Systemic Response To Injury and Metabolic Support Flashcards
Which injury activates the innate immune system to produce a Systemic Inflammatory Response?
Traumatic Injury
What are the 2 responses of SIR
○ an acute proinflammatory response resulting from innate immune system recognition of ligands
○ an anti-inflammatory response that may serve to modulate the proinflammatory phase and direct a return to homeostasis
.DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS) OR ALARMINS
Endogenous molecules that are produced as a consequence of tissue damage or cellular stress \
● These molecules interact with immune and non immune cell receptors to initiate a “sterile” systemic inflammatory response following severe traumatic injury.
Pathogen-Associated Molecular Patterns
e pathogen-associated molecular patterns (PAMPs), they interact with specific cell receptors that are located both on the cell surface and intracellularly. The best described of these receptors are members of the toll-like receptor family.
Binding of DAMP and PAMP elicits?
Same receptor Response
DAMPs Example
Best-characterized DAMP in the context of the injury- associated inflammatory response. ● Released passively from damaged or necrotic cells and is detected rapidly in the circulation within 30 minutes post injury
HIGH-MOBILITY GROUP PROTEIN B1
The diverse proinflammatory biologic responses that result from HMGB1 signaling include:
○ The release of cytokines and chemokines from macrophage/ monocytes and dendritic cells;
○ neutrophil activation and chemotaxis;
○ alterations in epithelial barrier function, including increased permeability
○ increased procoagulant activity on platelet surfaces
What activates the HMGB1 and TLR24 receptors?
Pro-inflammatory cytokine release (sickness behaviour)
Toll Like Receptor Signaling occurs via
s (TLR2, TLR4, TLR9) (activation of TLRs mainly occurs in myeloid cells)
receptor for advanced glycosylation end products (RAGE)
(thought to be receptor target in endothelial and somatic cells) CD24
A patient presenting with Pulmonary edema and Pleural Effusion activated which DAMP receptor?
HMGB1
Traumatic Brain Injury (TBI)
> identification of the RAGE as the receptor for HMGB1 in this setting has identified a new therapeutic strategy to ameliorate ALI following TBI
. MITOCHONDRIAL DNA (mtDNA)
Mitochondrial proteins and/or DNA can act as DAMPs by triggering an inflammatory response to necrosis and cellular stress.
stimulator of interferon gene pathway (STING)
Leaked from damaged mitochondria, leads both to inflammasome activation
mtDNA in Clinic
cf-mtDNA levels to be higher in injury nonsurvivors when compared to survivor thus it use as marker for prognosis
○ Targeting enzymes capable of digesting circulating mtDNA is an attractive therapeutic option
Function as molecular chaperones to monitor and maintain appropriate protein folding, physiological seen in our cytoplasm which discard improperly folded proteins
Protects cells from the effects of traumatic stress and alerts the immune system of the tissue damage by activating both innate and acquired immunity.
Intracellular proteins that are expressed during times of inflammation and oxidative stress or following tissue injury
HEAT-SHOCK PROTEINS
HSP90
Cytoplasm, ER, both inside and outside cell
Acts ad DAMP chaparone
Binds to RNAP2, glucocorticoid response, TLR expression, Chaparone IKK
HSP70
Inside and outisde cell
ER and homologus to BiP
Exogenous: Elicit cellular calcium, NF-kB activation and Cytokine
Anti-inflammatory
PATTERN RECOGNITION RECEPTORS (PRRS)
● DAMPs are ligand for Pattern Recognition Receptors
● Surface and cytoplasmic receptors that sense DAMPS and mediate the innate immune response
● Classes of receptors that are important for sensing damaged cells and cell debris / DAMPs which are the same receptors that cells use to sense invading pathogens
● Following receptor ligation, intracellular signaling modulates synthesis and release of cytokines and chemokines to either initiate or suppress the inflammatory response
PPR innate response classes (Schwartz)
TLR
CLR
NOD
NLR
RAGE
RLR
SOLUBLE PATTERN RECOGNITION MOLECULES: THE PENTRAXINS
● molecularly diverse group of molecules that share a conserved mode of action defined by complement activation, agglutination and neutralization, and opsonization
● synthesized at sites of injury and inflammation by macrophages and dendritic cells
Pentraxin is activated in the…
neutrophils and liver epithelial cells
CRP (Pentraxin)
o short pentraxin; first PRM to be identified
o acute-phase protein response in humans
o marker of the proinflammatory response in many clinical settings, including appendicitis, vasculitis, and ulcerative colitis
Serum amyloid Protein (SAP)
has 51% sequence similarity to human CRP, also contains the pentraxin molecular signature
PENTRAXIN 3 (PTX3)
o A long pentraxin family member, in the “sterile” inflammatory response associated with cellular stress
o Produced by various cells in peripheral tissues, including immune cells
o Plasma concentrations increase rapidly in various inflammatory conditions, including sepsis
I. CENTRAL NERVOUS SYSTEM REGULATION OF INFLAMMATION IN RESPONSE TO INJURY
NEUROENDOCRINE RESPONSE TO INJURY
● Hypothalamic-Pituitary-Adrenal Axis ● Sympathetic nervous system
Hypothalamic Regulation
● Corticotropin-releasing hormone
● Thyrotropin-releasing hormone
● Growth hormone-releasing hormone
● Luteinizing hormone-releasing hormone
Anterior Pituitary Regulation
● Adrenocorticotropic hormone ● Cortisol ● Thyroid-stimulating hormone ● Thyroxine ● Triiodothyronine ● Growth hormone ● Gonadotrophins ● Sex hormone ● Insulin-like growth factor ● Somatostatin ● Prolactin ● Endorphins
Posterior Pituitary Regulation
● Vasopressin ● Oxytocin
Autonomic System
● Norepinephrine ● Epinephrine ● Aldosterone
Renin-Angiotensin System
● Insulin ● Glucagon ● Enkephalins
Steps of HPA axis
Injury → Circulating cytokines or direct neural input via vagal fibers → hypothalamus → corticotropin-releasing hormone (CRH) release → anterior pituitary → ACTH release → zona fasciculata of the adrenal glands → glucocorticoids release
● These cytokines include tumor necrosis factor-α (TNF-α), IL-1α, IL-6, and the type I interferons (IFN-α/β)
CORTISOL
● Major glucocorticoid in humans, with anti-inflammatory actions
● actions through a cytosolic receptor, the glucocorticoid receptor (GR)
● modulate proinflammatory gene transcription, with a ‘net’ anti-inflammatory effect
CORTISOL INSUFFICIENCY SYNDROMES
● Adrenal insufficiency- atrophic adrenal glands caused by exogenous steroid administration
● Critical illness-related corticosteroid insufficiency (CIRCI)
o exaggerated proinflammatory response associated with a blunted adrenocortical response
MACROPHAGE MIGRATION INHIBITORY FACTOR
● Expressed from anterior pituitary, macrophages and T-lymphocytes \
● Counteract the anti-inflammatory activity of glucocorticoids
● MIF a central role in the exacerbation of inflammation associated with acute lung injury, detected in the affected lungs and in alveolar macrophages
● MIF upregulate the expression of TLR4 in macrophage
GROWTH HORMONE
● ● Expressed by the pituitary gland that has both metabolic and immune-modulatory effect ● Promotes protein synthesis and insulin resistance, enhances the mobilization of fat stores ● upregulated by hypothalamic GH-releasing hormone and downregulated by somatostatin ● Enhances phagocytic activity of immunocytes ● Enhances enhanced hepatic synthesis of insulin-like growth factor-1 (IGF-1)
IGF-1
● Anabolic growth factor that is known to improve the metabolic rate, gut mucosal function, and protein loss after traumatic injury ● Less than 5% of IGF-1 circulates free in the plasma ● Majority of IGF-1 bound to IGFBP-3 ● stimulates protein synthesis and glycogenesis; increases glucose uptake and lipid utilization ● Decreased in critical illness, leading to a catabolic state
GHRELIN
● a natural ligand for the GH-secretagogue receptor 1a (GHS-R1a) ● appetite stimulant that is secreted by the stomach ● GHS-R1a is expressed in a variety of tissues in different concentrations including the immune cells, B and T cells, and neutrophils ● role in promoting GH secretion, and in glucose homeostasis, lipid metabolism, and immune function ● high ghrelin levels were a positive predictor of ICU-survival in septic patients
Which ligand is a predictor for the survival of ICU patients?
Ghrelin
SYMPATHETIC NERVOUS SYSTEM
Preganglionic sympathetic fibers innervating the adrenal medulla (modified postganglionic neuron) → secretes acetylcholine → chromaffin cells → release epinephrine (EPI) and norepinephrine (NE)
SYMPATHETIC NERVOUS SYSTEM enhances
Enhance Th2 and decrease Th1 response
. INSULIN
● Hyperglycemia and insulin resistance are hallmarks of injury and critical illness due to the catabolic effects of circulating mediators, including catecholamines, cortisol, glucagon, and growth hormone. ● Although there is an increase in insulin production at the same time, severe stress is frequently associated with insulin resistance, leading to acute hyperglycemia.
Predictor for critical illness mortality
Hyperglycemia
The side effects of too much cortisol and growth hormone will be insulin resistance and hyperglycemia
ALDOSTERONE
● A mineralocorticoid released by the zona glomerulosa of the adrenal cortex ● It binds to the mineralocorticoid receptor (MR) of principal cells in the collecting duct of the kidney where it can stimulate expression of genes involved in sodium reabsorption and potassium excretion to regulate extracellular volume and blood pressure ● It reduces expression of the insulin-sensitizing factors which contribute to insulin resistance ● In dendritic cells, MR activation by aldosterone induces the secretion of proinflammatory cytokines ● This prevents insulin resistance ● It also gives negative feedback to anti-inflammatory effects by inducing pro-inflammatory cytokines.
THE CELLULAR STRESS RESPONSE
- Reactive Oxygen Species and the Oxidative Stress Response
- The Unfolded Protein Response
- Autophagy
- Apoptosis
- Necroptosis
- Pyroptosis
AAP RUN
REACTIVE OXYGEN SPECIES AND THE OXIDATIVE STRESS RESPONSE
Reactive oxygen and nitrogen species (ROS, RNS, respectively) are small molecules that are highly reactive due to the presence of unpaired outer orbit electrons ● Cause cellular injury to host cells and invading pathogens through the oxidation of cell membrane substrates, cellular proteins, and DNA ● ROS has also been shown to have important roles as signaling messengers, particularly in the immune system
provides negative feedback for ROS synthesis
Pyruvate kinase
. UNFOLDED PROTEIN RESPONSE
Cellular stress leads to the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER)
● The mechanism by which ER distress signals are sent to the nucleus to modulate transcription in an attempt to restore homeostasis
imp Protein in URP
IRE1
PK_RNA
PERK
AFT6
UPR clinical setting
UPR proteins elevated in critically ill, correlates with severity, linked to insulin resistance. UPR proteins serve as markers.
AUTOPHAGY
aka macroautophagy; a way of disposing of damaged organelles and debris aggregates, ROS
○ Phagophore
>autophagosome>autolyso some
AUTOPHAGY stimulated by_______, Inhibited by ________
Th1, Th2
APOPTOSIS
● Regulated cell death
● Mechanism for clearing senescent or dysfunctional cells without promoting an inflammatory response
○ This contrasts with cellular necrosis, which results in a disorganized sequence
mortality in sepsis is due to
Sometimes, with unregulated apoptosis
inflammatory products inhibit the
neutrophil apoptosis
Apoptosis proceeds primarily through two pathways:
the extrinsic pathway and the intrinsic pathway
PYROPTOSIS
● A form of regulated cell death that is dependent on the activity of the proinflammatory caspase enzyme associated with inflammasome
● In contrast to apoptosis, apoptosis has no involved inflammation, while pyroptosis is caused by inflammation
The similarity between pyroptosis and apoptosis
DNA fragmentation and positive annexin V staining
Pyroptosis is mainly observed in
macrophages, dendritic cells and neutrophils
MEDIATORS OF INFLAMMATION
- Cytokines 2. Eicosanoids 3. Plasma Contact system 4. Serotonin 5. Histamine
CEPSH
Cytokines
Class of protein signalling compounds that are essential for both innate and adaptive immune responses.
● Protein signaling compounds that mediate a broad sequence of cellular responses, including cell migration, DNA replication, cell turnover, and immunocyte proliferation
Anti-inflammatory mediators may also result in
immunocyte dysfunction and host immunosuppression
TNF (Tumor Necrosis Factor)
○ Among the earliest responders to injury
○ Half life of less than 20 minutes
○ Pro-inflammatory cytokine
○ Affects TNFR1 and TNFR2
TNFR1 are sequestered in the,
golgi
TNFR2 are confined to
plasma membrane
IL-1
○ Pro-inflammatory cytokine \
○ Similar physiologic effect as with TNF
○ Induces fever through prostaglandin activity \
○ Half life of less than 6 minutes
2 receptor types for IL1
○ IL-1R1 is widely expressed and mediates inflammatory signaling on ligand binding.
○ IL-1R2 is proteolytically cleaved from the membrane surface to soluble form on activation and thus serves as another mechanism for competition and regulation of IL-1 activity
IL-2
○ Promotes lymphocyte proliferation
○ Half life of less than 10 minutes
○ Is a multifunctional cytokine produced primarily by CD4+ T cells after antigen activation, which plays pivotal roles in the immune response
Other cellular sources for IL-2
CD8+ and NK T cells, mast cells, and activated dendritic cells, and is also essential for the development and maintenance of T regulatory (Treg) cells
Subunits of IL2-R
L-2Rs are formed from various combinations of three receptor subunits: IL-2Rα, IL-2Rβ, and IL-2Rγ
IL-4
Mainly a regulator of allergic and anthelmintic response
IL-6
○ One with the longest half-life ○ IL-6 levels in the circulation are detectable by 60 minutes post injury, peak between 4 and 6 hours, and can persist for as long as 10 days.
○ Plasma levels of IL-6 are proportional to the degree of injury
IL-10
○ One of the most prominent anti-inflammatory cytokine by regulating the duration and magnitude of inflammation in the host
○ IL-10 inhibits the secretion of proinflammatory cytokines, including TNF and IL-1
IL-12
○ Unique among the cytokines in being the only heterodimeric cytokine
IL-17
○ The major effector cytokine predominantly produced by a subset of helper T cells, the T helper (Th)-17 cells
○ The original described activity for IL-17A was to promote the differentiation of bone marrow progenitor cells along the granulopoietic lineage.
○ Subsequent studies have confirmed that IL-17A is required for increasing circulating neutrophil numbers following stress
Interferons
First recognized as soluble mediators that inhibited viral replication through the activation of specific antiviral genes in infected cells
GMC-SF/IL-3/IL-5
○ Compose a small family of cytokines that regulates the growth and activation of immune cells
○ Able to link the innate and acquired immune responses
○ With the exception of eosinophils, they are not essential for constitutive hematopoietic cell function
Rather, they play an important role when the host is stresse
EICOSANOIDS
Eicosanoids are derived primarily by oxidation of the membrane phospholipid, arachidonic acid (AA), which is relatively abundant in the membrane lipids of inflammatory cells
physiologic roles of Eicosanoids
● Eicosanoids have a broad range of physiologic roles, including neurotransmission, vasomotor regulation, and immune cell regulatio
Eicosanoids are associated with which injury
associated with acute lung injury, pancreatitis, and renal failu
C. FATTY ACID METABOLITES
● Fatty acid metabolites function as inflammatory mediators and as such have significant roles in the inflammatory respon
OMEGA-6 POLYUNSATURATED FAT METABOLITES: ARACHIDONIC AC
● It is derived by oxidation of the membrane phospholipid, arachidonic acid (AA). The major precursor of arachidonic acid is the omega-6 (n-6) polyunsaturated fatty acid (PUFA) linolenic acid, a major source of which is soybean oil
● This arachidonic acid has been targets of many drugs like
e glucocorticoids, NSAIDs, and leukotriene inhibitors
OMEGA-3 POLYUNSATURATED FAT METABOLITES: ALL-CIS-5, 8, 11, 14, 17-EICOSAPENTAENOIC ACID
D ● The second major family of PUFAs is the omega-3 fatty acid, alpha-linolenic acid, which is found primarily in cold water fish as advertised in your tuna commercials
● They have specific anti-inflammatory effects, including inhibition of TNF release from hepatic Kupffer cells, and leukocyte adhesion and migration
● Omega-3 fatty acid supplementation has the potential to dampen inflammat
How are Omega 3 different from Omega 6
● As compared with omega-6 derivatives, these have anti-inflammatory effects.
● Omega-3 supplementation has been used in the ICU setting because of patients with severe inflammation
Phospolipid Pathways
Eicosanoid table
PLASMA CONTACT SYSTEM
Complement
○ Part of the innate immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promotes inflammation and attacks the pathogens cell membrane
KALLIKREIN-KININ SYSTEM
● Group of proteins that contribute to both coagulation and inflammation.
● Kallikrein is both proinflammatory and procoagulant
physiologic processes of KK system
The kinins mediate several physiologic processes, including vasodilation, increased capillary, permeability, tissue edema, and neutrophil chemotaxis. \
● Bradykinin and kallikrein levels are increased following hemorrhagic shock and tissue injury.
SEROTONIN
● Serotonin is a monoamine neurotransmitter (5-hydroxytryptamine; 5-HT) derived from tryptophan
● Serotonin is a potent vasoconstrictor and also modulates cardiac inotropy and chronotropy.
● Serotonin is released at sites of injury for neutrophil recruitment.
Histamine
Short-acting endogenous amine
H1R
mediates vasodilation, bronchoconstriction, intestinal motility, and myocardial contractility. - mediates B and T cell responses.
H2R
- stimulates gastric parietal cell acid secretion - mediates mast cell degranulation, antibody synthesis, Th1 cytokine production, and T-cell proliferation
H3R
- is a presynaptic auto-receptor in the peripheral and central nervous system.
- participates in inflammation in the CNS.
H4R
is a modulator of chemoattraction and cytokine production
CELLULAR RESPONSE TO INJURY
- Cytokine Receptor Families and Their Signaling Pathways
- JAK-STAT Signaling
- Suppressor of Cytokine SIgnaling (SOCS)
- G-Protein Coupled Family of Receptors
- Tumor Necrosis Factor Superfamily
- Transforming Growth Factor-β Family of Receptor
. CYTOKINE RECEPTOR FAMILIES AND THEIR SIGNALING PATHWAYS
Receptor families:
- Type 1 cytokine receptors
- Type 2 cytokine receptors
- Chemokine receptors (members of G-protein-coupled receptors (GPCR))
- Tumor Necrosis Factor receptors (TNFR)
- Transforming Growth Factor receptors (TGFR)
