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Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature.

ABSTRACT: Pulmonary megakaryocytes participate in the pathogenesis of lung damage, particularly in acute lung injury. Although megakaryocytes are not mentioned as a characteristic histologic finding associated to pulmonary injury, a few studies reveal that their number is increased in diffuse alveolar damage (DAD). In this autopsy study, we have observed a relevant number of pulmonary megakaryocytes in COVID-19 patients dying with acute lung injury (7.61 ± 5.59 megakaryocytes per 25 high-power fields vs. 1.14 ± 0.86 for the control group, p < 0.05). We analyzed samples of 18 patients, most of whom died after prolonged disease and use of mechanical ventilation. Most patients showed advanced DAD and abnormal coagulation parameters with high levels of fibrinogen, D-dimers, and variable thrombocytopenia. For comparison, pulmonary samples from a group of 14 non-COVID-19 patients dying with DAD were reviewed. They showed similar pulmonary histopathologic findings and an increase in the number of megakaryocytes (4 ± 4.17 vs. 1.14 ± 0.86 for the control group, p < 0.05). Megakaryocyte count in the COVID-19 group was greater but did not reach statistical significance (7.61 ± 5.59 vs. 4 ± 4.17, p = 0.063). Regardless of the cause, pulmonary megakaryocytes are increased in patients with DAD. Their high number seen in COVID-19 patients suggests a relation with the thrombotic events so often seen these patients. Since the lung is considered an active site of megakaryopoiesis, a prothrombotic status leading to platelet activation, aggregation and consumption may trigger a compensatory pulmonary response.

SUBMITTER: Valdivia-Mazeyra MF

PROVIDER: S-EPMC7483503 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature.

Valdivia-Mazeyra Mariel F MF Salas Clara C Nieves-Alonso Jesús M JM Martín-Fragueiro Luz L Bárcena Carmen C Muñoz-Hernández Patricia P Villar-Zarra Karen K Martín-López Javier J Ramasco-Rueda Fernando F Fraga Javier J Jiménez-Heffernan José A JA

Virchows Archiv : an international journal of pathology 20200911 3

Pulmonary megakaryocytes participate in the pathogenesis of lung damage, particularly in acute lung injury. Although megakaryocytes are not mentioned as a characteristic histologic finding associated to pulmonary injury, a few studies reveal that their number is increased in diffuse alveolar damage (DAD). In this autopsy study, we have observed a relevant number of pulmonary megakaryocytes in COVID-19 patients dying with acute lung injury (7.61 ± 5.59 megakaryocytes per 25 high-power fields vs. ...[more]

PMID: 32915265

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Project description:Free iron in lung can cause the generation of reactive oxygen species, an important factor in chronic obstructive pulmonary disease (COPD) pathogenesis. Iron accumulation has been implicated in oxidative stress in other diseases, such as Alzheimer's and Parkinson's diseases, but little is known about iron accumulation in COPD. We sought to determine if iron content and the expression of iron transport and/or storage genes in lung differ between controls and COPD subjects, and whether changes in these correlate with airway obstruction. Explanted lung tissue was obtained from transplant donors, GOLD 2-3 COPD subjects, and GOLD 4 lung transplant recipients, and bronchoalveolar lavage (BAL) cells were obtained from non-smokers, healthy smokers, and GOLD 1-3 COPD subjects. Iron-positive cells were quantified histologically, and the expression of iron uptake (transferrin and transferrin receptor), storage (ferritin) and export (ferroportin) genes was examined by real-time RT-PCR assay. Percentage of iron-positive cells and expression levels of iron metabolism genes were examined for correlations with airflow limitation indices (forced expiratory volume in the first second (FEV1) and the ratio between FEV1 and forced vital capacity (FEV1/FVC)). The alveolar macrophage was identified as the predominant iron-positive cell type in lung tissues. Furthermore, the quantity of iron deposit and the percentage of iron positive macrophages were increased with COPD and emphysema severity. The mRNA expression of iron uptake and storage genes transferrin and ferritin were significantly increased in GOLD 4 COPD lungs compared to donors (6.9 and 3.22 fold increase, respectively). In BAL cells, the mRNA expression of transferrin, transferrin receptor and ferritin correlated with airway obstruction. These results support activation of an iron sequestration mechanism by alveolar macrophages in COPD, which we postulate is a protective mechanism against iron induced oxidative stress.

Project description:BackgroundLung damage in severe COVID-19 is highly heterogeneous however studies with dedicated spatial distinction of discrete temporal phases of diffuse alveolar damage (DAD) and alternate lung injury patterns are lacking. Existing studies have also not accounted for progressive airspace obliteration in cellularity estimates. We used an imaging mass cytometry (IMC) analysis with an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease.MethodsLung tissue was obtained at post-mortem from severe COVID-19 deaths. Pathologist-selected regions of interest (ROIs) were chosen by light microscopy representing the patho-evolutionary spectrum of DAD and alternate disease phenotypes were selected for comparison. Architecturally normal SARS-CoV-2-positive lung tissue and tissue from SARS-CoV-2-negative donors served as controls. ROIs were stained for 40 cellular protein markers and ablated using IMC before segmented cells were classified. Cell populations corrected by ROI airspace and their spatial relationships were compared across lung injury patterns.FindingsForty patients (32M:8F, age: 22-98), 345 ROIs and >900k single cells were analysed. DAD progression was marked by airspace obliteration and significant increases in mononuclear phagocytes (MnPs), T and B lymphocytes and significant decreases in alveolar epithelial and endothelial cells. Neutrophil populations proved stable overall although several interferon-responding subsets demonstrated expansion. Spatial analysis revealed immune cell interactions occur prior to microscopically appreciable tissue injury.InterpretationThe immunopathogenesis of severe DAD in COVID-19 lung disease is characterised by sustained increases in MnPs and lymphocytes with key interactions occurring even prior to lung injury is established.FundingUK Research and Innovation/Medical Research Council through the UK Coronavirus Immunology Consortium, Barbour Foundation, General Sir John Monash Foundation, Newcastle University, JGW Patterson Foundation, Wellcome Trust.

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Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature.

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Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature.

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