JOURNAL OF THE ROYAL SOCIETY OF MEDICINE

Volume 91

August 1 998

Trauma and the immune response

R M Smith MD FRCS P V Giannoudis BSc MD
SECTION OF ORTHOPAEDICS, 4 MARCH 1997

J R Soc Med 1998;91:417-420

Death after injury occurs in one of three phases. In the first

phase, patients die immediately because of devastating
trauma. In the second phase, during early resuscitation,
death may be related to hypoxia or hypovolaemia. In the
third phase, days or weeks following injury, death may be
due to the general physical consequences of injury, of which
the dominant manifestations are adult respiratory distress
syndrome (ARDS) and multiple organ failure (MOF). Of all
trauma deaths, about 45% occur in the first phase, 10% in
the second and 45% in the third. For a hospital, these thirdphase deaths present by far the greatest challenge. In the
UK half of them are due to head injuries, and half to MOF
and ARDS-two conditions in which widespread injury is
precipitated by an uncontrolled inflammatory response1.
In some respects the response resembles immunosuppression, in others immunoactivation. The latter has the
potential to cause cell-mediated damage in remote organs,
and key players in the host response are cytokines,
leukocytes and endothelium. Reactive oxygen species and
microcirculatory disturbances are also pivotal2. An understanding of the host's response to injury might enable us to
modify it and prevent the development of organ
dysfunction.
IMMUNOACTIVATION

Two models have been proposed for the exaggerated

immunoinflammatory response3. According to the 'one hit'
model, the initial massive tissue injury and shock gives rise
to an intense systemic inflammation syndrome (SIRS) with
remote organ injury. In the 'two hit' model, the initial SIRS
is less intense and normally resolves but the patient is
vulnerable to secondary inflammatory results that can
reactivate the SIRS and precipitate late MOF (Figure 1).
This second insult may take many forms, among them sepsis
and surgical procedures4. What components of the immune
system are involved? Those implicated include proinflammatory cytokines, activated polymorphonuclear
leukocytes and subsequent leukocyte endothelial-cell
interactions5. The major cytokines participating in the
Department of Trauma & Orthopaedics, St James's University Hospital, Beckett
Street, Leeds LS9 7TF, UK

Correspondence to: R M Smith

response to trauma include tumour necrosis factor-oa (TNFa), interleukin-1 (IL-1), IL-2, IL-6 and IL-86.
Each cytokine mediates various effects and their actions
can be additive. TNF-a and IL-1 (p), produced mainly by
monocytes, induce synthesis of acute phase proteins and
increase the adhesiveness of leukocytes on vascular
endothelium7. The serum of critically ill patients shows
high concentrations of TNF-ca8-10, but in the early stages
after injury the results have been mixed, ranging from
undetectable1 1-14 to highI5 16. (The contradictions may be
explained partly by the use of different sampling methods
and assays.) In addition, some workers report the presence
of high levels of naturally occurring inhibitors of TNF-a,
known as soluble TNF receptors17, which compete with the
membrane receptors for binding of free TNF-cx, thus
downregulating any detrimental TNF bioactivity and
making its detection in the peripheral circulation difficult18.
The published work is clearer with regard to the release of
IL-1, IL-2, IL-6 and IL-8; our group and others have
detected high levels shortly after accidental trauma19-21. IL6, in particular, is released rapidly after both surgical and
accidental trauma22'23 and its concentration correlates with
the degree of injury24.
Among the cellular elements in the inflammatory
cascade, the polymorphonuclear leukocyte is regarded as
the pivotal player. After activation it adheres to vascular
endothelium, subsequently passing into the surrounding
tissues where its proteolytic enzymes are released and cause
tissue destruction26-28. To bind to vascular endothelium,
activated leukocytes have to express surface glycoproteins

-4

Q)
r-1

|First hit
4

severe response

Reaction
/

? nature

Resolution

, MOF/ARDS
ISecond hit

MOF/ARDS

Figure 1 Inflammatory models (MOF/ARDS=Multiple organ failure/

adult respiratory distress syndrome)

417

JOURNAL OF THE ROYAL SOCIETY OF MEDICINE

Extra vascular space

Intra vascular space

Leukocyte

CD1 1-b

~~T~dot
ICAM

extravasation

i
Emum

E-selectin

Figure 2 Leukocyte-endothelial cell adhesion (ICAM=Intracellular

adhesion molecule)

(receptors) known as integrins29,30. Normally, circulating

leukocytes will not adhere to endothelial cells, and the
process involves a corresponding activation of the
endothelium, which expresses its own adhesion molecules namely, intracellular adhesion molecule-1 (ICAM1) and E-selectin. These receptors can be stimulated by a
variety of biological agents such as cytokines (TNF-a, IL-1,
IL-8), bacterial peptides, complement fragments and
endotoxin3l. E-selectin initiates and ICAM-1 completes
the adhesion process that allows migration of the leukocyte
across the vascular endothelium32 (Figure 2). As this
process takes place, soluble products of E-selectin and
ICAM- 1 are discarded into the circulation and can be
detected peripherally.
After migration, the tissue destruction mediated by
neutrophils is partly due to release of elastase, a neutral
proteinase stored in the azurophilic granules.
IL-6, soluble ICAM, soluble E-selectin and elastase can
be measured in the peripheral blood by enzyme linked
immunosorbent assays (ELISAs) while the activity of the
CD 1 lb receptors can be determined by fluorescent labelling
of living cells with monoclonal antibodies. Several groups
have reported activation of leukocytes (upregulation of
CD 1llb receptors and plasma elastase release), as well as
release of adhesion molecules from the endothelial cells,
after trauma33-36; and, again, the magnitude of these
responses has correlated with the extent of injury37.
Probably it is loss of control of this normal immunoinflammatory response that causes the widespread tissue
destruction characteristic of ARDS and MOF.
IMMUNOSUPPRESSION

418

Although selective immunostimulation may thus play a

critical part in the development of severe complications
after injury, it is clear that the predominant effect of
surgical or accidental trauma is immunosuppressive. Such
immunosuppression is widely thought to contribute to
infection and sepsis after trauma38.
After injury, the production of immunoglobulins and
interferon (IFN) falls and many patients become anergic as

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August 1 998

assessed by delayed hypersensitivity skin testing39. Defects

in neutrophil chemotaxis, phagocytosis, lysosomal enzyme
content and respiratory burst have also been reported40'41.
At the cellular level, much research has been focused on the
HLA-DR locus, which mediates the processing of antigen to
allow for cellular immunity and specific immune responses
to infection42. The expression of major histocompatibility
complex class II HLA-DR antigen on the surface of
circulating monocytes, an index of antigen presenting cell
capacity, is decreased after both surgical and accidental
trauma43.
The decline and recovery of HLA-DR expression on
monocytes relates closely to clinical outcome and may
predict which patients will develop complications after
trauma. In patients with uneventful recovery from severe
trauma, monocyte HLA-DR expression returns to normal
within a week; in those who develop sepsis but recover, it
takes three weeks to return to normal levels; while in
patients who develop sepsis and subsequently die, it never
returns to normal4. The expression of HLA-DR on
monocytes is one of the few indices of immunological
reactivity that correlate well with morbidity and mortality
from sepsis.
The mechanism for the downregulation of HLA-DR
expression is not clear. Cheadle et a]. thought it might
reflect an influx of immature monocytes from the bone
marrow, with constitutively lower HLA-DR expression45.
Wakefield et al. suggested blockage of the trafficking of
MHC class II molecules to the cell surface from intracellular
stores43. Lately, Klava et al.46 reported a correlation
between IL-10 gene expression and the fall in monocyte
HLA-DR antigen expression in patients undergoing major
abdominal surgery; thus postoperative immunosuppression
might be mediated by IL-10. Perhaps measurement of this
or other molecules will enable us to predict patient course
and target our treatments more effectively.
BIOLOGICAL VARIATION IN DEVELOPMENT OF
POST-TRAUMATIC COMPLICATIONS

Biological variation is increasingly cited as an explanation

why some patients develop serious post-traumatic complications and others do not47. It seems that biological
variation influences the outcome from any form of
traumatic insult. For example, polymorphism within the
TNF genotype determines whether TNF responses to a
standard endotoxin dose are high or low48. Genetic
polymorphism of the neutrophil receptor for immunoglobulin G, CD16, has also been reported and is associated
with functional differences in neutrophil phagocytosis49.
Inherited traits towards high or low levels of HLA-DR
expression are further evidence of a genetic component in
immune response to injury45. Lately, our group has been

JOURNAL OF THE ROYAL SOCIETY OF MEDICINE

able to correlate the decrease in HLA-DR expression on

monocytes with the pulmonary shunt, a preclinical
component of ARDs, and has hypothesized a link between
this potentially inherited cellular mechanism and the clinical
syndrome of ARDS50.
CONCLUSION

Both stimulation and suppression of the inflammatory

system are normal responses to injury, but exaggeration of
either can lead to serious complications. Molecular biology
is providing us with new therapeutic targets and the
potential to approach the treatment of diseases from new
directions. Unfortunately, specific molecular treatments to
block uncontrolled and harmful responses to injury have
been disappointing to date51'52, for reasons that may include
the difficulty of identifying patients who would benefit from
such therapies, the targeting of only one or two molecules
in complex inflammatory cascades and our lack of
understanding of fundamental disease processes. As knowledge increases, one day it may be possible to identify the
individuals at particular risk and then to block the harmful
responses to injury.
Acknowledgments We thank Professor P J Guillou for
guidance and access to laboratory facilities, and Professor
R A Dickson for the general support of his department.
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