2. OVERVIEW: INJURY –
ASSOCIATED SYSTEMIC
INFLAMMATORY RESPONSE
Minor host insults
- Localized inflammatory response that is
transient and most often beneficial
Major host insults
- Lead to amplified reaction, resulting in
systemic inflammation, remote organ
damage, and multiple organ failure
3.
4. DETECTION OF CELLULAR INJURY
- Mediated by members of damage-
associated molecular pattern family
Systemic inflammatory response that
limit damage and restore homeostasis:
1. Acute proinflammatory response
- Innate immune system recognize
ligands
2. Anti- inflammatory response
- Modulate proinflammatory phase and
return homeostasis
5. ALARMINS OR DAMAGE-
ASSOCIATED MOLECULAR
PATTERNS (DAMPS)
- With pathogen- associated molecular
patterns (PAMPs), interact with
specific cell receptors on cell surface
and intracellular
- Toll- like receptor family
6.
7. HIGH- MOBILITY GROUP
PROTEIN B1 (HMGB1
PROTEIN)
- Best characterized DAMP
- Rapidly released into circulation
within 30 minutes following trauma
8. PROINFLAMMATORY
BIOLOGIC RESPONSES
FROM HMGB1
SIGNALING:
1. Release cytokines and chemokines
from macrophages/ monocytes and
dendritic cells
2. Neutrophil activation and
chemotaxis
3. Altered epithelial barrier function
4. Increased procoagulant by platelets
10. EXTRACELLULAR MATRIC
MOLECULES AS DAMPS
- Has protein core with one or more
covalently attached
glycosaminoglycan chains, can be
membrane- bound, secreted, or
proteotically cleaved and shed from
cell surface
12. TOLL- LIKE RECEPTORS
- Evolutionarily conserved type 1
transmembrane proteins best
characterized PRRs in mammalian
cells
- Ligands include lipid, carbohydrate,
peptide and nucleic acid components
- Consists of extracellular domain
characterized by multiple leucine-
rich repeats (LRRs), and carboxy-
terminal, intracellular toll/ Il- 1
receptor (TIR) domain
13. NUCLEOTIDE- BINDING
OLIGOMERIZATION
DOMAIN- LIKE RECEPTOR
FAMILY
NLR
- Composed of intracellular PRRs that sense
endogenous (DAMPs) and exogenous (PAMPs)
molecules to trigger innate immune activation
Pyrin Domain- Containing 3 (NLRP3)
- Highly expressed in peripheral leukocytes
- Forms the key sensing component of larger,
multiprotein inflammasome complex
14. C- TYPE LECTIN
RECEPTORS
- Receptors of macrophages and
dendritic cells that detect molecules
released from damaged or dying
cells in order to retrieve and process
antigens from cells corpses for T- cell
presenation
- Selectin and mannose receptor
families that binds carbohydrates in
calcium- dependent fashion
15. SOLUBLE PATTERN
RECOGNITION
MOLECULES (PRMS):
PENTRAXINS
- Complement activation, agglutination
and neutralization, opsonization
- Synthesized at site of injury by
macrophage and dendritic cells,
neutrophils store them and release
rapidly following activation
C- reactive protein (CRP)
- Short pentraxin
- Acute phase protein response
16. CNS REGULATION OF
INFLAMMATION IN
RESPONSE TO INJURY
DAMPs and inflammatory molecules
convey stimulatory signals to CNS via
multiple routes.
Inflammatory stimuli interact with
receptors on brain to generate
proinflammatory mediators (cytokines,
chemokines, adhesion molecules, proteins
of complement system, and immune
receptors).
Inflammation can also signal the brain via
afferent fibers (vagus nerve).
19. HPA AXIS
- corticotropin- releasing hormone
(CRH) is secreted from
paraventricular nucleus of
hypothalamus act on anterior
pituitary to stimulate ACTH
secretion act on zona fasciculata to
synthesize and secrete
glucocorticoids
Cortisol
- Major glucocorticoid essential for
survival in physiologic stress
20. MACROPHAGE
INHIBITORY FACTORY
(MIF)
- Proinflammatory cytokine expressed
by anterior pituitary, macrophage
and T lymphocytes
- Counteract inflammatory activity of
glucocorticoids
- Correlated with NF- kB translocation
and respiratory burst in PMNs
21. GROWTH HORMONE
- Promote protein synthesis and
insulin resistance, enhance
mobilization of fat stores
- Enhance immunocyte phagocytosis
by increased lysosomal superoxide
production
Insulin- like Growth Factor (IGF)- 1
- Anabolic growth factor that
improves metabolic rate, gut mucosal
function and protein loss after
traumatic injury
22. GHRELIN
- Natural ligand for GH- secretagogue
receptor 1a
- Appetite stimulant secreted by
stomach
- Promote GH secretion and glucose
homeostasis, lipid metabolism and
immune function
23. CATECHOLAMINES
- Fight or flight response
- Effects: HR, myocardial
contractility, conduction velocity and
BP; redirect blood flow to skeletal
muscle; cellular metabolism;
mobilization of glucose from liver
via glycogenolysis, gluconeogenesis,
lipolysis and ketogenesis
24. ALDOSTERONE
- Mineralocorticoid released by zona
glomerulosa
- Interferes with insulin signaling
pathways and reduces expression of
insulin sensitizing factors,
adiponectin and peroxisome
proliferator activated receptor
25. INSULIN
- Hormone secreted by pancreas
- Mediates overall host anabolic state
through hepatic glycogenesis and
glycolysis, peripheral glucose
uptake, lipogenesis and protein
synthesis
26. CELLULAR STRESS
RESPONSES
1. Reactive Oxygen Species (ROS)
and Oxidative Stress response
ROS and Reactive Nitrogen Species
- Small molecules highly reactive due
to unpaired outer orbit electrons
- Cause injury through oxidation of
cell membrane substrates
27. 2. HEAT SHOCK
PROTEINS (HSP)
- Intracellular proteins increasingly
expressed during stress (burn,
inflammation, oxidative stress,
infection)
- Maintain appropriate protein folding
- May be proinflammatory or anti-
inflammatory
28. 3. UNFOLDED PROTEIN
RESPONSE
- Mechanism by which ER distress
signals are sent to nucleus to
modulate transcription in attempt to
restore homeostasis
29. 4. AUTOPHAGY
- cell’s way of disposing damaged
organelles and debris aggregates that
are too large to be managed by
proteosomal degradation
- Macroautophagy
- Engulfment of cytoplasm/ organelle
by isolation membrane
30. 5. APOPTOSIS
- Regulated cell death
- Energy dependent organized
mechanism for clearing senescent or
dysfunctional cells including
macrophages, neutrophils and
lymphocytes without promoting
inflammatory response
- 2 pathways: extrinsic and intrinsic
31. 6. NECROPTOSIS
- Cellular necrosis
- Premature uncontrolled death of
cells in living tissue caused by
accidental exposure to external
factors
- Loss of plasma membrane integrity
and cellular collapse with extrusion
of cytoplasmic contents but nuclei is
intact
37. 2. EICOSANOIDS
a. Omega- 6 polyunsaturated
metabolites: Arachidonic Acid
- prostaglandins, thromboxanes,
leukotrienes
- Anti inflammatory
b. Omega- 3 polyunsaturated fat
metabolites: All cis- 5,8,11,14,17
eicosapentaenoic acid
- Inflammatory mediators
38. 3. PLASMA CONTACT
SYSTEM
a. Complement
- Eliminate immune complexes and
damaged cells
- Mobilize hematopoietic stem cells
and lipid metabolism
Classical pathway
Lectin Pathway
Alternative Pathway
39. B. Kallikrein- Kinin System
- Group of proteins that contribute to
inflammation, blood pressure control,
coagulation and pain responses
40. 4. SEROTONIN
- Monoamine neurotransmitter (5-
hydroxytryptamine) derived from
tryptophan
- Potent vasoconstrictor and
modulates cardiac inotropy and
chronotropy
- Released by platelets
41. 5. HISTAMINE
- Short acting endogenous amine
- Rapidly released or stored in
neurons, skin, gastric mucosa, mast
cells, basophils and platelets
- Increased with hemorrhagic shock,
trauma, thermal injury and sepsis
42. CELLULAR RESPONSES TO INJURY
Cytokine Receptor Families and Their Signaling Pathways
Cytokines act on their target cells by binding to
specific membrane receptors. These receptor
families have been organized by structural motifs
and include:
• Type I Cytokine Receptors
• Type II Cytokine Receptors
• Chemokine Receptors
• TNF receptors (TNFRs)
• Transforming Growth Factor Receptors (TGFRs)
In addition, there are cytokine receptors that
belong to the immunoglobulin receptor
superfamilies.
43. JAK-STAT Signaling
A major subgroup of cytokines, comprising roughly 60 factors, bind to
receptors termed type I/II cytokine receptors. Cytokines that bind these
receptors include:
• Type I IFNs
• IFN-γ
• ILs (e.g., IL-6, IL-10, IL-12, and IL-13)
• Hematopoietic Growth Factors
These cytokines play essential roles in the INITIATION, MAINTENANCE,
and MODULATION of innate and adaptive immunity for host defense.
All type I/II cytokine receptors selectively associate with the Janus kinases
(JAKs), which represent a family of tyrosine kinases that mediate the
signal transduction for these receptors.
44. JAKs are constitutively bound to the cytokine receptors,
and on ligand binding and receptor dimerization, activated
JAKs phosphorylate the receptor to recruit signal
transducer and activator of transcription (STAT) molecules.
Activated STAT proteins further dimerize and translocate
into the nucleus where they modulate the transcription
of target genes.
Rather than being a strictly linear pathway, it is likely that
individual cytokines activate more than one STAT.
The JAK/STAT pathway is inhibited by the action of
phosphatase, the export of STATs from the nucleus, and
the interaction of antagonistic proteins.
45.
46. SUPPRESSORS OF CYTOKINE SIGNALING
Suppressor of cytokine signaling (SOCS) molecules are a
family of proteins that function as a negative feedback
loop for type I and II cytokine receptors by terminating
JAK-STAT signaling. There are currently eight family
members:
• SOCS1-3 (associated with cytokine receptor signaling)
• SOCS4-8 (associated with growth factor receptor
signaling)
Induction of SOCS proteins is also achieved through
activators of JAK-STAT signaling, creating an inhibitory
feedback loop through which cytokines can effectively
self-regulate by extinguishing their own signal.
47. SOCS molecules can positively and negatively influence
the activation of macrophages and dendritic cells and are
crucial for T-cell development and differentiation.
All SOCS proteins are able to regulate receptor signaling
through the recruitment of proteasomal degradation
components to their target proteins, whether the target is a
specific receptor or an associated adaptor molecule.
Once associated with the SOCS complex, target proteins
are readily ubiquinated and targeted to the proteasome for
degradation.
SOCS1 and SOCS3 can also exert an inhibitory effect on
JAK-STAT signaling via their N-terminal kinase inhibitory
region (KIR) domain, which acts as a pseudosubstrate for
JAK.
48. Chemokine Receptors Are Members of the
G-Protein–Coupled Receptor Family
-one of the largest and most diverse of the membrane protein
families.
GPCRs function by detecting a wide spectrum of extracellular
signals, including photons, ions, small organic molecules, and
entire proteins.
After ligand binding, GPCRs undergo conformational changes,
causing the recruitment of heterotrimeric G proteins to the
cytoplasmic surface (Fig. 2-8).
Heterotrimeric G proteins are composed of three subunits, Gα,
Gβ, and Gγ, each of which has numerous members, adding to the
complexity of the signaling.
PLASMINOGEN ACTIVATOR.
ENDOTHELIAL CELLS ALSO
PERFORM A CRITICAL
FUNCTION AS BARRIERS
THAT REGULATE TISSUE
MIGRATION OF CIRCULATING
CELLS.
DURING SEPSIS,
ENDOTHELIAL CELLS ARE
DIFFERENTIALLY
MODULATED, WHICH
49. When signaling however, G proteins perform functionally as
dimers because the signal is communicated either by the Gα
subunit or the Gβγ complex.
The GPCR family includes the receptors for catecholamines,
bradykinins, and leukotrienes, in addition to a variety of
other ligands important to the inflammatory response.
In general, GPCRs can be classified according to their
pharmacologic properties into
four main families:
• Class A rhodopsin-like
• Class B secretin-like
• Class C metabotropic glutamate/pheromone
• Class D frizzled receptors
50.
51. TUMOR NECROSIS FACTOR SUPERFAMILY
The signaling pathway for TNFR1 (55 kDa) and TNFR2 (75 kDa)
occurs by the recruitment of several adapter proteins to the
intracellular receptor complex.
Optimal signaling activity requires receptor trimerization.
TNFR1 initially recruits TNFR-associated death domain
(TRADD) and induces apoptosis through the actions of
proteolytic enzymes known as caspases, a pathway shared by
another receptor known as CD95 (Fas).
CD95 and TNFR1 possess similar intracellular sequences known
as death domains (DDs), and both recruit the same adapter
proteins known as Fas-associated death domains (FADDs) before
activating caspase 8.
52. TNFR1 also induces apoptosis by activating caspase 2 through
the recruitment of receptor-interacting protein (RIP).
RIP also has a functional component that can initiate NF-κB
and c-Jun activation, both favoring cell survival and pro-
inflammatory functions.
TNFR2 lacks a DD component but recruits adapter proteins
known as TNFR-associated factors 1 and 2 (TRAF1, TRAF2)
that interact with RIP to mediate NF-κB and c-Jun activation.
TRAF2 also recruits additional proteins that are antiapoptotic,
known as inhibitor of apoptosis proteins (IAPs).
53. TRANSFORMING GROWTH FACTOR-Β FAMILY OF
RECEPTORS
Transforming growth factor-β1 (TGF-β1) is a pleiotropic
cytokine expressed by immune cells that has potent
immunoregulatory activities.
Specifically, recent data indicate that TGF-β is essential for
T-cell homeostasis, as mice deficient in TGF-β1 develop a
multiorgan autoimmune inflammatory disease and die a
few weeks after birth, an effect that is dependent on the
presence of mature T cells.
The receptors for TGF-β ligands are the TGF-β superfamily
of receptors, which are type I transmembrane proteins that
contain intrinsic serine/threonine kinase activity.
54. These receptors comprise two subfamilies, the type
I and the type II receptors, which are distinguished
by the presence of a glycine/serine-rich membrane
domain found in the type I receptors.
Each TGF-β ligand binds a characteristic
combination of type I and type II receptors, both of
which are required for signaling.
55. CELL-MEDIATED
INFLAMMATORY RESPONSE
PLATELETS
small (2 μm), circulating fragments of a larger cell
precursor, the megakaryocyte, that is located chiefly
within the bone marrow.
Although platelets lack a nucleus, they contain both
mRNA and a large number of cytoplasmic and surface
proteins that equip them for diverse functionality.
While their role in hemostasis is well described, more
recent work suggests that platelets play a role in both
local and systemic inflammatory responses, particularly
following ischemia reperfusion.
56. Platelets express functional scavenger and TLRs
that are important detectors of both pathogens and
“damage”-associated molecules.
At the site of tissue injury, complex interactions
between platelets, endothelial cells, and circulating
leukocytes facilitate cellular activation by the
numerous local alarmins and immune mediators.
Once activated, platelets adopt an initial pro-
inflammatory phenotype by expressing and
releasing a variety of adhesion molecules,
cytokines, and other immune modulators.
57. LYMPHOCYTES AND T-CELL IMMUNITY
The expression of genes associated with the adaptive immune
response is rapidly altered following severe blunt trauma.
In fact, significant injury is associated with adaptive immune
suppression that is characterized by altered cell-mediated
immunity, specifically the balance between the major
populations of Th cells.
In fact, Th lymphocytes are functionally divided into subsets,
which principally include Th1 and Th2 cells, as well as Th17
and inducible Treg cells.
Derived from precursor CD4 + Th cells, each of these groups
produces specific effector cytokines that are under unique
transcriptional control.
58. CD4 T cells play central roles in the function of the
immune system through their effects on B-cell antibody
production and their enhancement of specific Treg cell
functions and macrophage activation.
The specific functions of these cells include the
recognition and killing of intracellular pathogens (cellular
immunity; Th1 cells), regulation of antibody production
(humoral immunity; Th2 cells), and maintenance of
mucosal immunity and barrier integrity (Th17 cells).
These activities have been characterized as pro-
nflammatory (Th1) and anti-inflammatory (Th2),
respectively, as determined by their distinct cytokine
signatures.
59.
60. DENDRITIC CELLS
Dendritic Cells are specialized antigen-presenting cells (APCs)
that have three major functions.
They are frequently referred to as “professional APCs” since
their principal function is to capture, process, and present both
endogenous and exogenous antigens, which, along with
their costimulatory molecules, are capable of inducing a
primary immune response in resting naïve T lymphocytes.
In addition, they have the capacity to further regulate the
immune response, both positively and negatively, through the
upregulation and release of immuno-modulatory molecules
such as the chemokine CCL5 and the CXC chemokine CXCL5.
61. Finally, they have been implicated both in the induction and
maintenance of immune tolerance as well as in the acquisition
of immune memory.
There are distinct classes and subsets of DC, which are
functionally heterogeneous.
Further, subsets of DC at distinct locations have been shown to
express different levels damage-sensing receptors (e.g., TLR)
that dictate a preferential response to DAMP at that site.
While relatively small in number relative to the total leukocyte
population, the diverse distribution of DC in virtually all body
tissues underlines their potential for a collaborative role in the
initiation of the trauma-induced sterile systemic inflammatory
response.
62. EOSINOPHILS
-are immunocytes whose primary functions are
antihelminthic.
-are found mostly in tissues such as the lung and
gastrointestinal tract, which may suggest a role in
immune surveillance.
-can be activated by IL-3, IL-5, GM-CSF,
chemoattractants, and platelet-activating factor.
Eosinophil activation can lead to subsequent release of
toxic mediators, including ROSs, histamine, and
peroxidase.
63. MAST CELLS
-important in the primary response to injury because they are
located in tissues. TNF release from mast cells has been found to
be crucial for neutrophil recruitment and pathogen clearance.
-are also known to play an important role in the anaphylactic
response to allergens.
On activation from stimuli including allergen binding, infection,
and trauma, mast cells produce histamine, cytokines, eicosanoids,
proteases, and chemokines, which leads to vasodilatation,
capillary leakage, and immunocyte recruitment.
-are thought to be important cosignaling effector cells of the
immune system via the release of IL-3, IL-4, IL-5, IL-6, IL-10, IL-
13, and IL-14, as well as macrophage migration–inhibiting factor.
64. MONOCYTE/MACROPHAGES
MONOCYTES are mononuclear phagocytes that circulate in the
bloodstream and can differentiate into macrophages,
osteoclasts, and DCs on migrating into tissues.
MACROPHAGES are the main effector cells of the immune
response to infection and injury, primarily through mechanisms
that include phagocytosis of microbial pathogens, release of
inflammatory mediators, and clearance of apoptotic cells.
In tissues, mononuclear phagocytes are quiescent. However,
they respond to external cues (e.g., PAMPs, DAMPs, activated
lymphocytes) by changing their phenotype.
65. In response to various signals, macrophages may undergo
classical M1 activation (stimulated by TLR ligands and IFN-γ)
or alternative M2 activation (stimulated by type II cytokines IL-
4/IL-13); these states mirror the Th1-Th2 polarization of T cells.
The M1 phenotype is characterized by the expression of high
levels of pro-inflammatory cytokines, like TNF-α, IL-1, and IL-
6, in addition to the synthesis of ROS and RNS.
M1 macrophages promote a strong Th1 response. In contrast,
M2 macrophages are considered to be involved in the
promotion of wound repair and the restoration of immune
homeostasis through their expression of arginase-1 and IL-10, in
addition to a variety of PRRs (e.g., scavenging molecules).
66. NEUTROPHILS
Neutrophils are among the first responders to sites of
infection and injury and, as such, are potent mediators of
acute inflammation.
Chemotactic mediators from a site of injury induce
neutrophil adherence to the vascular endothelium and
promote eventual cell migration into the injured tissue.
Neutrophils are circulating immunocytes with short half-
lives (4 to 10 hours).
However, inflammatory signals may promote the longevity
of neutrophils in target tissues, which can contribute to
their potential detrimental effects and bystander injury.
67. Once primed and activated by inflammatory stimuli, including
TNF, IL-1, and microbial pathogens, neutrophils are able to enlist
a variety of killing mechanisms to manage invading pathogens.
Phagocytosed bacteria are killed using NADPH oxygenase-
dependent generation of ROS or by releasing lytic enzymes and
antibacterial proteins into the phagosome.
Neutrophils can also dump their granule contents into the
extracellular space, and many of these proteins also have
important effects on the innate and adaptive immune responses.
Neutrophils do facilitate the recruitment of monocytes into
inflamed tissues.
These recruited cells are capable of phagocytosing apoptotic
neutrophils to contribute to resolution of the inflammatory
response.
68. ENDOTHELIUM-MEDIATED INJURY
Vascular Endothelium
Under physiologic conditions, vascular endothelium has overall
anticoagulant properties mediated via the production and cell
surface expression of heparin sulfate, dermatan sulfate, tissue
factor pathway inhibitor, protein S, thrombomodulin,
plasminogen, and tissue plasminogen activator.
Endothelial cells also perform a critical function as barriers that
regulate tissue migration of circulating cells.
During sepsis, endothelial cells are differentially modulated, which
results in an overall procoagulant shift via decreased production of
anticoagulant factors, which may lead to microthrombosis and
organ injury.
69. Neutrophil-Endothelium Interaction
The regulated inflammatory response to infection facilitates
neutrophil and other immunocyte migration to compromised
regions through the actions of increased vascular permeability,
chemoattractants, and increased endothelial adhesion factors
referred to as selectins that are elaborated on cell surfaces.
In response to inflammatory stimuli released from sentinel
leukocytes in the tissues, including chemokines, thrombin,
leukotrienes, histamine, and TNF, vascular endothelium are
activated and their surface protein expression is altered.
Within 10 to 20 minutes, prestored reservoirs of the adhesion
molecule P-selectin are mobilized to the cell surface where it can
mediate neutrophil recruitment.
70. After 2 hours, endothelial cell transcriptional processes
provide additional surface expression of E-selectin.
E-selectin and P-selectin bind P-selectin glycoprotein
ligand-1 (PSGL-1) on the neutrophils to orchestrate the
capture and rolling of these leukocytes and allow targeted
immunocyte extravasation.
Immobilized chemokines on the endothelial surface create
a chemotactic gradient to further enhance immune cell
recruitment.
Although there are distinguishable properties among
individual selectins in leukocyte rolling, effective rolling
most likely involves a significant degree of functional
overlap.
71.
72.
73. CHEMOKINES
-family of small proteins (8 to 13 kDa) that were first identified
through their chemotactic and activating effects on
inflammatory cells.
-produced at high levels following nearly all forms of injury in
all tissues, where they are key attractants for immune cell
extravasation.
-more than 50 different chemokines and 20 chemokine
receptors that have been identified.
-released from endothelial cells, mast cells, platelets,
macrophages, and lymphocytes.
-soluble proteins, which when secreted, bind to
glycosaminoglycans on the cell surface or in the ECM.
74. In this way, the chemokines can form a fixed
chemical gradient that promotes immune cell exit
to target areas.
Chemokines are distinguished (in general) from
cytokines by virtue of their receptors, which are
members of the G-protein–coupled receptor
superfamily.
Most chemokine receptors recognize more than
one chemokine ligand, leading to redundancy in
chemokine signaling.
75. The chemokines are subdivided into families
based on their amino acid sequences at their N-
terminus.
For example, CC chemokines contain two N-
terminus cysteine residues that are immediately
adjacent (hence the “C-C” designation), whereas
the N-terminal cysteines in CXC chemokines are
separated by a single amino acid.
The CXC chemokines are particularly important
for neutrophil (PMN) pro-inflammatory function.
76. NITRIC OXIDE
Nitric oxide (NO) was initially known as endothelium-
derived relaxing factor due to its effect on vascular smooth
muscle.
Normal vascular smooth muscle cell relaxation is
maintained by a constant output of NO that is regulated in
the endothelium by both flow- and receptor-mediated
events.
NO can also reduce microthrombosis by reducing
platelet adhesion and aggregation (Fig. 2-13) and
interfering with leukocyte adhesion to the endothelium.
NO easily traverses cell membranes, has a short half-life of
a few seconds, and is oxidized into nitrate and nitrite.
77. Endogenous NO formation is derived largely from the action of
NO synthase (NOS), which is constitutively expressed in
endothelial cells (NOS3).
NOS generates NO by catalyzing the degradation of L-arginine
to L-citrulline and NO, in the presence of oxygen and NADPH.
There are two additional isoforms of NOS: neuronal NOS
(NOS1) and inducible NOS (iNOS/NOS2).
The vasodilatory effects of NO are mediated by guanylyl cyclase,
an enzyme that is found in vascular smooth muscle cells and
most other cells of the body.
When NO is formed by endothelium, it rapidly diffuses into
adjacent cells where it binds to and activates guanylyl cyclase.
78. This enzyme catalyzes the dephosphorylation of guanosine
triphosphate (GTP) to cyclic guanosine monophosphate (cGMP),
which serves as a secondmessenger for many important cellular
functions, particularly for signaling smooth muscle relaxation.
NO synthesis is increased in response to proinflammatory
mediators such as TNF-α and IL-1β, as well as microbial products,
due to the upregulation of iNOS expression.
NO is reported to function as an immunoregulator, which is
capable of modulating cytokine production and immune cell
development.
This enzyme catalyzes the dephosphorylation of guanosine
triphosphate (GTP) to cyclic guanosine monophosphate (cGMP),
which serves as a second messenger for many important cellular
functions, particularly for signaling smooth muscle relaxation.
79. NO synthesis is increased in response to pro-
inflammatory mediators such as TNF-α and IL-1β,
as well as microbial products.
Increased NO is also detectable in septic shock,
where it is associated with low peripheral vascular
resistance and hypotension.
Increased production of NO in this setting
correlates with changes in vascular permeability
and inhibition of noradrenergic nerve
transmission.
80.
81. PROSTACYCLIN
Prostacyclin is a potent vasodilator that also inhibits platelet
aggregation. In the pulmonary system, PGI2 reduces pulmonary
blood pressure and bronchial hyperresponsiveness.
In the kidneys, PGI2 modulates renal blood flow and glomerular
filtration rate.
Prostacyclin acts through its receptor (a G-protein–coupled
receptor of the rhodopsin family) to stimulate the enzyme
adenylate cyclase, allowing the synthesis of cAMP from adenosine
triphosphate (ATP).
This leads to a cAMP-mediated decrease in intracellular calcium
and subsequent smooth muscle relaxation.
82. During systemic inflammation, endothelial
prostacyclin expression is impaired, and thus the
endothelium favors a more procoagulant profile.
Exogenous prostacyclin analogues, both
intravenous and inhaled, have been used to
improve oxygenation in patients with acute lung
injury.
83. ENDOTHELINS
Endothelins (ETs) are potent mediators of vasoconstriction and
are composed of three members:
• ET-1
• ET-2
• ET-3
ETs are 21-amino-acid peptides derived from a 38-amino-acid
precursor molecule.
ET-1, synthesized primarily by endothelial cells, is the most
potent endogenous vasoconstrictor and is estimated to be 10 times
more potent than angiotensin II.
ET release is upregulated in response to hypotension, LPS, injury,
thrombin, TGF-β, IL-1, angiotensin II, vasopressin,
catecholamines, and anoxia.
84. ETs are primarily released to the abluminal side of endothelial
cells, and very little is stored in cells; thus a plasma increase in ET
is associated with a marked increase in production.
The half-life of plasma ET is between 4 and 7 minutes, which
suggests that ET release is primarily regulated at the
transcriptional level.
Three ET receptors, referred to as ETA, ETB, and ETC, have been
identified and function via the G-protein–coupled receptor
mechanism.
At low levels, in conjunction with NO, ETs regulate vascular tone.
However, at increased concentrations, ETs can disrupt the normal
blood flow and distribution and may compromise oxygen
delivery to the tissue.
85. PLATELET-ACTIVATING FACTOR
Phosphatidylcholine is a major lipid constituent of the plasma
membrane.
Its enzymatic processing function as intracellular second
messengers.
One of these is arachidonic acid, the precursor molecule for
eicosanoids.
Another is platelet-activating factor (PAF). During acute
inflammation, PAF is released by immune cells following the
activation of PLA2.
The receptor for PAF (PAFR), which is constitutively expressed by
platelets, leukocytes, and endothelial cells, is a G-protein–coupled
receptor of the rhodopsin family.
86. NATRIURETIC PEPTIDES
The natriuretic peptides, atrial natriuretic factor (ANF) and
brain natriuretic peptide (BNP), are a family of peptides that are
released primarily by atrial tissue but are also synthesized by the
gut, kidney, brain, adrenal glands, and endothelium.
The functionally active forms of the peptides are C-terminal
fragments of a larger prohormone, and both N- and C-terminal
fragments are detectable in the blood (referred to a N-terminal
pro-BNP and pro-ANF, respectively).
ANF and BNP share most biologic properties including diuretic,
natriuretic, vasorelaxant, and cardiac remodeling properties that
are effected by signaling through a common receptor: the
guanylyl cyclase-A (GC-A) receptor.
88. • Initial hours following surgery/traumatic injury
• Reduced total body energy expenditure
• Urinary nitrogen wasting
• Following resuscitation and stabilization of function patient
Reprioritization of substrate utilization
89. METABOLISM DURING
FASTING
• Standard to which metabolic alterations after
acute injury and critical illness are compared
• A normal healthy adult requires approximately
22-25 kcal/kg per day drawn from CHO, lipid,
and CHON sources.
• Principal sources of fuel during short-term
fasting (<5 days) are derived from muscle CHON
and body FAT—most abundant source of energy
90.
91.
92. Glucagon, NE, vasopressin, angiotensin II
• promote the utilization of glycogen
stores during fasting
Glucagon, EPI, cortisol
• directly promote gluconeogenesis
EPI, cortisol
• Promote pyruvate shuttling to the liver
for gluconeogenesis
Precursors for hepatic gluconeogenesis:
lactate, glycerol, AA (alanine, glutamine)
93. • Lactate – released by glycolysis within
skeletal muscles, as well as by
erythrocytes and leukocytes
• Cori cycle – recycling of lactate and
pyruvate for gluconeogenesis which can
provide up to 40% of plasma glucose
during starvation.
94.
95.
96. METABOLISM AFTER
INJURY
• Injuries/infections induce neuroendocrine
and immunologic responses
• Magnitude of metabolic expenditure
appears to be directly proportional to the
severity of insult
• Increase in energy expenditure is mediated
by:
• Sympathetic activation
• Catecholamine release
97.
98. METABOLISM AFTER
INJURY
• Lipid metabolism after injury
• Ketogensis
• Carbohydrate metabolism
• Protein and Amino Acid metabolism
99. LIPID METABOLISM
• Lipid – nonprotein and noncarbohydrate fuel
sources that minimize protein catabolism in
the injured patient
• Triglycerides – predominant energy source
(50-80%) during critical illness and after
injury
• Triglyceride lipase – responsible for fat
mobilization
102. CARBOHYDRATE
METABOLISM
• Primarily refers to the utilization of
glucose
• Minimize muscle wasting: primary goal
for maintenance glucose administration
in surgical patients
103.
104. PROTEIN AND AMINO
ACID METABOLISM
• 80-120 g/d—average protein intake in
healthy, young adults
• Every 6g of protein 1g of nitrogen
• Degradation of 1g of protein4 kcal of
energy
• Protein catabolism after injury provides
substrates for gluconeogenesis
• AA cannot be considered a long-term fuel
reserve
106. NUTRITION IN THE
SURGICAL PATIENT
• Goal: prevent or reverse the catabolic
effects of disease or injury
• Ultimate validation of nutritional
support:
improvement in clinical outcome
restoration of function
107. ESTIMATING ENERGY
REQUIREMENTS
• Nutrtional assessment
- determine the severity of nutrient
deficiencies or excess and aids in predicting
nutritional requirements
- goals:
1) meet the energy requirements for the
metabolic processes, core temp maintenance,
and tissue repair
2) meet the substrate requirements for
protein synthesis
109. VITAMINS AND
MINERALS
•Easily met in the average patient
with an uncomplicated
postoperative course
•Usually not given in the absence of
preoperative deficiencies
110. OVERFEEDING
• Results from overestimation of caloric
needs
• May contribute to clinical deterioration via
increased oxygen consumption
increased CO2 production
prolonged need for ventilatory support
fatty liver
suppression of leukocyte function
hyperglycemia
increased risk of infection
112. RATIONALE FOR
ENTERAL NUTRITION
•Lower cost of enteral feeding
•Associated risks of the intravenous
route
•Reduced intestinal atrophy
•Reduced infectious complications
and acute-phase protein production
113. HYPOCALORIC
ENTERAL NUTRITION
• Recent evidence supports the idea of caloric
restriction improved cellular function
• Permissive underfeeding:
mortality &morbidity > target feeding
Trophic feedings – refer to providing a minimal
amount of enteral feedings, which are
presumed to have beneficial effects despite not
meeting daily caloric needs.
118. PARENTERAL
NUTRITION
•Continuous infusion of a
hyperosmolar solution containing
carbohydrates, proteins, fat, and
other necessary nutrition through an
indwelling catheter inserted into the
superior vena cava.
119. RATIONALE FOR
PARENTERAL NUTRITION
• Principal indications for parenteral nutrition:
malnutrition in patients for
sepsis whom use of
GIT surgical/traumatic injury for feeding is
not possible
• Intravenous nutrition may be used to supplement
inadequate oral intake.
120. PARENTERAL
NUTRITION
• Total Parenteral Nutrition
• Central parenteral nutrition
• Requires access to a large-diameter vein to
deliver the entire nutritional requirements of
the individual.
• Peripheral Parenteral Nutrition
• Allows administration via peripheral veins
• Considered if central routes are not available
or if supplemental nutritional support is
required.
121. INITIATION OF
PARENTERAL NUTRITION
• The basic solution contains:
• 15-25% dextrose
• 3-5% crystalline amino acids
• Intravenous vitamin preparations should
be added to parenteral formulas
• Parenteral nutrition solutions generally
can be increased over 2-3 days to achieve
the desired infusion rate
122. INITIATION OF
PARENTERAL NUTRITION
• 6 hours – urine /capillary blood glucose
level is checked
• At least 1x day – serum glucose
concentration
• K⁺ -essential to achieve positive nitrogen
balance and replace depleted
intracellular stores
• Delivery of parenteral nutrition requires
central intravenous access
Several of these receptors have characteristic signaling pathways that are associated with them.
Thus, JAKs and STATs are central players in the regulation of key immune cell function, by providing a signaling platform for pro-inflammatory cytokines (IL-6 via JAK1 and STAT3) and anti-inflammatory cytokines (IL-10 via STAT3) and integrating signals required for helper and regulatory T-cell development and differentiation.
A deficiency of SOCS activity may render a cell hypersensitive to certain stimuli, such as inflammatory cytokines and GHs.
Ligand binding to the PAFR promotes the activation and aggregation of platelets and leukocytes, leukocyte adherence, motility, chemotaxis, and invasion, as well as ROS generation.
They are both increased in the setting of cardiac disorders; however, recent evidence indicates some distinctions in the setting of inflammation.