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1.
Pathol Res Pract ; 225: 153552, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1440296

ABSTRACT

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by severe vascular remodelling, resulting in increased pulmonary vascular resistance with cardiac hypertrophy and heart failure. However, the diagnosis of PAH is often inaccurate. Many cases of PAH are incorrectly diagnosed or missed, and they are often associated with death. The aim of this study was to verify the morphological and histological criteria of fatal cases of PAH and evaluate the lymphocytic populations associated to lesions with reactive neo-angiogenesis. METHODS: Pulmonary lung sections from 10 cases of sudden unexpected death (SUD) in the absence of previously diagnosed diseases and in an apparent state of well-being, with final histological post autopsy diagnosis of PAH were collected. The pathological findings were compared using ten controls from non-pathological lung from deaths from other causes. The autopsies included 4 males (40%) and 6 females (60%) with an average age of 52.1 ± 10.1 years. Sections stained with hematoxylin and eosin (H&E) were revised for a morphological diagnosis. Subsequently, serial sections were performed and stained with immunohistochemistry for anti-CD20 (B-lymphocytes), anti-CD3 (T-lymphocytes), anti-CD4 (T-helper lumphocytes), anti-CD8 (T-cytotoxic lymphocytes) and anti-CD117/C-Kit (mast cells/MCs) to detect inflammatory infiltrate and different ratios of cell-type. Statistical analysis was conducted using a paired t-test looking at 100 cells in 3 different tissue samples representative of vascular lesion and 3 different random normal lung parenchyma fields without lesion (from 10 normal control lungs), to identify specific lymphocyte subpopulations in inflammatory infiltrates. RESULTS: There was a significant percentage increase of CD20 (p < 0.001), CD8 (p = 0.002), CD4 (p < 0.001), and CD117/C-Kit positive (C-Kit+; p < 0.001) cells mainly detected around wall vessels; while increased MCs positivity and C-Kit+ were observed especially in alveolar septa. In addition, reactive angiomatosis was observed. CONCLUSIONS: The inflammatory infiltrate should be included for a correct diagnosis of PAH besides the vascular remodelling. The inflammatory infiltrate seems to be implicated as a main factor in the pathogenesis. This finding is important to rule out secondary pulmonary hypertension, to identify SUDs of unknown causes and to add new elements to the literature that can explain the immunologically related pathogenesis of PAH.


Subject(s)
B-Lymphocytes/pathology , Lung/pathology , Mast Cells/pathology , Pulmonary Arterial Hypertension/pathology , T-Lymphocytes/pathology , Adult , Autopsy , Female , Humans , Male , Middle Aged
2.
Clin Exp Allergy ; 52(2): 324-333, 2022 02.
Article in English | MEDLINE | ID: covidwho-1437986

ABSTRACT

BACKGROUND: Deaths attributed to Coronavirus Disease 2019 (COVID-19) are mainly due to severe hypoxemic respiratory failure. Although the inflammatory storm has been considered the main pathogenesis of severe COVID-19, hypersensitivity may be another important mechanism involved in severe cases, which have a perfect response to corticosteroids (CS). METHOD: We detected the serum level of anti-SARS-CoV-2-spike S1 protein-specific IgE (SP-IgE) and anti-SARS-CoV-2 nucleocapsid protein-specific IgE (NP-IgE) in COVID-19. Correlation of levels of specific IgE and clinical severity were analysed. Pulmonary function test and bronchial provocation test were conducted in early convalescence of COVID-19. We also obtained histological samples via endoscopy to detect the evidence of mast cell activation. RESULT: The levels of serum SP-IgE and NP-IgE were significantly higher in severe cases, and were correlated with the total lung severity scores (TLSS) and the PaO2 /FiO2 ratio. Nucleocapsid protein could be detected in both airway and intestinal tissues, which was stained positive together with activated mast cells, binded with IgE. Airway hyperresponsiveness (AHR) exists in the early convalescence of COVID-19. After the application of CS in severe COVID-19, SP-IgE and NP-IgE decreased, but maintained at a high level. CONCLUSION: Hypersensitivity may be involved in severe COVID-19.


Subject(s)
Bronchi/immunology , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , Duodenum/immunology , Hypersensitivity/immunology , Immunoglobulin E/immunology , Mast Cells/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Bronchi/metabolism , Bronchi/pathology , COVID-19/metabolism , COVID-19/pathology , COVID-19/physiopathology , Case-Control Studies , Coronavirus Nucleocapsid Proteins/metabolism , Duodenum/metabolism , Duodenum/pathology , Female , Humans , Hypersensitivity/metabolism , Hypersensitivity/pathology , Hypersensitivity/physiopathology , Lung/physiopathology , Male , Mast Cells/metabolism , Mast Cells/pathology , Middle Aged , Mucous Membrane/immunology , Mucous Membrane/metabolism , Mucous Membrane/pathology , Phosphoproteins/immunology , Phosphoproteins/metabolism , Recovery of Function , Respiratory Hypersensitivity/physiopathology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Spike Glycoprotein, Coronavirus/metabolism , Young Adult
3.
J Leukoc Biol ; 110(3): 425-431, 2021 09.
Article in English | MEDLINE | ID: covidwho-1375609

ABSTRACT

The immune response plays a critical role in the pathophysiology of SARS-CoV-2 infection ranging from protection to tissue damage and all occur in the development of acute respiratory distress syndrome (ARDS). ARDS patients display elevated levels of inflammatory cytokines and innate immune cells, and T and B cell lymphocytes have been implicated in this dysregulated immune response. Mast cells are abundant resident cells of the respiratory tract and are able to release different inflammatory mediators rapidly following stimulation. Recently, mast cells have been associated with tissue damage during viral infections, but their role in SARS-CoV-2 infection remains unclear. In this study, we examined the profile of mast cell activation markers in the serum of COVID-19 patients. We noticed that SARS-CoV-2-infected patients showed increased carboxypeptidase A3 (CPA3) and decreased serotonin levels in their serum when compared with symptomatic SARS-CoV-2-negative patients. CPA3 levels correlated with C-reactive protein, the number of circulating neutrophils, and quick SOFA. CPA3 in serum was a good biomarker for identifying severe COVID-19 patients, whereas serotonin was a good predictor of SARS-CoV-2 infection. In summary, our results show that serum CPA3 and serotonin levels are relevant biomarkers during SARS-CoV-2 infection. This suggests that mast cells and basophils are relevant players in the inflammatory response in COVID-19 and may represent targets for therapeutic intervention.


Subject(s)
COVID-19/diagnosis , Carboxypeptidases A/metabolism , Inflammation Mediators/metabolism , Inflammation/diagnosis , Mast Cells/immunology , SARS-CoV-2/isolation & purification , Serotonin/metabolism , Biomarkers/analysis , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Humans , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Mast Cells/pathology , Severity of Illness Index
4.
Int J Mol Sci ; 22(11)2021 May 24.
Article in English | MEDLINE | ID: covidwho-1273453

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.


Subject(s)
Acute Lung Injury/drug therapy , Amides/pharmacology , Cytokines/metabolism , Ethanolamines/pharmacology , MAP Kinase Signaling System/drug effects , Palmitic Acids/pharmacology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Amides/therapeutic use , Animals , Ethanolamines/therapeutic use , Immunohistochemistry , Inflammation/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/immunology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Neutrophils/drug effects , Neutrophils/immunology , Palmitic Acids/therapeutic use , Peroxidase/metabolism , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
5.
J Allergy Clin Immunol ; 147(6): 2075-2082.e2, 2021 06.
Article in English | MEDLINE | ID: covidwho-1185028

ABSTRACT

Anaphylaxis to vaccines is historically a rare event. The coronavirus disease 2019 pandemic drove the need for rapid vaccine production applying a novel antigen delivery system: messenger RNA vaccines packaged in lipid nanoparticles. Unexpectedly, public vaccine administration led to a small number of severe allergic reactions, with resultant substantial public concern, especially within atopic individuals. We reviewed the constituents of the messenger RNA lipid nanoparticle vaccine and considered several contributors to these reactions: (1) contact system activation by nucleic acid, (2) complement recognition of the vaccine-activating allergic effector cells, (3) preexisting antibody recognition of polyethylene glycol, a lipid nanoparticle surface hydrophilic polymer, and (4) direct mast cell activation, coupled with potential genetic or environmental predispositions to hypersensitivity. Unfortunately, measurement of anti-polyethylene glycol antibodies in vitro is not clinically available, and the predictive value of skin testing to polyethylene glycol components as a coronavirus disease 2019 messenger RNA vaccine-specific anaphylaxis marker is unknown. Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.


Subject(s)
Anaphylaxis/immunology , COVID-19 Vaccines/adverse effects , COVID-19/immunology , Drug Hypersensitivity/immunology , Lipids/adverse effects , Nanoparticles/adverse effects , RNA, Messenger/adverse effects , SARS-CoV-2/immunology , Anaphylaxis/chemically induced , Animals , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Drug Hypersensitivity/pathology , Humans , Lipids/immunology , Lipids/therapeutic use , Mast Cells/immunology , Mast Cells/pathology , Nanoparticles/therapeutic use , RNA, Messenger/immunology , RNA, Messenger/therapeutic use , Risk Factors
6.
Biofactors ; 46(6): 927-933, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-966303

ABSTRACT

Recent articles report elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased COVID-19 patients. However, there has been no discussion of what may induce intravascular coagulation. Platelets are critical in the formation of thrombi and their most potent trigger is platelet activating factor (PAF), first characterized by Demopoulos and colleagues in 1979. PAF is produced by cells involved in host defense and its biological actions bear similarities with COVID-19 disease manifestations. PAF can also stimulate perivascular mast cell activation, leading to inflammation implicated in severe acute respiratory syndrome (SARS). Mast cells are plentiful in the lungs and are a rich source of PAF and of inflammatory cytokines, such as IL-1ß and IL-6, which may contribute to COVID-19 and especially SARS. The histamine-1 receptor antagonist rupatadine was developed to have anti-PAF activity, and also inhibits activation of human mast cells in response to PAF. Rupatadine could be repurposed for COVID-19 prophylaxis alone or together with other PAF-inhibitors of natural origin such as the flavonoids quercetin and luteolin, which have antiviral, anti-inflammatory, and anti-PAF actions.


Subject(s)
COVID-19/prevention & control , Cyproheptadine/analogs & derivatives , Disseminated Intravascular Coagulation/prevention & control , Platelet Activating Factor/antagonists & inhibitors , Pulmonary Embolism/prevention & control , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/prevention & control , Antiviral Agents/therapeutic use , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/blood , COVID-19/pathology , COVID-19/virology , Cyproheptadine/therapeutic use , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/pathology , Disseminated Intravascular Coagulation/virology , Gene Expression Regulation , Humans , Inflammation , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lung/drug effects , Lung/pathology , Lung/virology , Luteolin/therapeutic use , Mast Cells/drug effects , Mast Cells/pathology , Mast Cells/virology , Platelet Activating Factor/genetics , Platelet Activating Factor/metabolism , Pulmonary Embolism/blood , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , Quercetin/therapeutic use , SARS-CoV-2/drug effects , Severe Acute Respiratory Syndrome/blood , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology
7.
Front Immunol ; 11: 574862, 2020.
Article in English | MEDLINE | ID: covidwho-845301

ABSTRACT

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Mast Cells/immunology , Pneumonia, Viral/immunology , Pulmonary Alveoli/immunology , Pulmonary Edema/immunology , Thrombosis/immunology , Adult , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/immunology , Influenza, Human/pathology , Influenza, Human/virology , Interleukin-4/immunology , Male , Mast Cells/pathology , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proto-Oncogene Proteins c-kit/immunology , Pulmonary Alveoli/pathology , Pulmonary Alveoli/virology , Pulmonary Edema/pathology , Pulmonary Edema/virology , SARS-CoV-2 , Thrombosis/pathology , Thrombosis/virology
8.
J Allergy Clin Immunol ; 146(2): 300-306, 2020 08.
Article in English | MEDLINE | ID: covidwho-599332

ABSTRACT

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Disease Management , Mastocytosis, Cutaneous/drug therapy , Mastocytosis, Systemic/drug therapy , Pandemics , Pneumonia, Viral/epidemiology , Betacoronavirus/immunology , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Diphosphonates/therapeutic use , Expert Testimony , Glucocorticoids/adverse effects , Histamine Antagonists/therapeutic use , Humans , Immunosuppressive Agents/adverse effects , Mast Cells/drug effects , Mast Cells/immunology , Mast Cells/pathology , Mastocytosis, Cutaneous/diagnosis , Mastocytosis, Cutaneous/epidemiology , Mastocytosis, Cutaneous/pathology , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/epidemiology , Mastocytosis, Systemic/pathology , Myeloablative Agonists/adverse effects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Precision Medicine/methods , Risk Factors , SARS-CoV-2 , Vitamin D/therapeutic use
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