ; 40: 169, 2021.
Article in English | MEDLINE | ID: covidwho-1566818

ABSTRACT

Twenty months into the COVID-19 pandemic, we are still learning about the various long-term consequences of COVID-19 infection. While many patients do recover with minimal long-term consequences, some patients develop irreversible parenchymal and interstitial lung damage leading to diffuse pulmonary fibrosis. Unfortunately, these are some of the consequences of post-SARS-CoV-2 infection which thousands more people around the world will experience and which will outlast the pandemic for a long time to come. It is now being observed at various leading medical centres around the world that lung transplantation may be the only meaningful treatment available to a select group of patients experiencing serious lung damage and non-resolving COVID-19-associated respiratory failure, resulting from the triad of coronavirus infection, a hyper-inflammatory immune response to it and the inability of the human body to repair that injury.


Subject(s)
COVID-19 , Lung Transplantation , Pulmonary Fibrosis , Humans , Incidence , Lung/pathology , Pandemics , Pulmonary Fibrosis/epidemiology , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , SARS-CoV-2
3.
Lancet Respir Med ; 9(5): 487-497, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537196

ABSTRACT

BACKGROUND: Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications. METHODS: We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres-including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes-were collected by Northwestern University (Chicago, IL, USA) and analysed. FINDINGS: Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41-51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19. INTERPRETATION: The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients. FUNDING: National Institutes of Health. VIDEO ABSTRACT.


Subject(s)
COVID-19 , Critical Illness/therapy , Lung Transplantation/methods , Lung , Respiratory Distress Syndrome , Blood Transfusion/methods , COVID-19/complications , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/surgery , Critical Care/methods , Extracorporeal Membrane Oxygenation/methods , Female , Humans , Intraoperative Care/methods , Lung/diagnostic imaging , Lung/pathology , Male , Middle Aged , Outcome and Process Assessment, Health Care , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , Respiration, Artificial/methods , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/surgery , SARS-CoV-2/pathogenicity
4.
Front Immunol ; 12: 735922, 2021.
Article in English | MEDLINE | ID: covidwho-1477823

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Lung Injury/pathology , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Epithelial Cells/pathology , Female , Hemorrhage/pathology , Humans , Inflammation/pathology , Lung/pathology , Lung Injury/virology , Lymphopenia/pathology , Macrophage Activation/immunology , Macrophages/immunology , Male , Middle Aged , Myocytes, Smooth Muscle/pathology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/pathology
5.
Front Immunol ; 12: 687397, 2021.
Article in English | MEDLINE | ID: covidwho-1477818

ABSTRACT

Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.


Subject(s)
COVID-19/pathology , Phosphoric Diester Hydrolases/metabolism , Pulmonary Fibrosis/pathology , Respiratory Distress Syndrome/pathology , Anti-Inflammatory Agents/therapeutic use , COVID-19/blood , Dexamethasone/therapeutic use , Humans , Lung/pathology , Lysophospholipids/metabolism , Phosphoric Diester Hydrolases/blood , Pulmonary Fibrosis/blood , Respiratory Distress Syndrome/blood , SARS-CoV-2 , Signal Transduction/immunology
6.
Sci Rep ; 11(1): 19979, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462032

ABSTRACT

COVID-19 pandemic led to a worldwide increase of hospitalizations for interstitial pneumonia with thrombosis complications, endothelial injury and multiorgan disease. Common CT findings include lung bilateral infiltrates, bilateral ground-glass opacities and/or consolidation whilst no current laboratory parameter consents rapidly evaluation of COVID-19 risk and disease severity. In the present work we investigated the association of sFLT-1 and CA 15.3 with endothelial damage and pulmonary fibrosis. Serum sFlt-1 has been associated with endothelial injury and sepsis severity, CA 15.3 seems an alternative marker for KL-6 for fibrotic lung diseases and pulmonary interstitial damage. We analysed 262 SARS-CoV-2 patients with differing levels of clinical severity; we found an association of serum sFlt-1 (ROC AUC 0.902, decision threshold > 90.3 pg/mL, p < 0.001 Sens. 83.9% and Spec. 86.7%) with presence, extent and severity of the disease. Moreover, CA 15.3 appeared significantly increased in COVID-19 severe lung fibrosis (ICU vs NON-ICU patients 42.6 ± 3.3 vs 25.7 ± 1.5 U/mL, p < 0.0001) and was associated with lung damage severity grade (ROC AUC 0.958, decision threshold > 24.8 U/mL, p < 0.0001, Sens. 88.4% and Spec. 91.8%). In conclusion, serum levels of sFlt-1 and CA 15.3 appeared useful tools for categorizing COVID-19 clinical stage and may represent a valid aid for clinicians to better personalise treatment.


Subject(s)
COVID-19/blood , Mucin-1/blood , Pulmonary Fibrosis/blood , Vascular Endothelial Growth Factor Receptor-1/blood , Aged , Biomarkers/blood , COVID-19/complications , COVID-19/pathology , Female , Humans , Lung Diseases, Interstitial/blood , Lung Diseases, Interstitial/complications , Lung Diseases, Interstitial/pathology , Male , Middle Aged , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/pathology , SARS-CoV-2/isolation & purification
7.
Adv Respir Med ; 89(5): 477-483, 2021.
Article in English | MEDLINE | ID: covidwho-1456468

ABSTRACT

INTRODUCTION: COVID-19-associated pulmonary sequalae have been increasingly reported after recovery from acute infection. Therefore, we aim to explore the charactersitics of persistent lung parenchymal abnormalities in patients with COVID-19. MATERIAL AND METHODS: An observational study was conducted in patients with post-COVID lung parenchymal abnormalities from April till September 2020. Patients ≥18 years of age with COVID-19 who were diagnosed as post-COVID lung parenchymal abnormality based on respiratory symptoms and HRCT chest imaging after the recovery of acute infection. Data was recorded on a structured pro forma, and descriptive analysis was performed using Stata version 12.1. RESULTS: A total of 30 patients with post-COVID lung parenchymal abnormalities were identified. The mean age of patients was 59.1 (SD 12.6), and 27 (90.0%) were males. Four HRCT patterns of lung parenchymal abnormalities were seen; organizing pneumonia in 10 (33.3%), nonspecific interstitial pneumonitis in 17 (56.7%), usual interstitial pneumonitis in 12 (40.0%) and probable usual interstitial pneumonitis in 14 (46.7%). Diffuse involvement was found in 15 (50.0%) patients, while peripheral predominance in 15 (50.0%), and other significant findings were seen in 8 (26.7%) patients. All individuals were treated with corticosteroids. The case fatality rate was 16.7%. Amongst the survivors, 32.0% recovered completely, 36.0% improved, while 32.0% of the patients had static or progressive disease. CONCLUSION: This is the first study from Southeast Asia that identified post-COVID lung parenchymal abnormalities in patients who had no pre-existing lung disease highlighting the importance of timely recognition and treatment of this entity that might lead to fatal outcome.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/pathology , Pulmonary Fibrosis/diagnostic imaging , Pulmonary Fibrosis/pathology , Adult , COVID-19/complications , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Discharge , SARS-CoV-2/isolation & purification , Tomography, X-Ray Computed
8.
J Ethnopharmacol ; 283: 114701, 2022 Jan 30.
Article in English | MEDLINE | ID: covidwho-1446835

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Xuanfei Baidu Decoction (XFBD), one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, plays an important role in the treatment of mild and/or common patients with dampness-toxin obstructing lung syndrome. AIM OF THE STUDY: The present work aims to elucidate the protective effects and the possible mechanism of XFBD against the acute inflammation and pulmonary fibrosis. METHODS: We use TGF-ß1 induced fibroblast activation model and LPS/IL-4 induced macrophage inflammation model as in vitro cell models. The mice model of lung fibrosis was induced by BLM via endotracheal drip, and then XFBD (4.6 g/kg, 9.2 g/kg) were administered orally respectively. The efficacy and molecular mechanisms in the presence or absence of XFBD were investigated. RESULTS: The results proved that XFBD can effectively inhibit fibroblast collagen deposition, down-regulate the level of α-SMA and inhibit the migration of fibroblasts. IL-4 induced macrophage polarization was also inhibited and the secretions of the inflammatory factors including IL6, iNOS were down-regulated. In vivo experiments, the results proved that XFBD improved the weight loss and survival rate of the mice. The XFBD high-dose administration group had a significant effect in inhibiting collagen deposition and the expression of α-SMA in the lungs of mice. XFBD can reduce bleomycin-induced pulmonary fibrosis by inhibiting IL-6/STAT3 activation and related macrophage infiltration. CONCLUSIONS: Xuanfei Baidu Decoction protects against macrophages induced inflammation and pulmonary fibrosis via inhibiting IL-6/STAT3 signaling pathway.


Subject(s)
COVID-19/drug therapy , Drugs, Chinese Herbal , Inflammation/drug therapy , Macrophages/drug effects , SARS-CoV-2 , Signal Transduction/drug effects , Animals , Cell Survival/drug effects , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Fibroblasts/drug effects , Gene Expression Regulation/drug effects , Gene Regulatory Networks , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Male , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Phytotherapy , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/prevention & control , RAW 264.7 Cells , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism
9.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1442406

ABSTRACT

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Base Sequence , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interferon-alpha/blood , Pulmonary Fibrosis/pathology , RNA-Seq , Severity of Illness Index , Transcriptome/genetics , United Kingdom , United States
10.
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
11.
Am J Pathol ; 191(7): 1193-1208, 2021 07.
Article in English | MEDLINE | ID: covidwho-1283899

ABSTRACT

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-ß1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors , Furin/metabolism , Lung/drug effects , Pulmonary Fibrosis/drug therapy , Animals , Bleomycin , Cells, Cultured , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , Lung/metabolism , Lung/pathology , Male , Mice , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Treatment Outcome
12.
Am J Pathol ; 191(7): 1193-1208, 2021 07.
Article in English | MEDLINE | ID: covidwho-1242859

ABSTRACT

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-ß1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors , Furin/metabolism , Lung/drug effects , Pulmonary Fibrosis/drug therapy , Animals , Bleomycin , Cells, Cultured , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , Lung/metabolism , Lung/pathology , Male , Mice , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Treatment Outcome
13.
Immunol Rev ; 302(1): 228-240, 2021 07.
Article in English | MEDLINE | ID: covidwho-1241009

ABSTRACT

The COVID-19 pandemic rapidly spread around the world following the first reports in Wuhan City, China in late 2019. The disease, caused by the novel SARS-CoV-2 virus, is primarily a respiratory condition that can affect numerous other bodily systems including the cardiovascular and gastrointestinal systems. The disease ranges in severity from asymptomatic through to severe acute respiratory distress requiring intensive care treatment and mechanical ventilation, which can lead to respiratory failure and death. It has rapidly become evident that COVID-19 patients can develop features of interstitial pulmonary fibrosis, which in many cases persist for as long as we have thus far been able to follow the patients. Many questions remain about how such fibrotic changes occur within the lung of COVID-19 patients, whether the changes will persist long term or are capable of resolving, and whether post-COVID-19 pulmonary fibrosis has the potential to become progressive, as in other fibrotic lung diseases. This review brings together our existing knowledge on both COVID-19 and pulmonary fibrosis, with a particular focus on lung epithelial cells and fibroblasts, in order to discuss common pathways and processes that may be implicated as we try to answer these important questions in the months and years to come.


Subject(s)
COVID-19/pathology , Epithelial Cells/pathology , Fibroblasts/pathology , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/virology , Respiratory Mucosa/pathology , COVID-19/complications , Humans , SARS-CoV-2
14.
Expert Rev Respir Med ; 15(6): 791-803, 2021 06.
Article in English | MEDLINE | ID: covidwho-1203511

ABSTRACT

Introduction: Coronavirus disease 2019 (COVID-19) is still increasing worldwide, and as a result, the number of patients with pulmonary fibrosis secondary to COVID-19 will expand over time. Risk factors, histopathological characterization, pathophysiology, prevalence, and management of post-COVID-19 pulmonary fibrosis are poorly understood, and few studies have addressed these issues.Areas covered:This article reviews the current evidence regarding post-COVID-19 pulmonary fibrosis, with an emphasis on the potential risk factors, histopathology, pathophysiology, functional and tomographic features, and potential therapeutic modalities. A search on the issue was performed in the MEDLINE, Embase, and SciELO databases and the Cochrane library between 1 December 2019, and 25 January 2021. Studies were reviewed and relevant topics were incorporated into this narrative review. Expert opinion: Pulmonary sequelae may occur secondary to COVID-19, which needs to be included as a potential etiology in the current differential diagnosis of pulmonary fibrosis. Therefore, serial clinical, tomographic, and functional screening for pulmonary fibrosis is recommended after COVID-19, mainly in patients with pulmonary involvement in the acute phase of the disease. Further studies are necessary to determine the risk factors, markers, pathophysiology, and appropriate management of post-COVID-19 pulmonary fibrosis.


Subject(s)
COVID-19/complications , Pulmonary Fibrosis/etiology , COVID-19/diagnosis , COVID-19/pathology , COVID-19/therapy , Databases, Factual , Diagnosis, Differential , Disease Progression , Humans , Lung/pathology , Lung/virology , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/therapy , Risk Factors , SARS-CoV-2/physiology , Severity of Illness Index , Tomography, X-Ray Computed/methods
16.
J Med Virol ; 93(3): 1378-1386, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196511

ABSTRACT

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- ß, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- ß signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.


Subject(s)
COVID-19/complications , Indoles/therapeutic use , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/etiology , Pyridones/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19/metabolism , COVID-19/pathology , Humans , Lung/pathology , Patient Discharge , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Severity of Illness Index , Signal Transduction
17.
Front Immunol ; 12: 636118, 2021.
Article in English | MEDLINE | ID: covidwho-1190312

ABSTRACT

Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/virology , Immunologic Memory , Lung/immunology , Lung/virology , SARS-CoV-2/immunology , Age Factors , Animals , Biomarkers , CD8-Positive T-Lymphocytes/metabolism , COVID-19/metabolism , COVID-19/pathology , Disease Resistance/immunology , Homeostasis , Host-Pathogen Interactions/immunology , Humans , Immunophenotyping , Lung/metabolism , Lung/pathology , Lymphocyte Count , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
18.
Cell Transplant ; 30: 963689721996217, 2021.
Article in English | MEDLINE | ID: covidwho-1181030

ABSTRACT

COVID-19 has spread worldwide, including the United States, United Kingdom, and Italy, along with its site of origin in China, since 2020. The virus was first found in the Wuhan seafood market at the end of 2019, with a controversial source. The clinical symptoms of COVID-19 include fever, cough, and respiratory tract inflammation, with some severe patients developing an acute and chronic lung injury, such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). It has already claimed approximately 300 thousand human lives and the number is still on the rise; the only way to prevent the infection is to be safe till vaccines and reliable treatments develop. In previous studies, the use of mesenchymal stem cells (MSCs) in clinical trials had been proven to be effective in immune modulation and tissue repair promotion; however, their efficacy in treating COVID-19 remains underestimated. Here, we report the findings from past experiences of SARS and MSCs, and how SARS could also induce PF. Such studies may help to understand the rationale for the recent cell-based therapies for COVID-19.


Subject(s)
COVID-19/complications , Mesenchymal Stem Cell Transplantation , Pulmonary Fibrosis/etiology , Animals , COVID-19/blood , COVID-19/pathology , COVID-19/therapy , Coronavirus/isolation & purification , Humans , Mesenchymal Stem Cell Transplantation/methods , Pulmonary Fibrosis/blood , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/therapy , Renin-Angiotensin System , SARS-CoV-2/isolation & purification , Severe Acute Respiratory Syndrome/blood , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/therapy , Transforming Growth Factor beta/blood
19.
J Biomech Eng ; 143(8)2021 08 01.
Article in English | MEDLINE | ID: covidwho-1169857

ABSTRACT

Diffuse alveolar damage (DAD) is a characteristic histopathologic pattern in most cases of acute respiratory distress syndrome and severe viral pneumonia, such as COVID-19. DAD is characterized by an acute phase with edema, hyaline membranes, and inflammation followed by an organizing phase with pulmonary fibrosis and hyperplasia. The degree of pulmonary fibrosis and surface tension is different in the pathological stages of DAD. The effects of pulmonary fibrosis and surface tension on alveolar sac mechanics in DAD are investigated by using the fluid-structure interaction (FSI) method. The human pulmonary alveolus is idealized by a three-dimensional honeycomb-like geometry, with alveolar geometries approximated as closely packed 14-sided polygons. A dynamic compression-relaxation model for surface tension effects is adopted. Compared to a healthy model, DAD models are created by increasing the tissue thickness and decreasing the concentration of the surfactant. The FSI results show that pulmonary fibrosis is more influential than the surface tension on flow rate, volume, P-V loop, and resistance. The lungs of the disease models become stiffer than those of the healthy models. According to the P-V loop results, the surface tension plays a more important role in hysteresis than the material nonlinearity of the lung tissue. Our study demonstrates the differences in air flow and lung function on the alveolar sacs between the healthy and DAD models.


Subject(s)
Mechanical Phenomena , Models, Biological , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/pathology , Biomechanical Phenomena , Diffusion , Humans , Surface Tension
20.
J Gene Med ; 23(3): e3318, 2021 03.
Article in English | MEDLINE | ID: covidwho-1084739

ABSTRACT

Pulmonary fibrosis is characterized by progressive and irreversible scarring in the lungs with poor prognosis and treatment. It is caused by various factors, including environmental and occupational exposures, and some rheumatic immune diseases. Even the rapid global spread of the COVID-19 pandemic can also cause pulmonary fibrosis with a high probability. Functions attributed to long non-coding RNAs (lncRNAs) make them highly attractive diagnostic and therapeutic targets in fibroproliferative diseases. Therefore, an understanding of the specific mechanisms by which lncRNAs regulate pulmonary fibrotic pathogenesis is urgently needed to identify new possibilities for therapy. In this review, we focus on the molecular mechanisms and implications of lncRNAs targeted protein-coding and non-coding genes during pulmonary fibrogenesis, and systematically analyze the communication of lncRNAs with various types of RNAs, including microRNA, circular RNA and mRNA. Finally, we propose the potential approach of lncRNA-based diagnosis and therapy for pulmonary fibrosis. We hope that understanding these interactions between protein-coding and non-coding genes will contribute to the development of lncRNA-based clinical applications for pulmonary fibrosis.


Subject(s)
Genetic Markers/genetics , Pulmonary Fibrosis/genetics , RNA, Long Noncoding/genetics , Gene Expression Regulation , Genetic Therapy/methods , Humans , MicroRNAs/genetics , Proteins/genetics , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/therapy , RNA, Circular/genetics
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