Review
T H E P U T A T I V E M E C H A N I S M S O F M E D I A T O R S IN T IS S U E
R E S P O N S E T O T H E R M A L I N J U R Y
Berna K. O ktar, M.Sc. / İnci Alinean, M .D ., PH.D,
M a r m a r a U n iv e rs ity , S c h o o l o f M e d ic in e , D e p a r t m e n t o f P h y s io lo g y , Is t a n b u l, T u rk e y .
INTRODUCTION
Despite recent ad van ce s in burn care, se p sis still rem ains a major ca u se of burn morbidity and mortality. Five factors determine the se rio u sn e ss of a burn: depth, size , a re a (s) of involvement, age and general health of the burn victim (1). Burns are classified a s partial-thickness (first or second degree) or full-thickness (third or fourth degree) burns. P a rtia l-th ic k n e ss burns are characterized by superficial injury to varying portions of the ep id erm is, w hich m ay be produced by sunburn and sc ald s. Full-thickness burns involve injury to the entire derm is, including appendages (sw eat glands, hair follicles, etc.) and may extend into the fat and m uscle tissu es. Th e se burns are produced by flam e, chem ical contact or electrical current.
Initial treatment of the burn patient is aimed at relief of respiratory d istress, initiation of fluid resuscitation, and prevention of burn' shock (2). After initial treatment, the patient is admitted for
further non-operative treatm ent including
resu scitatio n , nutrition, infection control,
ventilation and other burn wound m anagem ent
tech n iq ue s. Im proved re su scita tio n , e arly
debridement and grafting, nutrition and critical care have improved outcom es in patients with burn injuries; however, se p sis and mutiple organ dysfunction still remain a s major c a u se s of burn- related deaths (3).
Remote Consequences of Thermal
Injury
Therm al Injury my c a u se dam age to multiple organs distant from the original burn wound and may lead to multiorgan failure (4). After a major
therm al injury, there is e xtra va sa tio n of
intravascular fluids into the injured site, which, without adequate fluid resuscitation, lead s to hyp ovo lem ia, sh o c k , and death. Flo w eve r, generalized tissue inflammation is present in uninjured organs within hours of injury, even in the absen ce of shock.
L o ca lize d therm al injury triggers an acu te p athophysiologic re sp o n se that in corpo rates vasodilatation to aid dissipation of the heat and activation of afferent nerve sig n als, which ca u se pain. Burn injury also c a u se s the local release of oxidants and arachidonic acid metabolites, which initiate burn wound edem a (5, 6). In addition, the activation of a number of system ic mediator
c a s c a d e s , e .g ., a com plem ent a ctivatio n ,
ara ch id o n ic acid re le a se and cytokine
production, result in a generalized neutrophil sequestration and most importantly a "priming" of
both local and sy ste m ic neutrophils and
m acrophages. Th e release of m ediators and activation of c a s c a d e m e c h a n ism s are in proportion to the total body surface area burned (6). In se ve re c a s e s , system ic, neurohumoral and inflammatory reaction p eaks at 5-7 days after the burn incident.
(A c c ep ted 5 March 2002 ) M arm a ra M e d ic a l J o u r n a l 2 0 0 2 ;1 5(1 ) :5 0 - 5 5
Correspondance to: İnci Alican, M.D, - Department of Physiology, School of Medicine,
Marmara University, 81326 Haydarpaşa, İstanbul, Turkey
Tissue response to thermal injury
Burn c a u s e s the in c re a se of m icro va scu lar perm eability due to direct effect of heat on endothelial cells and due to chem ical mediators
of inflam m ation su ch a s h istam ine and
prostaglandins (7). Th e increased m icrovascular perm eability a llo w s fluid le ak ag e into the interstitium which results in hypovolemia.
Reactive oxygen m etabolites (R O M s) have been implicated a s a primary c a u se of both local pro g ressive skin n e cro sis and distant organ injury in burns (8, 9). It h as been proposed that the so u rce of R O M s could be neutrophils sequestered in system ic organs a s a result of the system ic inflammatory reaction to a local burn insult. Organ injury remote to the region of thermal traum a is now known to be due to intravascular activation of com plem ent which results in activation of intravascular neutrophils and heads to the formation of toxic oxygen products (10). Th e contention that neutrophils play an important role in the development of remote organ injury is supported by the findings
w hich sh o w that postburn in tra va scu la r
hem olysis a s well a s lung injury of the skin were largerly prevented by neutrophil depletion in
exp erim en tal a n im a ls (1 1 ). T h u s, sin ce
sequestration of m etabolically active neutrophils in d u ce s tissu e injury, th e rap ie s that block
postburn le u ko se q u e stratio n m ay im prove
clinical outcom es by limiting remote tissue injury. In addition to this, antioxidants have been shown to attenuate mortality and morbitidy in a number of se p sis models (12).
Lipid peroxidation due to R O M s Is one
d eleterio u s c o n se q u e n c e of burn injury.
In cre ase d circulating lipid p e ro xid a se s have been dem onstrated in hum ans and burn animal models (13, 14). In addition to inflammation, lipid peroxidation in lung, liver, kidney and other tissu e s is se en in the early postburn period (14, 15). An increase in distant organ inflammation,
a s well a s tissu e oxidant-induced lipid
peroxidation, particularly in the liver, occurs within hours after a body burn, even in the a b sen ce of sho ck (14). It has been shown that early lipid peroxidation is su ccessfu lly prevented by infusion of the iron chalator deferoxam ine during the resuscitation period (16). Moreover, the im m unosuppressive agent FK 5 0 6 is of some benefit in the reduction of system ic neutrophilic injury and related lipid peroxidation in rats
following burn insult. It w as found to be effective in reducing lipid peroxidation and neutrophil infiltration especially at 24 h postinjury in lung, liver and kidney (17).
In addition to oxidants, the cytokines are also involved in a number of major responses to burn injury. Th e se include hemodynamic changes, tissue inflammation, wound healing, immune d e fe n se s, hyperm etabolism , and catabolism . Continued increased activity of som e of these
ag en ts, particularly T N F - a , is felt to be
responsible for the organ failure syndrom e seen with a persistent se p sis syndrom e. The major cytokines involved with the response to burn trauma, include T N F -a , lnterleukin-1 (IL-1), IL-2, IL-6, and interferon-a. The role of T N F -a in the septic response to endotoxemia is evident by the fact that pretreatment with T N F -a antibodies prevents the system ic response (18). T N F -a has been shown to be increased in the plasm a of burn patients, but alm ost a lw a y s in septic patients or patients who soon died (19). The specific role of IL-1 in the various aspects of burn injury is not well defined. Th is cytokine is most certain ly involved in the later resp on se of postburn se p sis and hypermetabolism (6). On the other hand, both IL-2 production and IL-2 action are well documented a s decreasing after burn injury (20). The decreased IL-2 correlates with increased mortality after a septic challenge in burn anim als (21). It is therefore clear that a deficiency of this cytokine plays an important role in the decreased resistance to infection in the burn patient. Another cytokine released very rapidly Into the circulation in re sp o n se to circulating endotoxin is IL-6. Serum levels of IL-6 are markedly increased in burn patients with peak response beginning about 1 w eek postburn (22). Circulating IL-6 levels appear to correspond with endotoxin levels and large increases appear to correspond with mortality.
A rach id on ic acid m etabolites are definitely involved both in the early and late responses after thermal injury (23). Arachidonic acid is
re le a se d from cell m am bran es after any
significant septic event. It is now well established that there is a m assive release after burn of both the vasodilator prostanoid, namely prostacyclin (P G I2 ) and the va so co n stricto r prostanoid, thromboxane A2 (T xA 2 ), as detected in burn edem a and plasm a (23). Th e characteristic blood
Berna K. Oktar, et al
flow maldistribution se en with se p sis appears to be related with e x c e ssiv e production of TxA 2 or P G I2 in va rio u s v a s c u la r b ed s (2 4 ). E a rly thromboxane release is considered to be at least in part responsible for a persistent d e cre ase in burn tissue blood flow (25). Th e local increase in TxA 2 has also been reported to stimulate platelet aggregation and neutrophil margination in the burn microcirculation. It has been demonstrated that thromboxane concentrations are markedly increased in patients im m ediately after burn
injury and during se p tic e p iso d e s (26).
Pretreatm ent of pigs with the sp e cific
thromboxane inhibitor O K Y 0 4 6 attenuated the increase in m esenteric v a scu la r resistan ce and restored the d ecrease in gut blood flow (27). All these findings indicate that the TxA 2 is involved in the system ic hem odynam ic response after burn insult. P G I2 is a potent vasodilator and is therefore known to accentuate va scu lar leak by
an in c re a se in local blood flow. T h e
lipooxygenase pathway products, leukotrienes B4, C 4 and D4 are shown to be involved in the later postburn response than any of the early changes (28). To date, however, there have been variable resp on ses reported with the use of
lip o o xyg en ase inhibitors and leukotriene
antagonists in burn se p sis.
Nitric oxide (NO) which is important in numerous p hysiological and p atho p hysio log ical even ts show s dram atic in c re a se s in plasm a and urine after thermal injury (29). Therm al injury induces the production of inducible NO syn th ase (¡N O S) in gut m ucosa. ¡N O S activity in c re a se s 24 h after the injury and up to a maximum of twofold 2 days after burn and d e c re a se s thereafter (30). The increase in ¡NOS activity in gut m ucosa has been found to correlate well with the increase in intestinal permeability, an index for barrier failure (30). According to these studies, the change in m ucosal ¡NOS activity after the burn occurs mainly in the enterocytes rather than in the m acrophages (30). Sup p ressio n of intestinal mucosal ¡N O S activity prevents barrier failure as dem onstrated by a d e c re a s e in bacterial
translocation o c cu rre n ce and intestinal
permeability (30). N O S inhibitors adm inistered as therapeutic treatm ent w ere also effective in suppressing va scu lar permeability 1 and 6 hours postburn (31). On the other hand, it has been suggested that ven u le constiction, w hich is
observed 5 h after thermal injury, is related to d ecreased NO production by endothelial cN O S
(3 2 ). D ietary arginine supplem entation
d e cre a se s the m RN A exp ression of inflammatory cytokines (i.e. T N F -a , interferon-a, IL-1 beta and IL-6) in the spleen, thym us, lung and liver after thermal injury in rats and im proves the survival rate (33). It has been observed that burn injury in hum ans is also asso ciate d with e x c e s s NO production (34). H ow ever, NO production w as not proportional to burn are a , and seem ed to be further enhanced in septic patients (34).
At c e lllu la r le ve l, therm al injury ind u ce s
programmed cell death with a concom itant loss in cellular m ass and absorptive su rface area in the gut (3 5 ). Th e rm al injury in d u ce s intestinal atrophy and c a u se s marked alterations in the morphology, growth, and function of the sm all intestinal epithelium (3 6 , 3 7 ). Post-therm al atrophy of the intestinal m ucosa w a s based on a d e cre a se in the m ucosa weight and a reduced intestinal cell proliferation, a s dem onstrated by dim inished DNA and protein sy n th e sis (37). Cutaneous thermal injury c a u se s a transient suppression of mitosis a s well a s induction of apoptosis in the sm all intestinal crypt (38). Sim ilarly, it induces hepatic cell apoptosis and proliferation which a sso c ia te s with an increase in hepatic N F-kB exp ression and a d e cre a se in hepatic protein concentration (39) (Fig . 1).
LOCAl. SKIN Bl'RN l I C o m p t e il ic i il ¡ t u i v a l i o n H u m w o u n d o - l o i i i / a l i o n 4 -A r a c h i d o n i c a c id r e le a s e C y t o k i n e p r o d u c t i o n X ( T N F - a . I I I . I I . - 2 . I I -6. I F N - y , R e l e a s e o l 'e n d o t o x i n a n d o tlie i b a c t e r ia l b y - p r o d u c t s I ( j u t b a r r i e r d is r u p t i o n i R e l e a s e o f o x i d a n t s , a r a c h i d o n i c a c id m e t a b o l it e s , p r o t e a s e s , e tc .
REMO I E ORGAN DAMAGE
---F i g . l : A brief su m m a ry of th e p a th o p h y sio lo g ic e v e n ts th at a p p e a r to b e a s s o c ia te d with re m o te c o n s e q u e n c e s of local skin burn.
Tissue response to thermal Injury
Burn-Induced A lte ra tio n s In
G astro in testin al Functions
Although the pathophysiological b asis of remote organ injury rem ains unclear, understanding the effecte of thermal injury on the gastrointestinal system is important for the physician involved in nutrition of the patient. Adynam ic ileus, gastric dilatation, increased gastric secretion and ulcer incidence, gastrointestinal hem orrhage, local and general redistribution of the blood flow with a d ecrease of m esenteric blood flow are among the effects of thermal injury on the gastrointestinal
syste m (4 0 ). R e la tiv e intestinal isch em ia
resulting from d ecreased splanchnic blood flow m any result in the activation of neutrophils and tissue-bound en zym es such a s xanthine oxidase. T h e se factors impair gut m ucosal barrier and result in bacterial translocation.
The gastrointestinal barrier is normally highly effective in containing its flora. H ow ever, subsequent to the stre ss of thermal injury, the barrier breaks down and lead s to the p assag e of inert particles and m icroorganism s a cro ss the intestinal w all, a condition termed "translocation". Endotoxin, a lipopolysaccharide derived from the outer m em b rane of gram -negative b acteria, tran slo cate s a c ro ss the gastrointestinal tract barrier within 1 hour of thermal injury (41). Although the burn wound is sterile initially, plasm endotoxin concentration re ach e s to a peak at 12 h and 4 days postburn (42). Bacterial by-products including endotoxin are potent activators of the m acrophages and neutrophils. T h is leads to the re le a se of m a ssiv e am ounts of oxid ants, arachidonic acid m etabolites, proteases, etc.,
w hich c a u s e further local and syste m ic
inflammation, induced tissue dam age (6).
The terminal ileum is an area of the intestine
p articu larly vu ln e ra b le to isch e m ia during
splanchnic vasoconstriction. A 30% body surface area burn in rats c a u se s a marked increase in lipid peroxidation in the terminal ileum within 24 h after therm al injury (4 3 ). A g g re ssive fluid resuscitation, pretreatm ent with the xanthine oxid ase inhibitor allopurinol or with an anti inflam m atory agent that inhibits neutrophil
degranulation a za p ro p a zo n e are effective
interventions for preventing b acterial
translocation and ileal lipid peroxidation (43).
Additionally, diets rich in glutamine-the most plentiful intracellular amino acid and the major fuel of enterocyte- and fiber have been found to d e c re a se the degree of intestinal bacterial translocation (44).
Chen et al. (45) demonstrated that the decrease in intestinal and colonic motility in the rat following burn injury w as accom panied by a delay in gastric emptying. In contrast, Hu et al. showed that the kinetics of gastric emptying w as not affected by thermal injury (46). In a study performed in our laboratory, we observed a significant delay in intestinal transit in both early and late p hases after burn injury in rats (47). Another interesting finding of this study w as the reversal of this effect by bombesin, a peptide essential in the m aintenance of gut integrity, intestinal motility and proliferation of gut m ucosa. Th is finding supports the previous studies in which bombesin w as found to prevent intestinal mucosal atrophy with a concomitant d ecrease in bacterial translocation after thermal injury (48).
CONCLUSION
Most of the studies cited here use animal models which are then extrapolated to the clinical setting. Th e ad van tag es in using an anim al model include complete control of burn size , severity and area of involvement. However, the validity of using an animal model in burn research has never been established, nor is it clear whether one animal sp ecies is superior to another in terms of extrapolation to hum ans.
It is obvious that modulation of the inflammatory response has trem endous potential for benefit.
P aren teral or topical nonsteroidal anti
inflammatory drugs, anti-endotoxin antibodies, antioxidants blockers of cytokine action are all agents currently available. In addition to these interventions, new therapeutic modalities may becom e available to protect and/or treat impaired gastrointestinal barrier in the near future. The key point is that it is essential for the clinician to choose the right pharm acological manipulation in order to be able to optimally utilize these future ad vances.
Berna K. Okiar, et aI
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