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How Coronavirus Kills: Acute Respiratory Distress Syndrome (ARDS)
Inflammation occurring by edema, causes a leakage into the tissue space so what happens here is that you get a viral infection, the virus affects the lungs and with a RDS entire lung becomes inflamed not in just one area like you would have with a pneumonia, with RDS the entire lung goes crazy with inflammation and so what happens, instead of having a nice thin area, inflammation get everywhere and you get a large barrier a fluid that goes into the interstitial space furthermore these capillaries start to become leaky and fluid starts to leak into alveolar space as well and this start to fill up with liquid, proteinaceous liquid, liquid that prevents oxygen from getting into the bloodstream and so instead of having nice oxygenated blood, this blood becomes hypoxic, and you become hypoxic with RDS and you have a hard time of breathing and that’s when you get placed on the ventilator, there is really nothing you can do to speed up this up, there’s nothing you can do to slow it down, you have to be supported on the ventilator so you are getting enough oxygen and that, the Machine can breath for you until just like everything else, the edema goes away, this fluid will eventually go away as well. The key though is keeping you supported during that period of time until the fluid goes away, and then once again the oxygen will be able to go back into the system and you will get oxygen back to the tissues.
ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation). Increased bradykinin levels are also responsible for the most common side effect of ACE inhibitor treatment; a dry cough.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Bradykinin contracts airway smooth muscle, is a potent bronchial vasodilator, increases microvascular leakage, stimulates epithelial cells to release bronchodilators and stimulates mucus secretion.
Inhaled bradykinin elicits many of the features of asthma, including bronchoconstriction, cough, plasma exudation, and mucus secretion.
KKS (kallikrein-kinin system) activation and liberation of bradykinin increases endothelial cell permeability.
Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.
Bradykinin induces vasodilation by stimulating production of nitric oxide, the arachidonic acid metabolites prostacyclin (PGI-2) and PGE-2, and endothelium-derived hyperpolarizing factor.
During inflammation, it is released locally from mast cells and basophils during tissue damage.
Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs.
Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.
ACE converts Ang I to Ang II and also inactivates bradykinin.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin.
Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks. Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.
Bradykinin could also contribute to the pathogenesis of ARDS
Then, ACE mediate the conversion of AngI to AngII, a major RAS effector. ACE is a protein with high expression on membranes of vascular endothelial cells, predominantly in lung tissue. The most of the RAS associated physiologic effects are run by interacting of AngII with a G-protein coupled AngII type 1 (AT1) receptor. This activates a physiologic pathway in different tracts, such as kidney, liver, central nervous system, respiratory, and cardiovascular system. Some crucial events are regulated via active AT1 receptors including arterial pressure, fluid and sodium balance, fibrosis, and cellular growth and migration.
In some pathological conditions, overactivation of AT1 may lead to damaging events like fibrosis in different organs such as liver and lungs, perhaps through increasing TGFβ expression.
Some studies indicate that ACE2 has a protective effect on the fibrogenesis and inflammation of different organs as well as liver and lung.
According to some recent studies, ACE2 has a regulatory effect on innate immunity and gut microbiota composition. Moreover, ACE2 has a determinant antifibrotic role in the lung injury induced by sepsis, acid aspiration, SARS, and lethal avian influenza A H5N1 virus.
It is also of note that ATR-1 Receptors increase with age and are increased in cancer, diabetes, hypertension, COPD. All of which are the populations at high risk for COVID-19. They are less in children, which is one reason hypertension is rare in children. As the Covid-19 virus attaches to the ACE2 it causes a decrease in ACE2 availability/activity. This would lead to a higher AngII and in patients with more AT-1, we would expect the effects would be worse, which is what we see in COVID-19. Another factor playing a role is that hypoxia causes cells to produce more AT-1. So the localized edema in the lungs decreases oxygen, which increased AT-1, which further leads to edema.
In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.
ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme ACE2, and that enzyme combined with the virus, than acts to enter the cell by way of the Angiotensin II receptor type 1 which is called the AT1, that are two known receptors by which angiotensin can do damage, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production, pulmonary hypertension, acute lung injury and lung fibrosis.
ARDS leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin‐(1–7) or an angiotensin II receptor (AT1) antagonist. Therapeutic intervention with Ang‐(1–7) attenuated the inflammatory mediator response, markedly decreased lung injury scores, and improved lung function, as evidenced by increased oxygenation. These data indicate that ARDS develops, in part, due to reduced pulmonary levels of Ang‐(1–7) and that repletion of this peptide halts the development of ARDS.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
A series of humoral alterations are a characteristic finding in sepsis, polytrauma, and other affections, which are often followed by an acute lung failure ARDS (adult respiratory distress syndrome) or multiple organ failure (MOF). Based on experimental and clinical findings, the cooperation of a variety of mediators and mediator systems are responsible for causing the disturbance of vascular tone and permeability and inducing the morphological transformation which finally may result in the failure of vital organs. Beside the classical mediators, such as catecholamines, histamine, serotonin, and bradykinin, increasing attention has recently focused on metabolites of arachidonic acid, cytokines, and products from circulating or resident inflammatory cells. Of all these humoral and cellular alterations, the activation and liberation of proteinases seems to play an essential role with regard to loss of capillary barrier function and interstitial edema formation.
Inflammation results in the release of mediators that cause vasodilation, increase microvascular permeability, and induce leukocyte infiltration.
An increase in serum C18 unsaturated free fatty acids is a predictor of the development of acute respiratory distress syndrome. Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS.
During intensive care treatment, patients with ARDS decrease their percentage plasma concentrations of total plasma linoleic acid, but increase their percentage concentrations of oleic and palmitoleic acids. As plasma linoleic acid concentrations decreased, there was usually an increase in plasma 4-hydroxy-2-nonenal (HNE) values, one of its specific peroxidation products, suggestive of severe oxidative stress leading to molecular damage to lipids.
Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS.
Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously ill patients, and identify those patients likely to develop ARDS. Thus, the serum acyl ratio may not only prospectively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS, but may also lead to new insights about the pathogenesis of ARDS.
Arachidonic acid (AA), an unsaturated fatty acid directly from the diet or indirectly from the metabolism of linoleic acid, is released from the breakdown of cell membrane phospholipids by the action of the enzyme phospholipase A2. Numerous stimuli, ranging from simple mechanical to specific chemical stimulation may activate what has been named the arachidonic acid cascade.
DNA is a critical molecule for oxidative damage leading to base modifications and strand breaks. The involvement of arachidonic acid suggests the lipid peroxidation may also be a requirement to mediate DNA damage under this condition.
Iron is required for many vital functions including oxygen transport and energy metabolism. Protective mechanisms maintain optimal iron concentration involving dynamic regulation of the transporters and iron storage proteins. In addition to these systemic regulatory mechanisms, the unique lung environment must provide detoxification from metal-induced oxidative stress and pathogenic infections.
Iron is required for many vital functions including oxygen transport and energy metabolism. About ¾ of total body iron is present in heme associated with hemoglobin, myoglobin and cytochromes, while nonheme iron is either stored in tissues or transported in the circulation bound to the serum protein transferrin. High iron stores promote oxidative stress triggering inflammatory responses and cellular injury that eventually leads to cell damage and death. The body has therefore developed protective mechanisms to maintain optimal iron concentration.
Acute respiratory distress syndrome (ARDS) is a type of inflammatory lung injury followed by endothelial activation and disruption of capillary membrane resulting in protein leakage Superoxide and hydrogen peroxide participate in the etiology of ARDS combined with ability of iron to catalyze more toxic reactive oxygen species. Hence, iron can exacerbate ARDS. High serum ferritin is associated with the development of ARDS. Ferritin stores iron, distributing between extracellular and intracellular spaces to play a detoxifying role. When iron levels increase, ferritin also increases to sequester reactive iron and as an acute reactive protein, ferritin synthesis is elevated during the inflammatory response. Increased ferritin levels observed in ARDS may result from increased tissue damage and lysis. Since chelatable low molecular weight iron in respiratory extracellular fluid becomes elevated in patients with ARDS compared to normal healthy volunteers, it has been proposed that the presence of pro-oxidant iron in lung epithelial fluid may contribute to susceptibility to oxidative damage. Lavage fluid of ARDS patients has elevated levels of total and nonheme iron as well as cellular content of Tf, ferritin and Lf. This indicates impaired pulmonary homeostasis of iron in ARDS, although it is unclear whether this is due to general increase in membrane permeability or altered iron metabolism.
“If you're overloaded with iron, when your cell can't use iron properly, any reductant including vitamin C will react to turn the highly oxidized iron into the partly reduced form ferrous iron. In which case that iron then becomes a major oxidant transferring its electrons to fats and proteins, DNA and so on.” Ray Peat
In addition to neutrophil activation, the unavoidable requirement of ARDS patients for high inspired oxygen concentrations (Fio2) also contributes to oxidative stress. Oxidant stress may be defined as an imbalance between the generation of oxygen derived species and the level of antioxidant protection within a system. Normally these are approximately in balance, but when the balance is tipped in favor of oxygen derived species cellular biochemistry is disturbed and a state of `oxidative stress` exists, which can lead to molecular damage. ARDS is an acute lung syndrome in which patients are experiencing severe oxidative stress from the disease process as well as from treatment with high Fio2 regimens.
Injury in ARDS involves the alveolar and pulmonary capillary epithelium. A cascade of cellular and biochemical changes is triggered by the specific causative agent. When initiated, this injury triggers neutrophils, macrophages, monocytes, and lymphocytes to produce various cytokines. The cytokines promote cellular activation, chemotaxis, and adhesion. The activated cells produce inflammatory mediators, including oxidants, proteases, kinins, growth factors, and neuropeptides, which initiate the complement cascade, intravascular coagulation, and fibrinolysis.
The cellular triggers result in vascular permeability to proteins, affecting the hydrostatic pressure gradient of the capillary. Elevated capillary pressure, such as the resulting from fluid overload or cardiac dysfunction in sepsis, increases interstitial and alveolar edema, which is evident in dependent lung areas and can be visualized as whitened area on X-rays. Alveolar closing pressure then exceeds pulmonary pressures, and alveolar closure and collapse begins.
In ARDS, fluid accumulation in lung interstitium, the alveolar spaces, and the small airways causes the lungs to stiffen, thus impairing ventilation and reducing oxygenation of the pulmonary capillary blood. The resulting injury reduces normal blood flow to the lungs. Damage can occur directly – by aspiration of gastric contents and inhalation of noxious gases – or indirectly – from chemical mediators released in response to systemic disease.
Platelets begin to aggregate and release substances, such as serotonin, bradykinin, and histamine, which attract and activate neutrophils. These substances inflame and damage the alveolar membrane and later increase capillary permeability. In the early stages, signs and symptoms may be undetectable.
Capillary permeability
Additional chemotactic factors released include endotoxins (such those present in septic states), tumor necrosis factor and interleukin-1. The activated neutrophils release several inflammatory mediators and platelet aggravating factors that damage the alveolar capillary membrane and increase capillary permeability.
Histamine and other inflammatory substances increase capillary permeability allowing fluids to move into the interstitial space. Consequently, the patient experience tachypnea, dyspnea, and tachycardia. As capillary permeability increases, proteins, blood cells, and more fluid leak out, increasing interstitial pressure and causing pulmonary edema. Tachycardia, dyspnea, and cyanosis may occur. Hypoxia (usually unresponsive to increasing fraction of inspired oxygen), decreased pulmonary compliance, crackles, and rhonchi develop. The resulting pulmonary edema and hemorrhage significantly reduce lung compliance and impair alveolar ventilation. The fluid in the alveoli and decreased blood flow damage surfactant in the alveoli. The reduces the ability of alveolar cells to produce more surfactant. Without surfactant, alveoli and bronchioles fill with fluid or collapse, gas exchange is impaired, and the lungs are much less compliant. Ventilation of the alveoli is further decreased. The burden of ventilation and gas exchange shifts to uninvolved areas of the lung, and pulmonary blood flow is shunted from right to left. The work of breathing is increased, and the patient may develop thick, frothy sputum and marked hypoxemia with increasing respiratory distress.
Mediators released by neutrophils and macrophages also cause varying degrees of pulmonary vasoconstriction, resulting in pulmonary hypertension. The result of the changes is a ventilation-perfusion mismatch. Although the patient responds with an increased respiratory rate, sufficient oxygen can’t cross the alveolar capillary membrane. Carbon dioxide continues to cross easily and is lost with every exhalation. As oxygen and carbon dioxide levels in the blood decrease, the patient develops increasing tachypnea, hypoxemia, and hypocapnia (low partial pressure of arterial carbon dioxide [PaCO2]).
Pulmonary edema worsens, and hyaline membranes form. Inflammation leads to fibrosis, which further impedes gas exchange. Fibrosis progressively obliterates alveoli, respiratory bronchioles, and the interstitium. Functional residual capacity decreases, and shunting becomes more serious. Hypoxemia leads to metabolic acidosis. At this stage, the patient develops increasing PaCO2, decreasing Ph and partial pressure of arterial oxygen (PaO2), decreasing bicarbonate (HCO3-) levels, and mental confusion.
The end result is respiratory failure. Systematically, neutrophils and inflammatory mediators cause generalized endothelial damage and increased capillary permeability throughout the body. Multiple organ dysfunction syndrome (MODS) occurs as the cascade of mediators affects each system. Death may occur from the influence of ARDS and MODS.
Local inflammatory responses
Summary:
Inflammation is the response of the body's vascularized tissues to harmful stimuli such as infectious agents, mechanical damage, chemical irritants, etc. Inflammation has both local and systemic manifestations and may be either acute or chronic. Local inflammatory response (local inflammation) occurs within the area affected by the harmful stimulus. Acute local inflammation develops within minutes or hours after the influence of a harmful stimulus, has a short duration, and primarily involves the innate immune system. The five classic signs of acute local inflammation are redness, swelling, heat, pain, and loss of function. These classical signs result from the sequence of events that are triggered by tissue damage and allow leukocytes to get to the site of damage to eliminate the causative factor. This sequence involves changes in local hemodynamics and vessel permeability, as well as a complex interaction of leukocytes with endothelium and interstitial tissue through which leukocytes escape the blood vessels. To sustain the vascular changes and attract more immune cells to the site of inflammation, leukocytes and tissue cells secrete a range of inflammatory mediators including interleukins and chemokines. Elimination of the causative factor by leukocytes leads to the resolution of acute inflammation and tissue repair with complete regeneration or scarring. Failure to eliminate the causative agent or prolonged exposure to the causative agent leads to chronic inflammation. It aims to confine the causative agent, may last months to years and primarily involves the adaptive immune system.
Acute local inflammation:
Acute inflammation is an immediate response to a pathogenic factor (e.g., trauma or infection) and has the following features:
Rapid onset (occurs minutes to hours after an encounter with a causative factor)
Transient and typically short-lasting (provided it is not caused by an immunological condition)
Involves the innate immune system
Characterized by five classic signs of inflammation, which are caused by the release of inflammatory mediators
The sequence of events in inflammatory response include:
Local hemodynamic changes (vasoconstriction → vasodilation)
Increase in vascular permeability
Extravasation of leukocytes
Phagocytosis and killing of the phagocytosed pathogen or lysis of the phagocytosed particles
Outcome of inflammatory response:
Mechanism / Signs:
Redness / Heat:
Release of vasoactive mediators by immune cells and endothelium → vasodilation → ↑ blood flow;
Mediators: Histamine, Bradykinin, Prostaglandins (PGE2, PGD2, and PGF2), NO
Swelling:
Release of mediators from immune cells and endothelium or damage to endothelium → separation of endothelial junctions → separation of endothelial cells → ↑ vascular permeability and ↑ paracellular movement of fluid → leakage of protein-rich fluid to the interstitial tissue → ↑ oncotic tissue in the interstitium → accumulation of fluid in the interstitium;
Mediators: Histamine, Leukotrienes (C4, D4, T4), Serotonin
Pain:
Stimulation of free nerve endings by certain mediators and H+ ;
Prolonged stimulation → sensitization of ion channels (e.g., TRPV1) → hyperalgesia;
Mediators: Bradykinin, PGE2
Loss of function:
Caused by the combined effect of other cardinal signs
Local hemodynamic changes:
Initial transient reflectory vasoconstriction followed by vasodilation
Vasodilation is induced by release of inflammatory mediators:
Mediator: Histamine Source: Basophils, platelets, mast cells
Mediator: Serotonin Source: Platelets
Mediator: Prostaglandins (PGE2, PGD2, and PGF2) Source: Leukocytes, platelets, endothelial cells
Mediator: Bradykinin Source: Plasma
Mediator: NO Source: Endothelial cells
Due to increased diameter of vessels and leakage of protein-rich fluid into the interstitial tissue, blood stasis occurs, which allows for margination of leukocytes.
Increase in vascular permeability:
Mechanisms
Retraction of endothelial cells
Due to the action of inflammatory mediators (histamine, serotonin, bradykinin, leukotrienes C4, D4, and T4); Occurs rapidly and does not last long; Results in opening of interendothelial spaces and paracellular leakage of plasma; Endothelial injury; Results in endothelial cell necrosis and detachment; Leakage lasts until the damaged area is thrombosed or repaired.
Effects
Leads to leakage of plasma content into the interstitial tissue, causing local edema; Allows migration of immune cells and proteins to site of injury or infection
Chemotaxis and leukocyte extravasation:
Within inflamed tissue, leukocytes (mainly neutrophils in early infection) interact with the vascular endothelium and leave the blood vessels to migrate to the site of infection. The process of neutrophil extravasation from the blood to the inflamed tissue occurs in 5 steps: margination, rolling, adhesion, diapedesis, and migration
Chronic local inflammation:
Chronic local inflammation is due to nondegradable pathogens, prolonged exposure to toxic pathogens, or autoimmune reactions.
Cells involved: mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells), fibroblasts
Leads to necrosis and fibrosis (simultaneous destruction and formation of new tissue)
May last for months to years
Mechanism involves two ways of activating macrophages
Classical (proinflammatory): mediated by Th1 cells secreting IFN-γ
Alternative (anti-inflammatory): mediated by Th2 cells secreting IL-4 and IL-13
Outcomes
Scarring
Amyloidosis
Neoplasia (e.g., chronic HCV infection → chronic hepatitis → hepatocellular carcinoma)
Granulomatous inflammation:
Granulomatous inflammation is a distinct type of chronic inflammation that is characterized by the formation of granulomas in the affected tissue. If the immune system is unable to completely eliminate a foreign substance (e.g., persistent pathogen, foreign body), the resulting granulomatous inflammation attempts to wall off the foreign substance within granulomas without completely degrading or eradicating it.
Pathophysiology:
Antigen-presenting cells present antigens to CD4+ Th cells and secrete IL-12 → stimulate differentiation into Th1 cells → Th1 cells activate macrophages by secreting IFN-γ → macrophages release cytokines (e.g., TNF), which stimulates the formation of epithelioid macrophages and giant cells
Epithelioid cells secrete TNF-α, which serves to maintain the granuloma.
Macrophages within the granuloma ↑ calcitriol (1,25-[OH]2 vitamin D3) activation → hypercalcemia
Bradykinin - Wikipedia
https://en.wikipedia.org/wiki/Kinin–kallikrein_system
Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system. - PubMed - NCBI
https://www.amboss.com/us/knowledge/Local_inflammatory_responses
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Pathophysiology
ARDS Acute Respiratory Distress in Adults
Proteinases as Mediators of the Disturbance of Pulmonary Vascular Permeability in Sepsis, Polytrauma, and ARDS
Figure 4.4, [Inflammation results in the release...]. - Capillary Fluid Exchange - NCBI Bookshelf
An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. - PubMed - NCBI
Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718378/
Inflammation occurring by edema, causes a leakage into the tissue space so what happens here is that you get a viral infection, the virus affects the lungs and with a RDS entire lung becomes inflamed not in just one area like you would have with a pneumonia, with RDS the entire lung goes crazy with inflammation and so what happens, instead of having a nice thin area, inflammation get everywhere and you get a large barrier a fluid that goes into the interstitial space furthermore these capillaries start to become leaky and fluid starts to leak into alveolar space as well and this start to fill up with liquid, proteinaceous liquid, liquid that prevents oxygen from getting into the bloodstream and so instead of having nice oxygenated blood, this blood becomes hypoxic, and you become hypoxic with RDS and you have a hard time of breathing and that’s when you get placed on the ventilator, there is really nothing you can do to speed up this up, there’s nothing you can do to slow it down, you have to be supported on the ventilator so you are getting enough oxygen and that, the Machine can breath for you until just like everything else, the edema goes away, this fluid will eventually go away as well. The key though is keeping you supported during that period of time until the fluid goes away, and then once again the oxygen will be able to go back into the system and you will get oxygen back to the tissues.
ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation). Increased bradykinin levels are also responsible for the most common side effect of ACE inhibitor treatment; a dry cough.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Bradykinin contracts airway smooth muscle, is a potent bronchial vasodilator, increases microvascular leakage, stimulates epithelial cells to release bronchodilators and stimulates mucus secretion.
Inhaled bradykinin elicits many of the features of asthma, including bronchoconstriction, cough, plasma exudation, and mucus secretion.
KKS (kallikrein-kinin system) activation and liberation of bradykinin increases endothelial cell permeability.
Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.
Bradykinin induces vasodilation by stimulating production of nitric oxide, the arachidonic acid metabolites prostacyclin (PGI-2) and PGE-2, and endothelium-derived hyperpolarizing factor.
During inflammation, it is released locally from mast cells and basophils during tissue damage.
Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs.
Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.
ACE converts Ang I to Ang II and also inactivates bradykinin.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin.
Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks. Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.
Bradykinin could also contribute to the pathogenesis of ARDS
Then, ACE mediate the conversion of AngI to AngII, a major RAS effector. ACE is a protein with high expression on membranes of vascular endothelial cells, predominantly in lung tissue. The most of the RAS associated physiologic effects are run by interacting of AngII with a G-protein coupled AngII type 1 (AT1) receptor. This activates a physiologic pathway in different tracts, such as kidney, liver, central nervous system, respiratory, and cardiovascular system. Some crucial events are regulated via active AT1 receptors including arterial pressure, fluid and sodium balance, fibrosis, and cellular growth and migration.
In some pathological conditions, overactivation of AT1 may lead to damaging events like fibrosis in different organs such as liver and lungs, perhaps through increasing TGFβ expression.
Some studies indicate that ACE2 has a protective effect on the fibrogenesis and inflammation of different organs as well as liver and lung.
According to some recent studies, ACE2 has a regulatory effect on innate immunity and gut microbiota composition. Moreover, ACE2 has a determinant antifibrotic role in the lung injury induced by sepsis, acid aspiration, SARS, and lethal avian influenza A H5N1 virus.
It is also of note that ATR-1 Receptors increase with age and are increased in cancer, diabetes, hypertension, COPD. All of which are the populations at high risk for COVID-19. They are less in children, which is one reason hypertension is rare in children. As the Covid-19 virus attaches to the ACE2 it causes a decrease in ACE2 availability/activity. This would lead to a higher AngII and in patients with more AT-1, we would expect the effects would be worse, which is what we see in COVID-19. Another factor playing a role is that hypoxia causes cells to produce more AT-1. So the localized edema in the lungs decreases oxygen, which increased AT-1, which further leads to edema.
In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.
ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme ACE2, and that enzyme combined with the virus, than acts to enter the cell by way of the Angiotensin II receptor type 1 which is called the AT1, that are two known receptors by which angiotensin can do damage, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production, pulmonary hypertension, acute lung injury and lung fibrosis.
ARDS leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin‐(1–7) or an angiotensin II receptor (AT1) antagonist. Therapeutic intervention with Ang‐(1–7) attenuated the inflammatory mediator response, markedly decreased lung injury scores, and improved lung function, as evidenced by increased oxygenation. These data indicate that ARDS develops, in part, due to reduced pulmonary levels of Ang‐(1–7) and that repletion of this peptide halts the development of ARDS.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
A series of humoral alterations are a characteristic finding in sepsis, polytrauma, and other affections, which are often followed by an acute lung failure ARDS (adult respiratory distress syndrome) or multiple organ failure (MOF). Based on experimental and clinical findings, the cooperation of a variety of mediators and mediator systems are responsible for causing the disturbance of vascular tone and permeability and inducing the morphological transformation which finally may result in the failure of vital organs. Beside the classical mediators, such as catecholamines, histamine, serotonin, and bradykinin, increasing attention has recently focused on metabolites of arachidonic acid, cytokines, and products from circulating or resident inflammatory cells. Of all these humoral and cellular alterations, the activation and liberation of proteinases seems to play an essential role with regard to loss of capillary barrier function and interstitial edema formation.
Inflammation results in the release of mediators that cause vasodilation, increase microvascular permeability, and induce leukocyte infiltration.
An increase in serum C18 unsaturated free fatty acids is a predictor of the development of acute respiratory distress syndrome. Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS.
During intensive care treatment, patients with ARDS decrease their percentage plasma concentrations of total plasma linoleic acid, but increase their percentage concentrations of oleic and palmitoleic acids. As plasma linoleic acid concentrations decreased, there was usually an increase in plasma 4-hydroxy-2-nonenal (HNE) values, one of its specific peroxidation products, suggestive of severe oxidative stress leading to molecular damage to lipids.
Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS.
Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously ill patients, and identify those patients likely to develop ARDS. Thus, the serum acyl ratio may not only prospectively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS, but may also lead to new insights about the pathogenesis of ARDS.
Arachidonic acid (AA), an unsaturated fatty acid directly from the diet or indirectly from the metabolism of linoleic acid, is released from the breakdown of cell membrane phospholipids by the action of the enzyme phospholipase A2. Numerous stimuli, ranging from simple mechanical to specific chemical stimulation may activate what has been named the arachidonic acid cascade.
DNA is a critical molecule for oxidative damage leading to base modifications and strand breaks. The involvement of arachidonic acid suggests the lipid peroxidation may also be a requirement to mediate DNA damage under this condition.
Iron is required for many vital functions including oxygen transport and energy metabolism. Protective mechanisms maintain optimal iron concentration involving dynamic regulation of the transporters and iron storage proteins. In addition to these systemic regulatory mechanisms, the unique lung environment must provide detoxification from metal-induced oxidative stress and pathogenic infections.
Iron is required for many vital functions including oxygen transport and energy metabolism. About ¾ of total body iron is present in heme associated with hemoglobin, myoglobin and cytochromes, while nonheme iron is either stored in tissues or transported in the circulation bound to the serum protein transferrin. High iron stores promote oxidative stress triggering inflammatory responses and cellular injury that eventually leads to cell damage and death. The body has therefore developed protective mechanisms to maintain optimal iron concentration.
Acute respiratory distress syndrome (ARDS) is a type of inflammatory lung injury followed by endothelial activation and disruption of capillary membrane resulting in protein leakage Superoxide and hydrogen peroxide participate in the etiology of ARDS combined with ability of iron to catalyze more toxic reactive oxygen species. Hence, iron can exacerbate ARDS. High serum ferritin is associated with the development of ARDS. Ferritin stores iron, distributing between extracellular and intracellular spaces to play a detoxifying role. When iron levels increase, ferritin also increases to sequester reactive iron and as an acute reactive protein, ferritin synthesis is elevated during the inflammatory response. Increased ferritin levels observed in ARDS may result from increased tissue damage and lysis. Since chelatable low molecular weight iron in respiratory extracellular fluid becomes elevated in patients with ARDS compared to normal healthy volunteers, it has been proposed that the presence of pro-oxidant iron in lung epithelial fluid may contribute to susceptibility to oxidative damage. Lavage fluid of ARDS patients has elevated levels of total and nonheme iron as well as cellular content of Tf, ferritin and Lf. This indicates impaired pulmonary homeostasis of iron in ARDS, although it is unclear whether this is due to general increase in membrane permeability or altered iron metabolism.
“If you're overloaded with iron, when your cell can't use iron properly, any reductant including vitamin C will react to turn the highly oxidized iron into the partly reduced form ferrous iron. In which case that iron then becomes a major oxidant transferring its electrons to fats and proteins, DNA and so on.” Ray Peat
In addition to neutrophil activation, the unavoidable requirement of ARDS patients for high inspired oxygen concentrations (Fio2) also contributes to oxidative stress. Oxidant stress may be defined as an imbalance between the generation of oxygen derived species and the level of antioxidant protection within a system. Normally these are approximately in balance, but when the balance is tipped in favor of oxygen derived species cellular biochemistry is disturbed and a state of `oxidative stress` exists, which can lead to molecular damage. ARDS is an acute lung syndrome in which patients are experiencing severe oxidative stress from the disease process as well as from treatment with high Fio2 regimens.
Injury in ARDS involves the alveolar and pulmonary capillary epithelium. A cascade of cellular and biochemical changes is triggered by the specific causative agent. When initiated, this injury triggers neutrophils, macrophages, monocytes, and lymphocytes to produce various cytokines. The cytokines promote cellular activation, chemotaxis, and adhesion. The activated cells produce inflammatory mediators, including oxidants, proteases, kinins, growth factors, and neuropeptides, which initiate the complement cascade, intravascular coagulation, and fibrinolysis.
The cellular triggers result in vascular permeability to proteins, affecting the hydrostatic pressure gradient of the capillary. Elevated capillary pressure, such as the resulting from fluid overload or cardiac dysfunction in sepsis, increases interstitial and alveolar edema, which is evident in dependent lung areas and can be visualized as whitened area on X-rays. Alveolar closing pressure then exceeds pulmonary pressures, and alveolar closure and collapse begins.
In ARDS, fluid accumulation in lung interstitium, the alveolar spaces, and the small airways causes the lungs to stiffen, thus impairing ventilation and reducing oxygenation of the pulmonary capillary blood. The resulting injury reduces normal blood flow to the lungs. Damage can occur directly – by aspiration of gastric contents and inhalation of noxious gases – or indirectly – from chemical mediators released in response to systemic disease.
Platelets begin to aggregate and release substances, such as serotonin, bradykinin, and histamine, which attract and activate neutrophils. These substances inflame and damage the alveolar membrane and later increase capillary permeability. In the early stages, signs and symptoms may be undetectable.
Capillary permeability
Additional chemotactic factors released include endotoxins (such those present in septic states), tumor necrosis factor and interleukin-1. The activated neutrophils release several inflammatory mediators and platelet aggravating factors that damage the alveolar capillary membrane and increase capillary permeability.
Histamine and other inflammatory substances increase capillary permeability allowing fluids to move into the interstitial space. Consequently, the patient experience tachypnea, dyspnea, and tachycardia. As capillary permeability increases, proteins, blood cells, and more fluid leak out, increasing interstitial pressure and causing pulmonary edema. Tachycardia, dyspnea, and cyanosis may occur. Hypoxia (usually unresponsive to increasing fraction of inspired oxygen), decreased pulmonary compliance, crackles, and rhonchi develop. The resulting pulmonary edema and hemorrhage significantly reduce lung compliance and impair alveolar ventilation. The fluid in the alveoli and decreased blood flow damage surfactant in the alveoli. The reduces the ability of alveolar cells to produce more surfactant. Without surfactant, alveoli and bronchioles fill with fluid or collapse, gas exchange is impaired, and the lungs are much less compliant. Ventilation of the alveoli is further decreased. The burden of ventilation and gas exchange shifts to uninvolved areas of the lung, and pulmonary blood flow is shunted from right to left. The work of breathing is increased, and the patient may develop thick, frothy sputum and marked hypoxemia with increasing respiratory distress.
Mediators released by neutrophils and macrophages also cause varying degrees of pulmonary vasoconstriction, resulting in pulmonary hypertension. The result of the changes is a ventilation-perfusion mismatch. Although the patient responds with an increased respiratory rate, sufficient oxygen can’t cross the alveolar capillary membrane. Carbon dioxide continues to cross easily and is lost with every exhalation. As oxygen and carbon dioxide levels in the blood decrease, the patient develops increasing tachypnea, hypoxemia, and hypocapnia (low partial pressure of arterial carbon dioxide [PaCO2]).
Pulmonary edema worsens, and hyaline membranes form. Inflammation leads to fibrosis, which further impedes gas exchange. Fibrosis progressively obliterates alveoli, respiratory bronchioles, and the interstitium. Functional residual capacity decreases, and shunting becomes more serious. Hypoxemia leads to metabolic acidosis. At this stage, the patient develops increasing PaCO2, decreasing Ph and partial pressure of arterial oxygen (PaO2), decreasing bicarbonate (HCO3-) levels, and mental confusion.
The end result is respiratory failure. Systematically, neutrophils and inflammatory mediators cause generalized endothelial damage and increased capillary permeability throughout the body. Multiple organ dysfunction syndrome (MODS) occurs as the cascade of mediators affects each system. Death may occur from the influence of ARDS and MODS.
Local inflammatory responses
Summary:
Inflammation is the response of the body's vascularized tissues to harmful stimuli such as infectious agents, mechanical damage, chemical irritants, etc. Inflammation has both local and systemic manifestations and may be either acute or chronic. Local inflammatory response (local inflammation) occurs within the area affected by the harmful stimulus. Acute local inflammation develops within minutes or hours after the influence of a harmful stimulus, has a short duration, and primarily involves the innate immune system. The five classic signs of acute local inflammation are redness, swelling, heat, pain, and loss of function. These classical signs result from the sequence of events that are triggered by tissue damage and allow leukocytes to get to the site of damage to eliminate the causative factor. This sequence involves changes in local hemodynamics and vessel permeability, as well as a complex interaction of leukocytes with endothelium and interstitial tissue through which leukocytes escape the blood vessels. To sustain the vascular changes and attract more immune cells to the site of inflammation, leukocytes and tissue cells secrete a range of inflammatory mediators including interleukins and chemokines. Elimination of the causative factor by leukocytes leads to the resolution of acute inflammation and tissue repair with complete regeneration or scarring. Failure to eliminate the causative agent or prolonged exposure to the causative agent leads to chronic inflammation. It aims to confine the causative agent, may last months to years and primarily involves the adaptive immune system.
Acute local inflammation:
Acute inflammation is an immediate response to a pathogenic factor (e.g., trauma or infection) and has the following features:
Rapid onset (occurs minutes to hours after an encounter with a causative factor)
Transient and typically short-lasting (provided it is not caused by an immunological condition)
Involves the innate immune system
Characterized by five classic signs of inflammation, which are caused by the release of inflammatory mediators
The sequence of events in inflammatory response include:
Local hemodynamic changes (vasoconstriction → vasodilation)
Increase in vascular permeability
Extravasation of leukocytes
Phagocytosis and killing of the phagocytosed pathogen or lysis of the phagocytosed particles
Outcome of inflammatory response:
Mechanism / Signs:
Redness / Heat:
Release of vasoactive mediators by immune cells and endothelium → vasodilation → ↑ blood flow;
Mediators: Histamine, Bradykinin, Prostaglandins (PGE2, PGD2, and PGF2), NO
Swelling:
Release of mediators from immune cells and endothelium or damage to endothelium → separation of endothelial junctions → separation of endothelial cells → ↑ vascular permeability and ↑ paracellular movement of fluid → leakage of protein-rich fluid to the interstitial tissue → ↑ oncotic tissue in the interstitium → accumulation of fluid in the interstitium;
Mediators: Histamine, Leukotrienes (C4, D4, T4), Serotonin
Pain:
Stimulation of free nerve endings by certain mediators and H+ ;
Prolonged stimulation → sensitization of ion channels (e.g., TRPV1) → hyperalgesia;
Mediators: Bradykinin, PGE2
Loss of function:
Caused by the combined effect of other cardinal signs
Local hemodynamic changes:
Initial transient reflectory vasoconstriction followed by vasodilation
Vasodilation is induced by release of inflammatory mediators:
Mediator: Histamine Source: Basophils, platelets, mast cells
Mediator: Serotonin Source: Platelets
Mediator: Prostaglandins (PGE2, PGD2, and PGF2) Source: Leukocytes, platelets, endothelial cells
Mediator: Bradykinin Source: Plasma
Mediator: NO Source: Endothelial cells
Due to increased diameter of vessels and leakage of protein-rich fluid into the interstitial tissue, blood stasis occurs, which allows for margination of leukocytes.
Increase in vascular permeability:
Mechanisms
Retraction of endothelial cells
Due to the action of inflammatory mediators (histamine, serotonin, bradykinin, leukotrienes C4, D4, and T4); Occurs rapidly and does not last long; Results in opening of interendothelial spaces and paracellular leakage of plasma; Endothelial injury; Results in endothelial cell necrosis and detachment; Leakage lasts until the damaged area is thrombosed or repaired.
Effects
Leads to leakage of plasma content into the interstitial tissue, causing local edema; Allows migration of immune cells and proteins to site of injury or infection
Chemotaxis and leukocyte extravasation:
Within inflamed tissue, leukocytes (mainly neutrophils in early infection) interact with the vascular endothelium and leave the blood vessels to migrate to the site of infection. The process of neutrophil extravasation from the blood to the inflamed tissue occurs in 5 steps: margination, rolling, adhesion, diapedesis, and migration
Chronic local inflammation:
Chronic local inflammation is due to nondegradable pathogens, prolonged exposure to toxic pathogens, or autoimmune reactions.
Cells involved: mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells), fibroblasts
Leads to necrosis and fibrosis (simultaneous destruction and formation of new tissue)
May last for months to years
Mechanism involves two ways of activating macrophages
Classical (proinflammatory): mediated by Th1 cells secreting IFN-γ
Alternative (anti-inflammatory): mediated by Th2 cells secreting IL-4 and IL-13
Outcomes
Scarring
Amyloidosis
Neoplasia (e.g., chronic HCV infection → chronic hepatitis → hepatocellular carcinoma)
Granulomatous inflammation:
Granulomatous inflammation is a distinct type of chronic inflammation that is characterized by the formation of granulomas in the affected tissue. If the immune system is unable to completely eliminate a foreign substance (e.g., persistent pathogen, foreign body), the resulting granulomatous inflammation attempts to wall off the foreign substance within granulomas without completely degrading or eradicating it.
Pathophysiology:
Antigen-presenting cells present antigens to CD4+ Th cells and secrete IL-12 → stimulate differentiation into Th1 cells → Th1 cells activate macrophages by secreting IFN-γ → macrophages release cytokines (e.g., TNF), which stimulates the formation of epithelioid macrophages and giant cells
Epithelioid cells secrete TNF-α, which serves to maintain the granuloma.
Macrophages within the granuloma ↑ calcitriol (1,25-[OH]2 vitamin D3) activation → hypercalcemia
Bradykinin - Wikipedia
https://en.wikipedia.org/wiki/Kinin–kallikrein_system
Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system. - PubMed - NCBI
https://www.amboss.com/us/knowledge/Local_inflammatory_responses
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Pathophysiology
ARDS Acute Respiratory Distress in Adults
Proteinases as Mediators of the Disturbance of Pulmonary Vascular Permeability in Sepsis, Polytrauma, and ARDS
Figure 4.4, [Inflammation results in the release...]. - Capillary Fluid Exchange - NCBI Bookshelf
An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. - PubMed - NCBI
Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718378/