SYSTEMIC RESPONSE TO

INJURY AND METABOLIC

SUPPORT

SYSTEMIC RESPONSE TO INJURY

AND METABOLIC SUPPORT
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Overview: Injury-Associated Sytemic Inflammatory Response

The Detection of Cellular Injury
Central Nervous System Regulation of Inflammation in Response to
Injury
The Cellular Stress Responses
Mediators of Inflammation
Cellular Response to Injury
Transcriptional and Translational Regulation of the Injury Response
Cell-Mediated Inflammatory Response
Endothelium-Mediated Injury
Surgical Metabolism
Nutrition in the Surgical Patient
Enternal Nutrition
Parenteral Nutrition

EVELINA MEILANY
Overview: Injury-Associated Sytemic
Inflammatory Response
The Detection of Cellular Injury
Central Nervous System Regulation of
Inflammation in Response to Injury

The Cellular Stress Responses

Mediators of Inflammation

Cellular Response to Injury

Transcriptional and Translational Regulation
of the Injury Response

SANG AYU KADEK WIDIARI

Cell-Mediated Inflammatory Response
Endothelium-Mediated Injury

CELL-MEDIATED
INFLAMMATORY RESPONE

PLATELETS

Platelets are small (2m), circulating fragments of a

larger cell precursor, the megakaryocyte, that is located
chiefly within the bone marrow.
While their role in hemostasis is well described, that
platelets play a role in both local and systemic
inflammatory responses, particularly following ischemia
reperfusion.

LYMPHOCYTES AND T-CELL IMMUNITY

The specific functions of these cells 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 proinflammatory
(Th1) and anti inflammatory (Th2), respectively, as
determined by their distinct cytokine signatures

Specific immunity mediated by helper T lymphoctes subtype 1 (T H1)

and subtype 2 (TH2) after injury.

DENDRITIC CELLS

dendritic cells (DCs) are also activated in response to

damage signals, to stimulate both the innate and the
adaptive immune responses.
DCs are specialized antigen-presenting cells (APCs)
that have three major functions.

EOSINOPHILS

Eosinophils are immunocytes whose primary functions

are antihelminthic.

MAST CELLS

Mast cells are important in the primary response to

injury because they are located in tissues.
Mast cells are thought to be important cosignaling
effector cells of the immune system via the release of IL3, IL-4, IL-5, IL-6, IL-10, IL-13, and IL-14, as well as
macrophage migrationinhibiting factor.

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.

NEUTROPHILS

Neutrophils are among the first responders to sites of

infection and injury and, as such, are potent mediators of
acute inflammation.

Neutrophils do facilitate the recruitment of monocytes

into inflamed tissues

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.

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

CHEMOKINES

Chemokines are a family of small proteins (8 to 13 kDa)

that were first identified through their chemotactic and
activating effects on inflammatory cells.

ENDOTHELIUM-MEDIATED INJURY

NITRIC OXIDE

Nitric oxide (NO) was initially known as endotheliumderived relaxing factor due to its effect on vascular
smooth muscle.
NO synthesis is increased in response to
proinflammatory mediators such as TNF- and IL-1, as
well as microbial products, due to the upregulation of
iNOS expression
Increased NO is also detectable in septic shock, where it
is associated with low peripheral vascular resistance and
hypotension.

Simplified sequence of selectin-mediated neutrophilendothelium

interaction after an inflammatory stimulus.

PROSTACYCLIN

Prostacyclin is a potent vasodilator that also inhibits

platelet aggregation.
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.

ENDOTHELINS

Endothelins (ETs) are potent mediators of

vasoconstriction and are composed of three
members: ET-1, ET-2, and ET-3.
ET release is upregulated in response to
hypotension, LPS, injury, thrombin, TGF-, IL-1,
angiotensin II, vasopressin, catecholamines, and
anoxia

Endothelial interaction with smooth muscle cells and with

intraluminal platelets.

PLATELET-ACTIVATING FACTOR

The receptor for PAF (PAFR)

PAFR ligation results not only in the upregulation of
numerous proinflammatory genes including COX-2,
iNOS, and IL-6, but also in the generation of lipid
intermediates such as arachidonic acid and
lysophospholipids through the activation of PLA2.
Human sepsis is associated with a reduction in the levels
of PAF-acetylhydrolase, which inactivates PAF by
removing an acetyl group.

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.

They are both increased in the setting of cardiac

disorders; however, recent evidence indicates some
distinctions in the setting of inflammation.

ELLA PUTRI SAPTARI

Surgical Metabolism
Nutrition in the Surgical Patient

SURGICAL
METABOLISM

METABOLISM DURING FASTING

Fuel metabolism during unstressed fasting state

has historically served as the standard to wich
metabolic alterations after acute injury and
critical illness are compared

In the healthy adult , principal sources of fuel

during short term fasting (<5 days) are derived
from muscle protein and body fat, with fat being
the most abundant source of energy

METABOLISM AFTER INJURY

LIPID METABOLISM AFTER INJURY

KETOGENESIS

CARBOHYDRATE
METABOLISM

PROTEIN & ASAM AMINO

ACID METABOLISM

NUTRITION IN THE
SURGICAL PATIENT
ESTIMATION OF ENERGY
REQUIREMENTS

VITAMINS AND MINERALS

OVERFEEDING

SYIFA MASHFUFAH AGMA

Enternal Nutrition
Parenteral Nutrition

CELLULAR RESPONSE TO INJURY

Cytokines act on their target cells by binding to
specific membrane receptors
Cytokine receptors that belong to the
immunoglobulin receptor superfamilies. Several
of these receptors have characteristic signaling
pathways

JAK - STAT SIGNALING

JAKs and STATs are central players in the

regulation of key immune cell function.
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

All SOCS proteins are able to regulate receptor

signaling through the recruitment of proteasomal
degradation components to their target proteins
A deficiency of SOCS activity may render a cell
hypersensitive to certain stimuli, such as
inflammatory cytokines

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.

The G subunits also include the Gq pathway,

which stimulates phospholipase C- to produce
the intracellular messengers inositol
trisphosphate and diacylglycerol. Inositol
triphosphate triggers the release of calcium from
intracellular stores, whereas diacylglycerol
recruits protein kinase C to the plasma
membrane for activation

TNFR1 also induces apoptosis by activating

caspase 2 through the recruitment of receptorinteracting protein (RIP)

TRANSCRIPTIONAL AND
TRANSLATIONAL REGULATION OF
THE INJURY RESPONSE

Many genes are regulated at the point of DNA

transcription and thus influence whether
messenger RNA (mRNA) and its subsequent
product are expressed.

DNA TRANSCRIPTION

The DNA access of protein machineries involved

in transcription processes is tightly regulated by
histones.
The role of histone modifications in the
regulation of gene expression is referred to as
epigenetic control.
Histone methyltransferases in proinflammatory
gene programs

mRNA transcript including 3 mechanisms: (a)

splicing (b) Capping and (c) the addition of a
polyadenylated tail