Just abstract
News Media and Social Media flapping their gums and chasing their tailsā¦
Meā¦Hello? Can we do a Science please??
YES, high temperatures are reportedly deleterious to corona virus viability.
NO, jet engine afterburner temperature blow drying your nose hairs, is not a AMA recommended prophylactic therapy.
Everyone step back about 10 to 12 feet please, take a deep breatheā¦and hold it, 2, 3, 4ā¦
Exhaleā¦Repeat please about 10 times.
Cough into your elbow sleeve if needed.
Now turn off the TV and facebook and Twitter for about 8 hours.
Iāll post right here if you miss anything important. Meanwhile call your Mom or other family. Check on your neighbor or friends. Eat a cookie if your able.
Gotta get rid of this crud, hack, cough, Wheeeeeeeezeā¦
Stay away from strangers! Stranger Danger!..(and friends too!)
One of my colleagues from my old project sent me thisā¦
Canāt touch this!..(or should you either!)
U2 Dragonlady Airmen demonstrating social distancing while sporting the new aeronautical fashion trends for 2020
Interesting, inflammatory cytokines are one thing mast cells do best.
"However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts. There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge.
These cells are a major and under-appreciated local source of type I and III interferons following viral challenge. However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections.
More recently, a complex picture of MCs during infection has emerged, whereby they may promote effective immunity to infection under some circumstances, but also have the potential to contribute to tissue damage and impair vascular integrity, especially upon secondary infection.
MCs themselves are resistant to becoming productively infected with influenza or RSV but have a protective response that includes the production of cytokines and chemokines promoting the recruitment of antiviral effector cells. In addition, human MCs produce substantial amounts of type I IFNs which would promote a local antiviral response and resistance to infection.
Of course, in a more disseminated infection, especially in situations where MC numbers were elevated, these responses could also contribute to potentially damaging inflammation.
In the case of RV, MCs themselves are productively infected, but retain the ability to initiate host defence processes. Together with the potential impact of antiviral antibody responses (via both complement products and Fc receptor-mediated activation), it would be expected that the impacts of MCs on infection and the potential for a more damaging inflammatory response would be heightened upon secondary or subsequent infection"ā¦
The role of C5a in acute lung injury induced by highly pathogenic viral infections
Renxi Wang,He Xiao,Renfeng Guo,Yan Li &Beifen Shen
Pages 1-7 | Received 19 Jan 2015, Accepted 31 Mar 2015, Published online: 25 Jan 2019
Abstract
The complement system, an important part of innate immunity, plays a critical role in pathogen clearance. Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. In highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic C5a were produced as a result of excessive complement activaiton. Overproduced C5a displays powerful biological activities in activation of phagocytic cells, generation of oxidants, and inflammatory sequelae named ācytokine stormā, and so on. Blockade of C5a signaling have been implicated in the treatment of ALI induced by highly pathogenic virus. Herein, we review the literature that links C5a and ALI, and review our understanding of the mechanisms by which C5a affects ALI during highly pathogenic viral infection. In particular, we discuss the potential of the blockade of C5a signaling to treat ALI induced by highly pathogenic viruses.
Keywords:acute lung injury, C5a, pro-inflammatory cytokines
Introduction
The epithelium of the lung is vulnerable to damage caused by inhaled microorganisms and other noxious particles. Many studies suggested the presence of complement components at the alveolar epithelium, where inhaled airborne particles and microorganisms are deposited.1-3 In addition, the complement system has been implicated in the development of acute lung diseases induced by highly pathogenic viruses including influenza A virus H1N1,4 H5N1,5 H7N9,6 severe acute respiratory syndrome coronavirus (SARS-Cov),7 Middle East respiratory syndrome coronavirus (MERS-Cov).8 However, the specific contributions of complement to lung diseases based on innate and adaptive immunity are just beginning to emerge. Elucidating the role of complement-mediated immune regulation in these diseases will help identify new targets for therapeutic interventions.9
Complement activation leads to the formation of bioactive molecules, including the anaphylatoxins, C3a and C5a, and the lytic membrane attack complex (C5b-9).10 The complement-activated product C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants.10 C5a also displays other powerful biological activities including inducing ācytokine storm.ā On the other hand, blockade of C5a signaling has demonstrated potential benefits in the treatment of acute lung injury (ALI) induced by highly pathogenic viruses. In this article, we summarize recent developments in our understanding of the role of C5a in mediating aute lung injury induced by highly pathogenic viruses.
ACUTE LUNG INJURY INDUCED BY HIGHLY PATHOGENIC VIRAL INFECTIONS
Highly pathogenic virus
Due to high mutation rates of viruses, every several years to decades a highly pathogenic virus emerges. Especially in the recent decades, there were more than five highly pathogenic viruses such as SARS coronavirus in 2002, avian influenza A/H5N1 virus in 1997, H1N1 virus in 2009, H7N9 virus in 2013, and MERS coronavirus in 2012. As exemplified by coronaviruses and influenza viruses, bats and birds are natural reservoirs for providing viral genes during evolution of new virus species and viruses for interspecies transmission.11,12 This is the primary cause of an outbreak by jumping directly from bird to human.
The novel influenza A virus (IAV) pandemic poses a serious threat to public health. The data provided by the World Health Organization demonstrated that the 2009 H1N1 influenza pandemic caused over 18 138 deaths from outbreak to May 30, 2010; highly pathogenic H5N1 resulted in the deaths of 385 people from 2003 to Feb 27, 2015; the avian-originating H7N9 has resulted in over 560 human infections, leading to 135 deaths since emerging in 2013 to Feb 27, 2015.
Except for influenza A virus, coronaviruses such as SARS-CoV and MERS-CoV represent another serious threat to public health. Between November 2002 and July 2003, an outbreak of SARS caused an 8096 cases and 774 deaths according to World Health Organization. MERS-CoV was a novel human coronavirus that caused outbreaks of a SARS-like illness in the Middle East in March of 2014.13 In two months, 536 laboratory-confirmed cases and 145 deaths have been reported globally.14
There is an H5N1 vaccine for human use, but there is currently no H7N9, SARS or MERS vaccine available. Current vaccination strategies are still inadequate at providing protection against epidemic outbreaks. Thus, it is urgent to explore the mechanism by which highly pathogenic viruses induce diseases.
Acute lung injury induced by highly pathogenic viral infections
Although highly pathogenic virus infections have the different epidemiology, there is a similar rapid progression to acute respiratory distress syndrome (ARDS).15 For example, histopathological changes in the lung from patients infected with H5N1 are highly similar to those of patients with SARS.16 Except for influenza A H5N1 virus, avian influenza A H7N9 virus in 2013 also caused severe pneumonia.17 Postmortem biopsy of 3 patients infected with H7N9 in 2013 showed acute diffuse alveolar damage: patient 1, who died 8 days after symptom onset, had intra-alveolar hemorrhage, whereas patients 2 and 3, who died 11 days after symptom onset, had pulmonary fibro proliferative changes.18
Patients infected with H5N1 develop rapidly progressive pneumonia, further resulting in ALI or ARDS.19,20 ALI may be a critical cause of death in patients with H5N1 infection.19,21 Like H5N1 infection, H7N9 also causes serious lung pathology. In addition, SARS-CoV infection caused ALI that may progress to life-threatening ARDS. MERS-CoV infection resulted in a more severe pneumonia than SARS-CoV infection.22
Respiratory distress is the most common cause of death in patients infected with highly pathogenic virus. In terms of therapy, lung protective ventilation is the cornerstone of supportive care.23 Extracorporeal membrane oxygenation is routinely used in many centers for the treatment of severe respiratory tract infections. However, due to few effective treatment options, ALI is often fatal for patients infected with highly pathogenic viruses. This suggests that serious lung pathology should be of particular concern.
COMPLEMENT AND C5a ACTIVATION IN ACUTE LUNG INJURY INDUCED BY HIGHLY PATHOGENIC VIRAL INFECTIONS
After a microorganism infection begins, the host quickly activates the complement system to clear infected pathogens.24 During the complement activation, the high levels of products such as C5a are commonly involved in exacerbated inflammatory reactions that can cause direct harm to the host following infections.25,26,27
IAV belongs to the Orthomyxoviridae family with single-stranded negative-sense RNA virus,28 and has the capacity to activate the complement system.29 In addition, the avian influenza hemagglutinins typically bind alpha 2-3 sialic acid receptors, whereas human influenza hemagglutinins bind alpha 2-6 sialic acid receptors.30 Thus, H5N1 replicates in the lower respiratory tract, then causes complement activation.31 This suggests that upon influenza infection, the high levels of C3 and C5 including fragments C3a and C5a are produced.
Complement activation possibly contributes to the observed tissue damage in severe viral infection.32 Studies demonstrated that ALI in H5N1-infected mice was caused by excessive complement activation such as release of C5a.5 Thus, complement activation plays a critical role in the pathogenesis of virus-induced acute lung injury.
Among the complement activation products, the anaphylatoxin C5a is one of the most potent inflammatory peptides.33 Increased levels of C5a were found in bronchoalveolar lavage fluid (BALF) and serum from patients infected with fatally H1N1 pandemic virus.4,34 C5a had also been found to increase in BALF of mice infected with highly pathogenic avian influenza H5N1 but not following seasonal IAV infection.35 On the other hand, BALF from recovered patients with ARDS demonstrated significantly reduced C5a-dependent chemotactic activity.36 Thus, C5a might play a critical role in the pathogenesis of virus-induced acute lung injury.
THE MECHANISMS UNDERLYING C5a-MEDIATED ACUTE LUNG INJURY INDUCED BY HIGHLY PATHOGENIC VIRAL INFECTIONS
C5a-mediated inflammatory cells migrate into lung tissue
Compared to normal controls, SARS patients had increased cellularity of BALF with increased alveolar macrophages.37 Thus, mononuclear cell infiltration might have an important role in the pathogenesis of ALI induced by highly pathogenic viruses like SARS.
Anaphylatoxin C5a has been implicated in the pathogenesis of ARDS by mediating neutrophil attraction, aggregation, activation, and subsequent pulmonary endothelial damage.38,39,40,41 Reversely, C5a-dependent chemotactic activity is significantly decreased in recovered patients with ARDS.36 These suggest that C5a-mediated mobilization and activation of immune cells might be the central events to tissue injury caused by highly pathogenic viral infections.
Two chemoattractants C5a and interleukin 8 (IL-8) can be synthesized by cells in the lung (e.g., macrophages, epithelial cells, endothelial cells, smooth muscle cells and neutrophils).33 IL-8 levels have also been found to correlate with neutrophil numbers and the degree of lung dysfunction.42 C5a could strongly amplify IL-8 expression from human whole blood cells induced by lipopolysaccharides and other types of toll-like receptors agonists via extracellular-signal-regulated kinases 1/2 and p38, but not c-Jun N-terminal kinase.43 The data suggest that C5a might be a critical effector molecule to mediate lymphocyte attraction by itself or indirectly by enhancing the production of IL-8.
Altogether, C5a-mediated lymphocyte attraction plays a critical role in the pathogenesis of ALI induced by highly pathogenic viruses.
C5a-mediated neutrophil extracellular traps
Neutrophil extracellular traps (NETs) are primarily composed of DNA from neutrophils, which bind pathogens with antimicrobial proteins. NETs are beneficial in antimicrobial defense and can help fight against invading pathogens. However, an excess of NETs contributes to the pathology of a number of diseases including those of the lung.44 NETs are found in infection-related ALI models of influenza virus.45,46
In vitro studies demonstrated that C5a, in association with granulocyte-macrophage colony-stimulating factor, is able to induce the release of NETs.47 C5a is also able to activate macrophages and endothelial cells and to promote vascular leakage and the release of NETs.10 Thus, NETs are induced by C5a during IAV infection and are associated with alveolar damage in IAV-induced pneumonitis.45
The excess of NET components are potent factors in lung injury. NET increases the permeability of the alveolar-capillary barrier by cleaving endothelial actin cytoskeleton, E-cadherin and VE-cadherin.48 The antimicrobial peptide LL-37 in NET structures presents cytotoxic and proapoptotic properties towards endothelial and epithelial cells.49 NET also induces the release of proinflammatory cytokines.48 The data suggest that C5a-mediated neutrophil extracellular traps aggravate ALI in patients infected with highly pathogenic virus.
C5a-mediated release of reactive oxygen species
C5a is a strong chemoattractant for neutrophils and monocytes; it then activates these cells to generate oxidative burst with release of reactive oxygen species (ROS), especially O2 and H2O2.10 A study demonstrated that ROS are primary pathogenic molecules in pneumonia from mice infected with influenza virus.50 The amount and duration of exposure of generated ROS, released from respiratory, immune, and inflammatory cells, determined the extent of lung damage.50 In lung fibroses, inflammatory cells produce a significantly greater amount of ROS. Critically, antioxidant treatment significantly reduces lung damage and mortality in influenza-infected mice.51 These studies demonstrated a critical role of reactive oxygen intermediates (ROIs) in virus-induced epithelial damage.
C5a-C5aR interaction plays a critical role in oxidative burst.52 Interception of C5a/C5aR signaling with a C5aR antagonist significantly inhibited oxidative burst in neutrophils induced with E. coli. Similarly, anti-C5a blocked the oxidative burst in whole blood induced with Neisseria meningitides.53 Phosphorylation of p47phox is essential for assembly of NADPH oxidase and the subsequent production of O2 and H2O2.10 C5a is a strong activator of mitogen-activated protein kinase (including p42/p44), which is an important kinase for p47phox phosphorylation.
Except for directly affecting tissue damage, oxidant production might also be involved in signal transduction pathways. IL-8 expression is enhanced by the oxidant sensitive transcription factor nuclear factor-ĪŗB54 activated in the lungs of influenza-infected mice.55 This means that oxygen-derived free radicals might exert much greater effects on the pathogenesis of the disease by indirectly inducing other proinflammatory mediators. Thus, C5a-mediated oxygen-derived free radicals are thought to be important events in the pathogenesis of the disease.
C5a-mediated release of histones
Histones are essential regulators of genome function in eukaryotic cells. The NS1 protein of influenza A H3N2 subtype possesses a histone-like sequence (histone mimic), and could target the human RNA polymerase-associated factor 1 transcription elongation complex which has a crucial role in the antiviral response.56 Thus, the virus used NS1 histone mimic to suppress human RNA polymerase-associated factor 1 transcription elongation complex-mediated antiviral response.
Diversely modified histone regulates gene replication, repair and transcription. After activation with influenza, H3K4me3 reduced association of interferon I (IFN-I) and IFN-III promoters in dendritic cells (DCs) to suppress antiviral gene expression.57 In contrast to IFNs, the association of tumor necrosis factor-Ī± (TNF-Ī±) promoter was not disturbed.57
Histone can be excreted into cells to reduce intracellular histone to suppress antiviral gene expression. In the setting of ALI both in humans and in mice, histone presence has been found in BALF.58 In addition, when polymorphonuclear leukocytes are incubated in vitro or in vivo with C5a, neutrophil extracellular histones-contained extracellular traps (NETs) develop.59 These results suggest that engagement of C5a with its receptors led to the appearance of extracellular histones in BALF.
Extracellular histones significantly enhance inflammatory response by inducing nucleotide-binding domain and leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome.58 Furthermore, airway instillation of histones resulted in intense lung injury and inflammation, together with fibrin clots in pulmonary veins.60 C5a-mediated release of histones has an important contribution to the pathogenesis of ALI.
C5a-mediated the upregulation of adhesion molecules
The process of leukocyte adhesion to endothelial cells is the first critical step in neutrophil migration into an area of inflammation. Adhesion molecules on the surface of endothelial cells have an important role in inflammatory cell migration. In fact, C5a can regulate the expression of adhesion molecules.61 C5a directly activates endothelial cells to upregulate adhesion molecules such as P-selectin. In addition, C5a and TNF-Ī± cooperate to enhance upregulation of intercellular adhesion molecule 1 and E-selectin.62 Thus, C5a is an effective mediator in the first step in inflammatory cell migration into the lung.
Adhesion molecules on the surface of inflammatory cells also have an important role in inflammatory cell migration. In vitro studies demonstrated upregulation of CD1lb/CD18 expression on neutrophils induced by C5a.10 In addition, C5a also induced the expression of Ī²1 and Ī²2 integrin on blood neutrophils.63,64 Thus, enhanced adhesive interactions of neutrophils to endothelial cells promote inflammatory cell migration into inflammatory sites.
The adhesion molecules effectively enhanced pro-inflammatory cytokines such as TNF-Ī± production by pulmonary macrophages, which, in turn, promotes the inflammatory response.62 Blockade of CDllb, CD18, intercellular adhesion molecule 1, or P-selectin significantly reduced ALI damage by neutrophil content of the lungs.65 Anti-C5a might protect tissue injury in various organs by limiting neutrophil sequestration through downregulating the expression of adhesion molecules.10 These studies suggest that C5a-mediated upregulation of adhesion molecules promotes the inflammatory response.
C5a-mediated adaptive immune response
C5a induces innate immune cells including mast cells, neutrophils, and macrophages to release cytokines such as IL-12, TNF-Ī± and macrophage inflammatory proteins-1Ī±.66 IL-12 is a strong activator of CD8+ T cells, whereas TNF-Ī± promotes transendothelial migration of T cells by up-regulating vascular adhesion molecules and induces IFN-Ī³ expression in T cells.66 These data demonstrate that C5a indirectly induces adaptive immune response by activating innate immune cells.
Be gone for a bit, holler for Pam Hodges, Maria Dastur, Tom, or Jana Pearce if you get in a bind. Itās labs time.
The histamine-cytokine network in allergic inflammation
Gianni Marone, MD, Francescopaolo Granata, MD, Giuseppe Spadaro, MD, Arturo Genovese, MD, and Massimo Triggiani, MD, PhD Naples, Italy
"Histamine exerts immediate proinflammatory effects mediated mostly by the activation of H1-receptors.
However, the possibility is emerging that this mediator can also influence local immune responses and tissue damage by modulating the release of cytokines as well as the activity of cells such as macrophages, basophils, eosinophils, and fibroblasts.
Thus, we might envisage that histamine has a fundamental and possibly dual role in bronchial asthma, ie, as an acute pro-inflammatory molecule and as a long-term immune modulator regulating the complex network of cytokines operating in this disease.
The observation that fexofenadine inhibits the activation of macrophages induced by histamine suggests a new perspective in the long-term treatment of allergic inflammation.
Indeed, it is conceivable that long-term treatment with fexofenadine might positively influence the tissue damage and remodeling occurring in chronic asthma.
A better knowledge of the regulatory role of histamine on the functions of immunocompetent cells, and the effects of activating histamine receptors on these cells, might lead to new therapeutic approaches to control the mitigation of long-term evolution of bronchial asthma."
Stuck at home? Have some Grey Poupin?
From the folks at The Mastocytosis Society!!
Our 2020 Rare Disease Day Initiative continues with our second in the new series of
TMS Patient Voice Forums!
We hope you will join us for the
Patient Voice Forum
for
Mastocytosis: Systemic and Cutaneous
Wednesday, March 25, 2020
8:00 pm (Eastern Time)
Featuring Dr. Cem Akin and Dr. Matt Giannetti
Please note other physicians will likely be added to the panel
We want to hear from you!
All TMS Members are invited to submit questions, comments and thoughts by emailing, nurses@tmsforacure.org with āPatient Voice Forum-Mastocytosisā in the subject line. If you do not use this subject line your questions may be overlooked and not included.
Please note that only general medical questions/comments can be submitted/addressed about Mastocytosis; physicians cannot give one-on-one advice to patients in this forum.
All submissions must be received by Friday, March 20, 2020.
Additional call-in details will be provided as it nears.
Thank you so much for your participation in what we know will be a very meaningful event for our entire community.
For those who missed our first webinar on Mast Cell Activation Syndrome a video recording can be found here.
If you want to stay healthy and not catch or spread this virus, Itās that damn numbers thing again.
Thanks to all the MasterMinds today!
A good read on ACE-2 Receptor aging on us old farts.
From NHS in UK. Comorbidities and priorities in social distancing
A good read on ACE-2 Receptor aging on us old farts.
Okay Team,
Need some deep digging.
Papers on the effects of mast cell stabilizers (Cromolyn, Quercetin, Ketotifen) or Antihistamines on SARS COV-2, either Positive (helps) or Negatively (hurt).
Primarily
- on cytokine related pneumonia symptoms and lung damage
or
- Cardiovascular and kidney inflammation and damage.
1, 2, 3 GOOOOOO!!