Pathophysiology of chronic inflammation,
ethiopathogenesis, consequences,
systemic inflammation, SIRS, MODS
Immune system
• Immune system = cells, tissues and molecules that
mediate resistance to infections
• Immunology = study of the structure and function of the
immune system Immunity = host resistance to pathogens
and their toxic effects
• Immune response = collective and coordinated response
to the introduction of foreign substances into an individual
mediated by cells and immune molecules system
The role of the immune system
̶ Defense against microbes
̶ Defense against tumor
̶ Homeostasis: destruction of abnormal or dead cells (e.g. dead red
or white blood cells, antigen-antibody complex)
The components of the immune system
The type of immune response
̶ Innate (non-adaptive): the first-line immune response relies on
mechanisms that existed before infection
̶ Acquired (adaptive) immunity: The second line of response (if
innate immunity fails) relies on mechanisms involving cellular
memory of key T- and B-lymphocytes
Timeline
Innate immunity
̶ Based on genetic background
̶ Relies on existing system components
̶ Rapid response: within minutes of
infection
̶ Not specific: the same molecules / cells
respond to many pathogens
̶ No memory: the same response after
repeated exposure
̶ Does not lead to clonal expansion
Innate immunity mechanisms
̶ Mechanical barriers / excretion on the skin surface, acidic pH in
the stomach, cilia
̶ Humoral mechanisms
̶ Lysozymes, basic proteins, complement, interferons
̶ Mechanisms of cell defense by natural killers (NK cells)
neutrophils, macrophages, mast cells, basophils, eosinophils
Adaptive immunity
̶ Based on resistance acquired during life
̶ Relies on the genetic background of the individual
and cell growth
̶ The reaction is slower, in a number of days
̶ It is specific
̶ Each cell responds to one epitope on the antigen
̶ It has anamnestic memory
̶ Repeated exposure leads to a faster and stronger
reaction
̶ It leads to clonal expansion
Adaptive immunity mechanisms
• Cell-mediated immune response (CMIR)
• T-lymphocytes
• Elimination of intracellular microbes that survive
inside phagocytes or other infected cells
• Humoral immune response (HIR)
• B-lymphocytes
• antibody-mediated
• Elimination of intracellular microbes or their toxins
Adaptive immunity: mechanisms
Inflammation
Inflammation is a protective response intended
to eliminate the initial cause of cell injury as well
as the necrotic cells and tissues resulting from
the original insult
The reaction of vascularized living tissue to local
injury.
How to accomplishes protective mission?
Inflammation serves to destroy, dilute or isolate the
injurious agent (microbes, toxins) and eliminate the
necrotic cells and tissues.
Inflammation is part of a broader protective
response (innate immunity )
It starts a series of events which leads as far as
possible to the healing and reconstitution of the
damaged tissue.
Cells and molecules that play important roles in inflammation
Steps of the inflammatory
response
(1) Recognition of the injurious agent
(2) Recruitment of leukocytes
(3) Removal of the agent
(4) Regulation (control) of the response
(5) Resolution
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Inflammation
Acute inflammation
 rapid in onset (seconds or
minutes)
 relatively short duration,
lasting for minutes, several
hours, or a few days
 its main characteristics:
 the exudation of fluid and
plasma proteins (edema)
 the emigration of
leukocytes, predominantly
neutrophils.
 is of longer duration
 associated histologically with
the presence of lymphocytes
and macrophages, the
proliferation of blood vessels,
fibrosis, and tissue necrosis.
 Less uniform.
Chronic inflammation
Components of acute inflammation
VASCULAR CHANGES CELLULAR EVENTS
 Vasodilation: alterations
in vessel caliber resulting
in increased blood flow
 Increased vascular
permeability: permit
plasma proteins to leave
the circulation
 Emigration of the leukocytes
from the microcirculation and
accumulation in the focus of
injury
 Principal leukocytes in acute
inflammation are neutrophils
(polymorphonuclear
leukocytes).
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Chronic inflammation
̶ Is a pathogenic process of chronic duration (weeks, months,
years)
̶ Where attempts at healing, inflammation and persistent tissue
damage occur in different proportions
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Causes of chronic inflammation
̶ Persistent infection
̶ Toxic agents (pollutants, etc)
̶ Immune-mediated inflammatory diseases
Can Inflammation cause
considerable harm to the body?
They may induce harm
e.g. anaphylactic reaction
rheumatoid arthritis
atherosclerosis
pericarditis
Zápatí prezentace23
Primary chronic inflammation
̶ Is the cause of tissue damage in some of the most common and
disabling human diseases
̶ Rheumatoid arthritis
̶ Atherosclerosis
̶ Primary pulmonary fibrosis
̶ Tuberculosis
̶ Also, the chronic inflammation has been implicated in progression
of cancerous lesions
Tissues and cells involved in inflammatory
response :
The fluid and proteins of plasma, circulating cells, blood vessels and
connective tissue
•The circulating cells: neutrophils, monocytes, eosinophils,
lymphocytes, basophils, and platelets.
• The connective tissue cells are the mast cells, the connective
tissue fibroblasts, resident macrophages and lymphocytes.
•The extracellular matrix, consists of the structural fibrous proteins
(collagen, elastin), adhesive glycoproteins (fibronectin, laminin,
nonfibrillar collagen, tenascin, and others), and proteoglycans
Inflammation
During repair, the injured tissue is replaced by :
• Regeneration of native parenchyma cells
• Filling of the defect by fibroblastic tissue or both
Inflammation and repair are protective response
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Morphological features of chronic
inflammation
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Fibrosis
• Fibrosis is defined by the overgrowth,
hardening, and/or scarring of various tissues
and is attributed to excess deposition of
extracellular matrix components including
collagen.
• Fibrosis is the end result of chronic
inflammatory reactions induced by a variety
of stimuli including persistent infections,
autoimmune reactions, allergic responses,
chemical insults, radiation, and tissue injury.
Matthias Mack, Matrix Biology, Volumes 68–69, 2018,
Zápatí prezentace28
Major tissues affected by fibrosis and
possible contributing factors
• Liver—Viral hepatitis, schistosomiasis, and alcoholism are leading causes of cirrhosis worldwide.
• Lung—The interstitial lung diseases (ILDs) include a diverse set of disorders in which pulmonary inflammation and fibrosis
are the final common pathological manifestations. There are more than 150 different causes of ILDs, including sarcoidosis,
silicosis, drug reactions and infections, as well as collagen vascular diseases, such as rheumatoid arthritis and systemic
sclerosis (scleroderma). Idiopathic pulmonary fibrosis, the most common type of ILD, has no known cause
• Kidney disease—Diabetes damages and scars the kidneys, which can lead to a progressive loss of function. Untreated
hypertension can contribute
• Heart and vascular disease—Following a heart attack, scar tissue can impair the ability of the heart to pump blood.
Hypertension, atherosclerosis and restenosis also contribute
• Eye—Macular degeneration, retinal and vitreal retinopathy can lead to blindness
• Skin—Including keloids and hypertrophic scars. Systemic sclerosis and scleroderma, burns and genetic factors may also
contribute
• Pancreas—Poorly understood but possible autoimmune/hereditary causes
• Intestine—Crohn’s disease/inflammatory bowel disease. Pathogenic orgnanisms
• Brain—Alzheimer’s disease, AIDS
• Bone marrow—Cancer and ageing
• Multi-organ fibrosis—(a) Due to surgical complications; scar tissue can form between internal organs, causing contracture,
pain and, in some cases, infertility; (b) chemotherapeutic drug-induced fibrosis; (c) radiation-induced fibrosis as a result of
cancer therapy/accidental exposure; (d) mechanical injuries
J Pathol. 2008 Jan; 214(2): 199–210
Zápatí prezentace29
Innate immune cells in fibrosis
• Dysregulated innate and
adaptive immune
responses are major
contributors to fibrosis.
• However, cell-intrinsic
modifications in fibroblasts
and other structural cells
can also contribute to
fibrosis
Zápatí prezentace30
The role of macrophages in chronic
inflammation
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The role of macrophages in chronic
inflammation and ECM remodelling
Macrophages play a pivotal
role in secretion of ECM
components and in ECM
remodelling.
They are major sources of
matrix metalloproteinases
(MMPs) and tissue inhibitor
of metalloproteinases
(TIMPs) and are the primary
cells involved in the
phagocytosis of cellular
debris and infectious agents.
Zápatí prezentace32
The role of neutrophils in chronic
inflammation and ECM remodelling
Activated neutrophils have recently
been found to form neutrophil
extracellular traps (NETs) that are
involved in immune responses to
pathogens.
NETs are composed of chromatin and
granular proteins, including nuclear
DNA, histones, MMP-9,
myeloperoxidase (MPO), neutrophil
elastase (NE), and cathepsin G.
Zápatí prezentace33
Age-dependent consequences
SIRS – systemic inflammatory response
syndrome
• Generalized acute inflammatory reaction that spreads throughout
the body
• Intense inflammatory response to primary local, multiple or
otherwise complex damage
• In SIRS, subsequent inflammation is not limited to the area where
the inflammation occurred, but spreads throughout the body
• Even common inflammation spreads throughout the body - the
difference from SIRS is that in SIRS, the mechanisms of
inflammation control stop working
SIRS
• Generalized deregulated destructive
process
• Often associated with the devastation
of distant organs
• In hypersensitivity individuals, SIRS
may occur even with very small
amounts of antigen
•Classification:
1) septic SIRS - associated with infection
2) non-septic SIRS - after severe trauma, hypoxemia,
burns, poisoning, incompatible transfusion
Sepsis
̶ Disseminated microbial infection
̶ 50% - gram-positive bacteria, 30% gram-negative
bacteria, 5% polymicrobial
infections, 5% yeasts
and fungi and 1% anaerobes
̶ 1/3 of those affected die
Primary SIRS
Secondary SIRS
Definition of systemic inflammatory
response syndrome (SIRS) and
multiple organ dysfunction syndrome
(MODS)
Systemic inflammatory response
syndrome
• The systemic inflammatory response to a
variety of severe clinical insults is manifest by
two or more of the following conditions:
• Temperature > 38°C or < 36°C
• Heart rate > 90 beats/min
• Respiratory rate > 20 breaths/min or Paco2 <
32 mmHg (or ventilator dependence)
• White blood cell count > 12 000 cells/mm3, <
4000 cells/mm3 or > 10% band forms
Mulitple organ dysfunction
syndrome
The presence of altered function
involving at least two or more organ
systems in an acutely ill patient
such that homeostasis cannot be
maintained without intervention
Definitions
• Multiple Organ Dysfunction Syndrome “MODS”
1991 Consensus conference of the American College of
Chest Physicians (ACCP) and the Society of Critical Care Medicine
(SCCM)
Dysfunction replaced failure to accentuate the reversible nature of
the condition
• Underlying concept
Sepsis, systemic inflammatory response syndrome (SIRS), acute
respiratory distress syndrome (ARDS), and MODS are closely
related phenomena
Mortality in intensive care unit black
Mortality to hospital discharge black + dark grey
Mortality to 1 year black + dark grey + light grey.
Mayr VD et al Causes of death and determinants of outcome in critically ill patients Crit Care 10:R154, 2006.
Most organ failure assessment systems assign values to six organ
systems
• Respiratory
• Cardiovascular
• Renal
• Hematology
• Hepatic
• Central nervous system
Definitions
Pathogenesis of multiple organ dysfunction Crit Care Clin
2000;16:337-352
Multiple System Organ Failure Score
Organ failure Criteria
Cardiovascular Heart rate ≥ 54/min
Mean arterial pressure ≤ 49 mm Hg or systolic blood pressure < 60 mm Hg
Ventricular tachycardia or fibrillation
PH ≤ 7.24 with PaCO2 ≤ 49 mm Hg
Respiratory Respiratory rate ≤ 5/min or ≥ 49/min
PaCO2 ≥ 50 mm Hg
Alveolar to arterial oxygen tension gradient ≥ 350 mm Hg
Dependent on ventilator or CPAP on second day of OSF
Renal Urine output ≤ 479/mL/24 hours or ≤ 159 mL/8 hours
Blood urea nitrogen ≥ 100 mg/dL
Creatinine ≥ 3.5 mg/dL
Hematologic White blood cell count ≤ 1000/mm3
Platelets ≤ 20,000/mm3
Hematocrit ≤ 20%
Neurologic Glasgow coma score ≤ 6 (in the absence of sedation)
42 Abbreviations: CPAP, continuous positive airway pressure; OSF, organ system failure; PaCO2, arterial CO2 tension.
Definitions and grading of organ
dysfunction (MODS score)
43 Mayr VD et al Causes of death and determinants of outcome in critically ill patients Crit Care 10:R154, 2006.
Potential Pathophysiologic Mechanisms
Producing MODS
• Circulating immune/inflammatory
mediators
• Primary cellular injury
• Mitochondrial Injury/ down-regulation
• Inadequate tissue/organ perfusion
Hypoperfusion
Ischemia/reperfusion
Microaggregation and/or DIC
• Diffuse endothelial cell injury
• Circulating humoral factors
• Protein calorie malnutrition
• Bacterial-toxin translocation
• Adverse effect of directed treatment or
medication
Inflammatory Model
• MODS is caused by an overwhelming
imbalance between systemic inflammatory
response and counter regulation (antiinflammatory)
response.
• May be activated by a number of external and
internal factors, including pro-inflammatory
(e.g., infection, sepsis, shock, and trauma)
and immunosuppression (e.g., Blood
transfusion, infection, and steroids).
• The imbalance in favor of inflammatory
response causes loss of the host's ability to
localize the inflammation to initial inciting
factor, leading to systemic inflammation and
tissue damage. Karima et. al, The molecular pathogenesis of endotoxic shock
and organ failure Mol Med Today 1 March 1999, 123-132
• Multiple organ dysfunction - result of the
dysregulation of mitochondria
• Mitochondrial activity is down-regulated as a
protective reflex to inciting factors
• Failure to recover mitochondrial function
results in self perpetuating cycle of cell
damage furthering shutdown of mitochondria
• Findings imply a metabolic shutdown rather
than structural damage as a key
pathophysiological mechanism
Bioenergetics Model
Giacomo Stanzani, et al. Biochimica et Biophysica Acta (BBA) - Molecular
Basis of Disease, Volume 1865, Issue 4, 2019.
Progression of Bioenergetics Dysfunction
Mervyn Singer, Mitochondrial function in sepsis: Acute phase versus multiple organ failure (Crit Care Med 2007; 35)
Sepsis-induced cardiomyopathy (SIC)
• cardiovascular abnormalities during sepsis recognised
for over 50 years
• an intrinsic and reversible systolic and diastolic
dysfunction of both the left and right sides of the
heart induced by sepsis
• potential reversibility observed in numerous
studies
• Both macroscopic and microscopic findings
of myocarditis have been noted at post-mortem
while evidence of non-ischemic cardiac injury
compatible with inflammation or
tissue acidosis was observed
Hollenberg, S.M., Singer, M. Nat Rev Cardiol 18,
424–434 (2021).
Patophysiology of SIC
Numerous circulating factors contribute
• include both pathogen-associated molecular
patterns (PAMPs) such
as lipopolysaccharide (LPS) and host-produced
danger-associated molecular patterns (DAMPs)
• These endogenous danger signals include
cytokines, heat-shock proteins, high-mobility
group box 1, histones, activated complement
components, and mitochondrial DNA.
• interaction of a wide range of signalling
pathways rather than any single individual factor
Front. Immunol., 24 August 2017
Mitochondrion
• Besides their role in ATP production, mitochondria also
play an essential role in numerous other cell functions
• calcium homeostasis,
• hormone metabolism,
• thermoregulation,
• reactive oxygen and nitrogen species production,
• cell signalling,
• key regulators of apoptosis and cell death.
• Mitochondrial dysfunction and bioenergetic failure are
thus increasingly recognized as central to the
pathophysiology of numerous cardiovascular diseases.
• These findings suggest a key role for both a cellular
bioenergetic deficit, and more specifically mitochondrial
dysfunction, and a metabolic shutdown, in the
pathogenesis of sepsis-induced organ failure.
Front. Cardiovasc. Med., 14 July 2023
Sepsis and cradiac dysfunction - summary
51
Suzuki, T., Suzuki, Y., Okuda, J. et al. j intensive care 5, 22 (2017).
Multifactor Models - Gut
Gut-liver-lung axis
• Initiation of the inflammatory state
can occur in any of these organs
following trauma or shock.
• The gut can leak inflammatory
mediators into the portal circulation,
causing a response in the liver.
• Inflammatory mediators then travel
in the hepatic vein to the inferior
vena cava and to the lungs.
• The lungs may become injured and
release inflammatory substances
themselves, which travel
systemically to distant organs
(including the gut). Zhang, X., Liu, H., Hashimoto, K. et al. Crit Care 26, 213 (2022).
LPS, Lipopolysaccharide.
Gut-liver-lung axis in response to shock and hemorrhage Martinez-Mier G, Toledo-Pereyra LH,
Ward PA: J Trauma 51:408, 2001.
Zápatí prezentace54
SIRS and Covid-19
Zápatí prezentace55
Pathogenesis of Covid-19 disease – key
steps
Zápatí prezentace56
SIRS, MODS and Covid-19
Shock - definition
 Severe tissue hypoperfusion resulting in low supply of oxygen to the organs
 Systemic hypotension (of various causes) is present
 P = Q  R
 Q ~ CO = SV  f
 CO depends on
a) cardiac function
b) venous return (→preload)
• R – systemic resistance (mostly arterioles) - afterload
Zápatí prezentace59
̶ In early shock, compensation occurs by modulation of cardiac
output and vascular tone by the autonomic nervous system.1
Carotid baroreceptors respond to decreased blood pressure by
triggering increased sympathetic signaling. This autonomic
nervous system-mediated sympathetic response results in an
increase in contractility and heart rate, thereby increasing cardiac
output.
Zápatí prezentace60
Shock categories
Zápatí prezentace61
Shock
Zápatí prezentace62
Neurogenic shock – special situation
• state of imbalance between sympathetic and
parasympathetic regulation of cardiac action and vascular
smooth muscle. The dominant signs are profound
vasodilation with relative hypovolemia while blood volume
remains unchanged, at least initially.
• Direct injury to the centers for circulatory regulation due to
compression (brainstem trauma), ischemia (e.g., basilar
artery thrombosis), or the influence of drugs
• Altered afferents to the circulatory center in the medulla
oblongata due to fear, stress, or pain or dysregulated
vagal reflexes
• Interruption of the descending connection from the bulbar
regulatory centers to the spinal cord, especially in patients
who have sustained trauma above the middle of the
thoracic spine (paraplegia).
Dtsch Arztebl Int. 2018 Nov; 115(45): 757–768.
Phases of shock
̶ Compensation of initiating cause
̶ Decompensation
̶ Refractory shock
Compensatory mechanisms and their limits
 Activation of sympathetic nervous system (tens of seconds)
 Activation of RAAS (cca 1 hour)
 Vasoconstriction (if possible) – but it leads into lower blood
supply
 Vasodilatation in some tissues (esp. myocardium)
 Positively inotropic effect of SNS (if possible) – but at cost of
higher metabolic requirements of the heart
 Increased heart rate – but CO decreases in high HR (>150
bpm)
 Keeping circulating volume by lower diuresis – but at cost of
acute renal failure
 Shift to anaerobic metabolism – but at cost of ↓ ATP a ↑
lactate (acidosis)
 Increased respiratory rate (but shallow breathing results in ↑
relative deadspace)
 Shift of saturation curve of hemoglobin to right (↑2,3-DPG)
 Hyperglycemia – but there is decreased utilization of Glc in
the periphery
Heart rate [min-1]
Cardiacoutput[dm3.min-1]
Decompensated shock
̶ ↓ BP
̶ ↓ diuresis
̶ Brain hypoperfusion – involvment of mental functions
̶ Acrocyanosis
̶ Tachypnea
̶ “Golden hour“
Refractory shock
1) Vasodilatation ↔ hypoperfusion
̶ Endothelial cells contain two isoforms of nitric oxid synthase – constitutive (eNOS) and
inducible (iNOS)
̶ In lasting hypoxia of endothelial cells there is increased iNOS activity (primarily
physiological mechanism)
̶ ↑NO increases vasodilation and hypoperfusion
̶ Lactate acidosis → hypotension (lactate – prognostic factor)
2) Myocardial hypoxia ↔ lower contractility
̶ Lower myocardial perfusion leads into ↓CO, which further reduces coronary flow
̶ Myocardium does not benefit from the shift of Hb saturation curve – efficiency of O2
extraction is already at its maximum
3) Brain hypoperfusion ↔ ↓SNS activity
̶ Lower perfusion of vasomotor centre leads first into SNS hyperactivity, which is then
followed by its supression
̶ That leads into ↓brain perfusion
Zápatí prezentace67
Thank you for you attention
Zápatí prezentace68
Pathogenesis of Covid-19 disease
̶ Coronaviruses belong to the Coronaviridae family in the Nidovirales order
̶ Corona represents crown-like spikes on the outer surface of the virus; thus, it
was named as a coronavirus
̶ Coronaviruses are enveloped viruses, minute in size (65–125 nm in diameter)
and contain a single-stranded RNA as a nucleic material, size ranging from
26 to 32kbs in length
Zápatí prezentace69
Covid-19
̶ The virus that causes COVID-19 is known as SARS-CoV-2
It appears to have first emerged in Wuhan, China, in late 2019.
̶ The outbreak has since spread across China to other countries around the world. By the end
of January, the new coronavirus had been declared a public health emergency of
international concern by the WHO.
̶ The most commonly reported symptoms include a fever, dry cough and tiredness, and in mild
cases people may get just a runny nose or a sore throat.
̶ In the most severe cases, people with the virus can develop difficulty breathing, and may
ultimately experience organ failure. Some cases are fatal.
̶
Zápatí prezentace70
Human coronaviruses
̶ The most likely ecological reservoirs for
coronaviruses are bats, but it is believed
that the virus jumped the species barrier
to humans from another intermediate
animal host.
̶ This intermediate animal host could be a
domestic food animal, a wild animal, or a
domesticated wild animal which has not
yet been identified.
Zápatí prezentace71
Covid-19 timeline
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Pathogenesis of Covid-19 disease
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Pathogenesis of Covid-19 disease
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Pathogenesis of Covid-19 disease
̶ Coronavirus is one of the major pathogens that primarily targets
the human respiratory system. Previous outbreaks of
coronaviruses (CoVs) include the severe acute respiratory
syndrome (SARS)-CoV and the Middle East respiratory syndrome
(MERS)-CoV which have been previously characterized as agents
that are a great public health threat. In late December 2019, a
cluster of patients was admitted to hospitals with an initial
diagnosis of pneumonia of an unknown etiology.
Zápatí prezentace75
Pathogenesis of Covid-19 disease