Discovery of the Mechanism of COVID-19, SIRS and SEPSIS, Defense and Treatment.

Mast cells and Histamine Storm an Overlooked Aspects in COVID-19 and in Ventilated Patients Potential Role of Antihistamine.

MA Magdalena Filcek^1*, MD Mayank Vats², MD Anna Skrzyniarz-Plutecka³
 

1*. Specialist Neuro-architecture, Master of Interior Architecture, pilot of hot air balloons, innovator of many patented projects: Vinci Power Nap® - Dream’s Space® and the Balonodrom Project©. Poland

2. Senior Specialist -  Interventional Pulmonologist, Pulmonologist, Intensivist & Sleep Physician at Rashid Hospital and Dubai hospital. UAE

3. Head of Anesthesiology and Intensive Care Department, Masovian Oncology Hospital, Wieliszew, Warsaw University Maria Sklodowska-Curie, Specialist in Anesthesiology and Intensive Care and with experience in Infectious Diseases. Poland

Consultant : PhD Ewa Aplas - specialist molecular genetic, biotechnology. Poland

Consultant : MD, PhD Mirosaw Mastej - specialist histamine and HIT. Poland

Consultant : MSc Pharm Andrzej Kotarski - specialist pharmacy. Poland

Consultant : PhD Agata Kolodziejczyk - specialist biomimetics, Director of Scientific Projects Analog Astronaut  Training Center. Poland

Consultant:  MD, PhD Grzegorz Gogolewski - specialist in internal diseases and emergency medicine - Clinic of Emergency Medicine and Cathedral and the Clinic Internal Medicine and Allergology AM in Wroclaw. Poland

Corresponding Author: MA Magdalena Filcek - Specialist Neuro-architecture, Master of Interior Architecture, pilot of hot air balloons, innovator of many patented projects: Vinci Power Nap® -Dream’s Space® and the Balonodrom Project©. Poland

Copy Right: © 2021 MA Magdalena Filcek, this is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  

Received Date: September 20, 2021

Published date: October 01, 2021

Abstract

The entire human population is waiting for a revolutionary discovery regarding the current pandemic. There is an urgent global need to identify therapies that will prevent SARS-CoV-2 infection and improve patient outcomes with COVID-19. Understanding the pathophysiology is a key research priority. In this article, we identify the mechanism and possible effective prevention with treatment of COVID-19 from the onset of the first symptoms to severe cases requiring ventilator assistance. We show a possible process that can lead to hyperimmune / systemic inflammatory response syndrome and what can trigger it this discovery led us to define preventive drugs with favorable safety profiles that could have significant benefits by becoming widely available for COVID-19 prevention and treatment options, saving many people around the world.

 SARS-CoV-2 could act as one of environmental triggers for mast cells in lungs to release the storm of histamine which either directly or indirectly open the way for another triggers (cytokines, TNFα, IL-1, IL-6, etc), leading to inflammations and damages of many organs. Histamine by affecting the H1, H2, H3, H4 receptors, causes an allergic and pseudo-allergic reaction called histamine intolerance (HIT), considering also the relationship with the key genes.

Stimulation of this histamine H receptors, among others leads to: bronchospasm, cough, shortness of breath, in-crease in platelet aggregation, decrease in saturation, tachycardia, vasodilation and increase in their permeability, edema, diarrhea, hypotension, characteristic severe fatigue, fever, headache, neurological changes, as well as multi-organ changes including hyper inflammation in the lungs, intestines, heart, kidneys, liver. The above symptoms of a systemic inflammatory reaction are also observed in the developing COVID-19 and its multi-organ complications.

Moreover, mast cells could be also activating under the influence of markedly low air temperature and dryness, as well as too high pressure/volume of air delivered by ventilator into the lungs of patients with COVID-19 - releasing again avalanche ejection of histamine from the granules, also cytokines, tryptase, etc.

There is a high probability that the symptoms of SIRS and SEPSIS as well as COVID-19, could be histamine storm with histamine intolerance symptoms, which, in its acute form, can lead to anaphylactic shock. The discovery of this mechanism could improve the health of millions of people by strategically disseminating the simple idea of histamine intolerance, the dose of antihistamines, selected enzymes, genes and the improvement of the use of mechanical ventilation.

Keywords: COVID-19, SARS-CoV-2, HIT, histamine, intolerance, antihistamines, DAO, HNMT, cytokines, tryptase, mast cells, SIRS, SEPSIS

Acronyms/Abbreviations:

ARDS - Acute respiratory distress syndrome

CFS - Chronic fatigue syndrome

COVID -19 - coronavirus disease 2019

COPD - Chronic obstructive pulmonary disease

CRH - Corticotropin releasing factor

DAO - Diamine Oxidase

EAA - Extrinsic Allergic Alveolitis

 (Hypersensitivity Pneumonitis)

ECMO - Extra Corporeal Membrane Oxygenation

EIB - Exercise-Induced Bronchoconstriction

EVW - Extravascular water

HH - Heated Humidifier

HIT - Histamine Intolerance

HME - Heat Moisture Exchanger

HNMT - Histamine N-methyltransferase

ICU - Intensive Care Unit

SEPSIS - Specific reaction of the body to infection

SIBO - Small intestinal bacterial overgrowth

SIRS - Systemic inflammatory response syndrome

VAP - Ventilator associated pneumonia

Introduction

The COVID-19 pandemic, caused by the corona virus SARS-CoV-2, reached millions of the global population, and is associated with a high incidence of patients suffering from severe acute respiratory syndrome (SARS) which in turn places them at significant risk of death. The whole process starts with breathing difficulty or shortness of breath, with time „many of these patients require admission to an intensive care unit (ICU) and 80% of them require invasive mechanical ventilation” [1][2][3] and it has been linked to lasting damage to the lungs.

Early reports indicated „that those patients when ventilated are at high risk of nosocomial pneumonia, [4] and, especially, ventilator associated pneumonia (VAP)" [5][3] With time more serious conditions occur in COVID-19 patients, such as systemic inflammation, organ dysfunction and failure, so similar to the symptoms of SIRS or closely related to SEPSIS.

In this hypothesis we are showing that not only the cytokine storm but also histamine storm can make this systemic inflammation which occurs in patients also with COVID-19.

"The biological impact of histamine follow its interaction with four types histamine receptors, H1R, H2R, H3R, and H4R, all of which belong to the G protein coupled receptor family” [6].

In response to various environmental/ physical/ allergic stimuli there is activation of a complex interaction between several inflammatory cells, including basophils, mast cells, lymphocytes, dendritic cells, neutrophils, and eosinophils” [7][8].

"Among these, mast cell histamine is an axial player in stimulating the development of allergic related inflammatory diseases by regulating the maturation and activation of leukocytes and directing their migration to target sites where they cause chronic inflammation. Histamine also exerts a various other immune regulatory functions by modulating the functions of monocytes, T cells, macrophages, neutrophils, eosinophils, B cells, and dendritic cells” [6] leading to the immunoparalysis effects of critical illness very similar to SEPSIS [9][10].

The hypothesis is on the subject of activation of mast cells in lungs stimulated at the beginning by the virus, and then by too low air temperature delivered to the lungs from the ventilator, under the influence of which (and / or pressure caused by too high pressure / volume of air in the lungs) mast cells are activated, causing them to release large amounts of histamine, leading to problems with breathing, increased blood clotting, inflammation and too much cytokine release. Histamine in large amounts leads to histamine intolerance and damages many organs: lungs, heart, kidneys, peripheral nervous system, and many others very similar symptoms to COVID-19 (see the pictures below and the table at: [11][12][13][14]).

The severity of the COVID-19 disease and its symptoms in the respiratory system depends on the course of the immune response to the infection, often not the infection itself, but an excessive reaction to it causes the disease to progress to a severe form.

Excessive reactivity of the immune system or its failure may lead to disease progression to a severe state, serious tissue damage (not only in the respiratory system), thromboembolic events, and long-term consequences of COVID-19 disease and prolonged complications.

In this article we are showing that it is not only the cytokine storm but also histamine storm that can make this hyperimmune reaction and systemic inflammation which occurs in patients with COVID-19.

„New Study Estimates More Than 900,000 People Have Died Of COVID-19 In U.S. We have estimated to date that 6.9 million people have died from COVID-19 globally already” [15]. The analysis comes from researchers at the University of Washington's Institute for Health Metrics and Evaluation, who looked at excess mortality from March 2020 through May 3, 2021 [16][17][18]. The pandemic can result in an increased number of deaths from other causes for a number of reasons, including weakened healthcare systems, their capacity, and failing to treat other diseases.

The failure to predict the future course of the current pandemic has so far created many uncertainties related to the biological, epidemiological and clinical features of COVID-19, and we believe that with our hypothesis this can be changed.

The author found that the symptoms of COVID-19 SIRS, SEPSIS are similar as HIT that is why she recommends antihistamines and enzyme DAO neutralizing histamine as help to treat above diseases.
 

1.1 Background of discovery

The parents of the first author at the end of January 2021 had got COVID-19, both had pneumonia and got to hospital. Mother of the author recovered after 3 weeks, but her Father unfortunately got worse and was admitted to the pulmonary hospital. After one week he was put in coma together with a muscle relaxant and put under a ventilator.

The statistics showing a mortality rate of 88% of COVID-19 patients placed under ventilation in Poland were terrifying, and the media informed that it was partially due to too high mechanical pressure of air which damaged the lung alveoli.

The author started to search why it is like this to help her Father survive during mechanical ventilation. She was searching and learning everything about breathing, artificial respiration, mechanical ventilators, etc. She has found that the first idea of a ventilator was done by Leonardo da Vinci but the first working ventilator was an invention of Jean-François Pilatre de Rozier, made in the early 1880s, the French great inventor and teacher of chemistry, and physics of gasses [19], who became first pilot of hot air balloons in history of humankind.

Magdalena Filcek is also a pilot of hot air balloons and a scientist, inventor, she started to analyze how to lower the mechanical pressure and use the law of physics instead. As a pilot she knows the physics of gases and Charles Law, which allows balloons to fly.

She started to think about the lungs as balloons and tried to help to uplift them by warming the air. She asked doctor what is the temperature of air going to her Father's lungs from the ventilator, and got the information that the air has probably the „room temperature”, that is around 20ºC. From that she knows that it is 17ºC below what is needed for lungs, for good oxygen CO2 exchange. She knows from physics that this level of temperature will not give correct humidity level needed for lungs as well.

Moreover, because of Charles Law, the pressure of this air temperature as being warmed up in the lungs will increase, causing damage. She wanted to know what damage can be done in lungs by too cold and too dry air so she pursued research in science articles. She have found that only 5 degree below what is needed leads to really big problems.

Moreover, she has read in science articles that there are a very large number of mast cells are in the human lungs which can be activated also by viruses, too low temperature as well as too high pressure, all of which lead to the release of a histamine storm.

When the author become aware of what this amount of histamine is doing in the body, she realized that the symptoms are very similar to COVID-19, SIRS and SEPSIS symptoms, and concluded that in this case the antihistamines should help to stop the development of disease. She consulted the details of this discovery with more than 50 doctors, pulmonologists, anesthesiologists, allergists, respirator technicians, physicists, geneticists, doctors from internal and emergency medicine. The hypothesis was sent to Dr. Mayank Vats, Senior Pulmonologist, Internist and Sleep Physician at Dubai hospital, to check if it is correct and if antihistamines are effective treatment for patients. Then she contacted Dr. Miroslaw Mastej specialist of histamine to consult this subject in her discovery and then with Dr. Anna Skrzyniarz-Plutecka to check the temperature of air from ventilators on the ICU and to consult the hypothesis regarding antihistamines and their role in patient treatment under anesthesia machines during operations. Above doctors were surprised by such great results after employing this discovery in the care plan.

The author made consultations also with Agata Kolodziejczyk the Director of Scientific Projects Analog Astronaut Training Center, during the looking for the possibility to create a device to warm and humidity the air going from respirator to her Father lungs, with available on market and easy to use elements (almost like during Apollo 13 mission).

The Father of the author was in coma under ventilation for 1,5 months and during this time every second day the author was calling the doctors to consult the next steps of discovery so the doctors could make some improvements for her Father treatments also with using antihistamines.

After 3 months, the Father of the author left hospital and is at home, breathing and talking by himself, engaging in rehabilitation for gut health and muscular strength to be able to walk again.

This traumatic situation probably will need the rehabilitation not only for his body and mind but also for the whole close family as the stress and anxiety was too hight for few months and can lead to PTSD.

2. Respirator and inflammatory response factors

In the physiological state, the pressure in the lungs is lower than outside, whereas in mechanical ventilation it is higher. „The ventilator blows air, the alveoli and entire lungs expand, fill with oxygen, then (after reaching a certain maximum value of the pressure of the pumped gas), it cuts off and the chest passively descends, exhales" says Dr. Katarzyna Kramek-Romanowska from the Institute of Biocybernetics and Biomedical Engineering of the Polish Academy of Sciences in Warsaw [20]. VAP occurs in more than 86% cases after connecting patients to the ventilator [3]. ”Patients with severe COVID-19 associated ARDS requiring ECMO had a very high late onset VAP rate” [3] based on research of the inflammatory factor analysis built on a case of an ICU patients with ventilator associated pneumonia [21][22], which suggests that secondary pneumonia develops with time.

During the COVID-19 pandemic very often there were too many ventilators and too few specialists to operate them [23]. Without the right equipment at the right time, which cannot meet the physiological needs of the patient's body which is "put at great risk" [24].

The invasive devices together with sedation are important reasons for breach of natural defense [25].

2.1. Temperature of air in lungs

During spontaneous breathing „the temperature of the inhaled  air increases during its passage through the upper airway, and at the level of the alveolar-capillary interface, it is at body temperature (37ºC), with 100% relative humidity and 44mg/L absolute humidity" [26][27]. Oxygen from a wall installation or container is very cold due to expansion. The mixture of air flowing from the ventilator and flowing into the lungs may be at average "room" temperature of about 23 degrees Celsius ( or even less depends on the temperature in the room). During endotracheal intubation the natural air ways are bypassed. Cold and dry gases are delivered to the patients but have to be heated and humidified as well [28].

„Hypothermia is defined as core temperature of less than 36º centigrade” [29]. ”Hypothermia has many complications namely increased perioperative blood loss due to impaired blood coagulation pathways, altered drug metabolism, which leads to prolonged drug actions, delayed recovery and morbid cardiac events such as arrhythmias. Others are post operative shivering, prolonged hospital stay and patients’ less satisfaction with surgical and anesthesia experience” [30]. Lastly, hypothermia results in impaired wound healing and susceptibility to wound infection [31]. Better postoperative outcomes are achieved when normothermia is maintained perioperatively” [32].

„In spite of overwhelming evidence demonstrating the reduced complications and costs associated with maintaining normothermia, it’s been estimated that only 30 to 40 percent of surgical patients now receive some type of active perioperative warming. This is alarming in light of the frequency of inadvertent hypothermia. A recent study showed that without effective warming, as many as 90 percent of surgical patients will become hypothermic. In Europe, The United States and around the world, millions of patients continue to receive inadequate warming therapy or no warming at all - even though hypothermia has been called the most frequent, preventable complication of surgery. One U.S. physician has described maintaining normothermia this way: “There are few, if any, anesthetic interventions that have been proven to so markedly improve the outcome of surgery with so little effort, risk, and cost, making this a nearly ideal area for performance measurement and improvement” [33][34][35].

2.2. Heated Humidifier (HH) & Heat Moisture Exchanger (HME)

Ventilators deliver the air mix in a given volume, pressure and time rate to the patient's lungs during mechanical breathing.

From our observations most of respirators do not have a HH or HME device, and patients get air into their lungs without heating and humidifying [36] (which is not used due to the often given excuse which is the possibility of bacterial proliferation), the reason of this could be that some of those devices are disposable and should be exchanged but they are not. If the filters are not changed every 7 days or more frequently, there is a risk of bacterial contamination [37]. It should be noted that COVID-19 patients are kept long term under ventilators (weeks or even months).

For economic reasons many hospitals use the HME (which doesn't heat the air to a good temperature anyway) or do not use any devices to heat and humidify the air [38], but regular filters only.

There is little science research regarding the heated humidifiers for mechanically ventilated adults and children compared to heat and moisture exchangers [39] questioning if HME device are really doing what they are supposed to do [40] checking its efficiency of airway in anesthetized humans [41].

"Commonly used methods of humidifying inhaled  gases include heated humidifiers (HH), heat and moisture exchangers (HME) and hygroscopic condenser humidifiers.

- HH - Heated humidifiers provide warm, saturated gas at the artificial airway" [42] but „HHs without a heated wire have been associated with a higher risk of VAP” [43].

„In review of Cochrane Review [44][45] have been found no difference in the risk of VAP when HMEs or HHs were used, other reviews also reported no difference between HH and HME in the risk of artificial airway occlusion, pneumonia [46], mortality or length of ICU stay [43].

As with our findings, Siempos and colleagues found that HME reduced humidification costs [39][43].

- HME - Heat Moisture Exchanger may not prevent hypothermia and should not be used alone as it is not sufficient [47]. There are no studies of HMEs working at different range of humidity and temperature, all the measurements were done in "conditions laid down ISO 9360 (water bath temperature set at 37 °C, tidal volume 250–1000 ml)” [48][49][50][51][52][53].

As a conclusion only HHs, that can warm and moisturize the air properly are good solution to use with ventilators in treatment of the ICU patients.

2.3. The nasal function

The nose plays the main role as efficient heat and humidity exchanger, and it is the most used route by which the air enters the lungs [54][55][56].

"We normally breathe through the nose, which in 90% moisturizes  and heats the air we breathe to 35-36°C degrees before it reaches the lungs” [57][58][59].

„The ability of the human nose to warm and humidify the respiratory air is important to maintaining the internal environment of the lungs, since ambient air is conditioned to nearly alveolar conditions (at body temperature and fully saturated with water vapor) upon reaching the nasopharynx” [57] „and the intrathoracic airways play little role in the conditioning process, even in frigid environments” [60][61][62].

Patients with a ventilator tube in the trachea cannot use their nose to heat and humidify the air so the temperature reaching the lungs directly can be much lower than required - even by 15 degrees below, if the room temperature is 20°C degrees [63].

In many cases the air could be too cold and too dry.

2.4. The impact and consequences of cold on the respiratory tract.

It is known from research that “patients with bronchial hyper responsiveness are at risk of bronchospasm from sudden inhalation of cold air due to changes in the internal balance of the lower respiratory tract. When the air temperature drops quickly without gradual adaptation, even with changes as low as 2°-3°C, but especially with changes greater than 5°C, negative consequences for the respiratory system may occur and the patient is at risk of severe exacerbation of the disease and may find himself in a clinical condition characterized by an exacerbation of respiratory symptoms of chronic / obstructive (like asthma and COPD) within a few hours or days [64].

Cold airway damage is caused not only by direct temperature effects but also by hyperventilation. Air-way cooling is improved by increasing airflow in the airways. Breathing air at + 20°C at 15 l/min lowers the temperature of the trachea to 34°C, while breathing similar air at 100 l/min lowers this temperature to 31°C" [65]. „To understand the mechanisms of cold air provoked respiratory symptoms is essential for successful management of the symptoms” [66].

„Current evidence indicates that the stimulus of airway cooling and/or drying is translated into airflow limitation via the generation of bronchoactive mediators, neural reflexes or hyperemia and edema that result in a net narrowing of the airway [67][68]. In addition, airway instability may occur, which could lead to airway closure and derecruitment of some airways” [69].

„We conclude that the peripheral airways of asthmatic individuals with EIB are responsive to cool, dry air, and may play an important role in EIB” [70][71] and „that breathing dry air produces an acute reduction of extravascular water (EVW) of the loose connective tissue of the airways and an increase in the maximum response to histamine” [72].

The above research shown that the low temperatures in our lungs causes bronchoconstriction which decreases the lungs’ capacity.

2.5. Humidity of air the basics of physics

„Dry air from ventilators - peripheral airways responsiveness to cool, dry air - causes marked epithelial lesions and local inflammation” [73].

Regarding the air humidity that is measured as the amount of water vapor in the air. „Maximum humidity is the maximum amount of water vapor contained in a given amount of air, and is strongly related to the air temperature. The higher the air temperature, the more water vapor can be in it. Exceeding the maximum humidity (e.g. as a result of air temperature drop) causes water vapor condensation” [74][75].

The amount of water vapor in the air is limited and depends on the temperature of the mixture (humid air), as it is shown in „Air Properties: Temperature and Relative Humidity” [76][77].

„Changes in relative humidity and temperature of the anesthetic gases were measured (…). It is concluded that the output of relative humidity and temperature in the circle system is not sufficient to prevent broncho-epithelial damage. Ciliary beat automaticity appears to behave according to an all or nothing principle” [78].

„With dry air we found widespread loss of the ciliae on scanning electron microscopy in 10 of 12 animals, associated with detachment or sloughing of the epithelium, subepithelial vascular congestion, edema, and cellular infiltration on light microscopy. Our data demonstrate that a short exposure of the trachea to dry air causes marked epithelial lesions and local inflammation” [79][80][81][82]. Too cold and too dry air from a ventilator together with too high air pressure can activate the mast cells, release a lot of histamine and cytokines inducing and participating in inflammatory processes that can lead to VAP - secondary pneumonia [83].

Calcifications, adhesions and scarring, "burns" in the lungs can be the result high mechanical pressure as well as too low temperature and dryness of the air supplied can damage the alveoli, and dry the lungs from the inside.

From the observation of doctors: Even though patients with COVID-19 are symptomatic with dyspnea, initial x-rays often show no opacification. Blood, however, note marked increase of cytokines, which leads the doctors can notice that the VAP develops with time.

3. Mast cells:

Mast cells (known as masticates or labrocytes) are type of white blood cells produced in the bone marrow, being a part of the immune system. They are located all over the body but the highest numbers of mast cells are located in places constituting the main gateway to infection - where the body meets the environment: the skin, lungs (directly in the epithelium lining of the respiratory system) and urinary and gastrointestinal tract (in the intestines), connective tissue, mucous membranes and around the nerves. Also they can be found in the heart, as well as in the immediate vicinity of blood and lymph vessels, and their number in these places is very high. This may indicate that mast cells are among the first cells to recognize an invading pathogen” [84] can be classified as "rapid reaction forces" playing a significant role during the processes of defense mechanisms.

Mast cells are the first to respond to protect body from germs and infections and are referred to as „the starting factor in the inflammatory process" [85]. They have ability to phagocytosis and have up to a thousand basophilic granules in which released the substances during the inflammatory reactions and tissue structure [86][87].

Mast cells are the major producer of histamine in the body and are a type of innate immune cells involved in the body's defense against biological , chemical and physical factors. In response to „the factor attack” they can react violently, releasing the contents of their granules: histamine, tryptase, heparin, prostaglandin D2, leukotrienes and other clinically relevant mediators, with a strong effect. Mast cells play an important role in specific and innate immunity as well as in allergic inflammation associated with IgE. On their surface is the FcεRI receptor that binds IgE antibodies [88]. When a mastocyte comes into contact with an allergen or are activated by factor, it releases histamine, which affects other neighboring and distant cells [89].

During severe allergic or pseudo allergic reactions, substances secreted in large amounts by mast cells cause systemic symptoms, multiorgan inflammatory response syndrome, including anaphylactic shock” [90][91].

They also contain proteases (e.g. tryptase or chymase), due to the presence of proteolytic enzymes, they can be divided into 2 subpopulations: "tryptase only (MCT) cells and cells that have both tryptase and chymase (MCTC) proteases. MCTs are found in the alveolar wall of the lungs, while MCTCs are found in the skin, blood vessels, and the intestinal submucosa” [92].

Many new studies shown participation of mast cells not only in allergic reactions, but also in the innate and acquired immune responses, in inflammatory processes [85][93] in the formation of blood vessels and the development of neoplasms (including the hematopoietic system) [94]. They can also cause mastocytosis causes a wide range of symptoms, which can vary depending on the type of mastocytosis (cutaneous, systemic or aggressive (ASM) [95][96][97]). The symptoms of the systemic mastocytosis are very similar to COVID-19 [98].

Mast cells produce metalloproteinases substances that cause inflammation, joint problems breaking down collagen, skin problems, unsealing the intestinal mucosa and the blood brain barrier [99]. „Also the role of mast cells in autoimmune diseases has been described, including in systemic lupus erythematosus and rheumatoid arthritis and anti tumor activity (e.g. secreting TNF α)” [87].

„The allergic response to innocuous antigens reflects the pathophysiological aspects of a defensive immune response whose physiological role is to protect against helminthic parasites. It is triggered by antigen binding to IgE antibodies bound to the high affinity IgE receptor FcεRI on mast cells. Mast cells are strategically distributed beneath the mucosal surfaces of the body and in connective tissue. Antigen crosslinking the IgE on their surface causes them to release large amounts of inflammatory mediators. The resulting inflammation can be divided into early events, characterized by short-lived mediators such as histamine, and later events that involve leukotrienes, cytokines, and chemokines, which recruit and activate eosinophils and basophils. The late phase of this response can evolve into chronic inflammation, characterized by the presence of effector T cells and eosinophils, which is most clearly seen in chronic allergic asthma” [100].

Apart of above mast cells are also involved with vital functions in the body: by taking part in wound healing with forming new blood vessels, bone growth and secretion of gastric acid.

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