mechanism by which, in the face of a second
encounter with the same challenge, the response
is more rapid and more effective. 27
In septic patients an early increase in
leukocytes is observed at the expense of PMN
cells. Lymphocytes are markedly decreased in
sepsis at the expense of CD4 + T cells and B
cells. 28,29 After the onset of sepsis, an increased
expression of co-inhibitory markers such as PD-1
and cytotoxic antigen-4 (CTLA-4) lymphocytes is
detected in both T cells and in experimental
models of sepsis. Increased activity of regulatory T
cells (Treg), which are immunosuppressive cells,
has been described. 31 CD8+ T cells are considered
effector cytotoxic cells. They decrease in patients
with septic shock. 32 B lymphocytes produce
antibodies that can neutralise microorganisms by
opsonization and activate complement proteins
to eliminate bacteria by phagocytosis. Patients
with septic shock have decreased levels of B
lymphocytes in blood. 33
Pro-inflammation vs anti-inflammation
Patients who survive the initial inflammatory
response develop a reactive anti-inflammatory
response to counteract the effects of the cytokines
that have been released and to decrease their
synthesis, until a balance that will allow the body
to effectively fight the infection has been
reached. 34 The predominance of one or the other
is directly related to the concentration of TH1 or
TH2, in turn related to the presence of IL-2 and
IL-4, respectively. 35,36
The reactive anti-inflammatory response
is based on the release of specific inhibitory
cytokines and soluble receptors of pro-
inflammatory cytokines: 37 IL-1 receptor
antagonists (IL-1RA) and TNF; TGF-b; IL-4, IL-6,
IL-10, IL-11 and IL-13; specific receptors for IL-4,
IL-6, IL-10, IL-11 and IL-13. A deep and sustained
anti-inflammatory response can induce a state of
profound immunosuppressionin the patient, and
even to anergy. 38 This ‘immune paralysis’ leaves
the majoroty of sepsis patients at the mercy of
commonplace nosocomial infections (Figure 2).
Cellular alterations and organ failure:
the ‘motor of sepsis’
During the past 30 years, the link (pivotal
element) between the described alterations and
the associated organ dysfunction have been
investigated. 39 The exact mechanism is unknown
but the following pathogenic factors have been
suggested:
• Tissue ischaemia: During sepsis, there is a state
of peripheral hypoperfusion from the initial
onset, in which there is a marked hypovolaemia,
vascular regulationdisturbances and cardiac
dysfunction that contribute to tissue
hypoperfusion. 40
• Cytopathic lesions and mitochondrial
dysfunction: Inflammatory mediators can
directly alter cellular function by altering
mitochondrial function and thereby the transport
of electrons. This results in impairment of aerobic
metabolism due to poor use of available oxygen,
which significantly affects oxidative
phosphorylation and induces cytotoxicity. 41,42
In addition, damaged mitochondria can trigger
cell death pathways through the release of
mitochondrial cytochrome C43. The importance
13
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of mitochondrial dysfunction during sepsis is
evidenced by the observations that cellular ATP
levels correlate with survival in human and
experimental models of sepsis. 44,45
• Apoptosis: Programmed cell death has special
relevance in cellular regeneration, and is
extremely altered in sepsis. There are several
ways in which apoptosis is involved in
immunosuppression including depletion of key
effector cells in both innate and adaptive
immunity. 46 Treatment of T lymphocytes with
apoptotic cells induces the release of anti-
inflammatory cytokines, including IL-10 and
TGFb, which can induce a state of anergy or
a change of TH1 to TH2 phenotype. Inflammatory
mediators can delay the apoptosis of macrophages
and polynuclear neutrophils and on the contrary
increase the apoptosis of lymphocytes and
dendritic cells in addition in certain parenchymal
and endothelial and epithelial cells. Patients with
septic shock have increased levels of PD-1 and
PD-L1 in their monocytes and T lymphocytes. 47
Studies have shown that increased regulation
of PD-L1 in granulocytes results in enhanced
lymphocyte apoptosis. 48
• Immunosuppression: Immunosuppression
is accompanied by an increased incidence of
sepsis. 49 It is also shown that there is a period of
immunosuppression that can reach anergy and
the inability to respond to another episode of
infection after a period of excess inflammation. 50
The sepsis-induced immunosuppression affects
both the cellular effectors of the innate immune
system and those of the adaptive immune system.
In these patients, nosocomial infections have
a worse evolution and there is an increase in
mortality. 51
• Hyperinflammation (‘cytokine storm’): In
some patients, especially in the young, there is an
excessive systemic activation characterised by a
surge of inflammatory cytokines such as IL-1, TNF,
and IL-17, in a relatively short period of time. 35
• Microcirculation: alteration of the
microcirculation is fundamental in sepsis; its
regulation is affected and produces functional
arteriovenous shunts that, in conjunction with
the formation of micro-thrombi in the capillaries,
explain tissue hypo-perfusion, hypoxia and
cellular dysfunction, and the development of
organ dysfunction. 39 The relationship between
systemic haemodynamics and microcirculation in
septic shock is dynamic. At an early stage,
microcirculatory abnormalities are sensitive to
flow and tend to improve with the optimisation
of systemic haemodynamics. Later on, the
pathophysiological mechanisms are more
complex and the alterations are independent. 53
• The endothelium and glycocalyx: the vascular
endothelium regulates the movement of blood
componenets to the tissues and plays a crucial
role in the development of sepsis. 53–55 The
synthesis of nitric oxide 56 and adrenomedullin 57,58
determines the vascular tone and a large part of
the haemodynamic alterations of those with
sepsis. The glycocalyx also expresses immune
receptors (DAMP and PAMP) that can activate
inflammatory pathways, alter vascular
permeability and activate coagulation. 59
The glycocalyx of the endothelial cells is
altered during sepsis, thereby triggering a
significant desquamation. 60 This degradation of