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166
C. I. Günter and H.-G. Machens
https://t.me/medicina_free
and pro-regenerative effects of EPO have been
published by Brines etal. [11] and by Arcasoy
[9] in 2008.
16.3 EPO Receptors
The different effects of EPO within the different
organ systems (erythropoiesis, versus antiinammatory and pro-regenerative effects) can
be explained by a different afnity for the individual receptor types and receptor subtypes [12].
The tissue-protective properties are mediated by
the EPO hetero-receptor, whose afnity for EPO
is lower than that of the EPOR2 receptor, which
mediates the erythropoietic effect of EPO.The
EPO hetero-receptor is usually not detectable in
healthy tissue, but has been described posttraumatically [11]. Among other things, this
could explain why EPO is only pro-regenerative
and pro-proliferative after trauma [5]. As the
proof of the EPO hetero-receptor has not yet been
achieved beyond doubt, this approach is still
controversial.
A major problem in the study of the nonhematopoietic effects of EPO is that the previous
antibodies to the EPO hetero receptor are in all
likelihood non-specic. It turned out that the
antibodies used also bind to other cytokine receptors, which makes it difcult to interpret the
results [13, 14]. It is therefore particularly important in the future to re-evaluate the present results
with new, highly specic antibodies that are
being intensively worked on. Ultimately, only
with the help of a specic antibody it can be claried whether a separate EPO hetero receptor
exists and in which molecular signaling pathways
it plays a role.
16.4 Adverse EPO Eects
In addition to the desired effects of EPO, undesirable effects are also described [3]. Three of
these are known only for longer-term EPO therapy: increased risk of thrombosis [15, 16], antibody formation [17] against rhEPO, and an
increase in blood pressure [18, 19]. Regarding
the thrombophilia caused by EPO, however, the
group around Corwin has shown that in patients
with adequate weight-adapted thrombosis prophylaxis using low-molecular-weight heparin,
the thrombosis tendency is not greater under
EPO therapy than in the control group without
EPO administration [20].
The blood pressure increase problem has so
far only been described in patients who had previously exhibited blood pressure abnormalities.
Here, an acceptable risk minimization should be
feasible through careful evaluation and patient
selection. An unprecedented problem is the
treatment of tumor anemias with EPO.In principle, EPO is approved for the treatment of
tumor anemia. In the meantime, however, numerous studies have shown that EPO therapy has a
negative effect on patients’ survival time [19–
21]. The discussion of whether this is due solely
to the optimized oxygenation rates after anemia
correction or to the pro-angiogenic and antiapoptotic or the pro-thrombotic effects of EPO,
has not yet been completed. However, a direct,
active oncogenic effect of EPO has not yet been
demonstrated [21, 22].
16.5 EPO inSeverely Burned
Patients
As early as 1972, the concentration of autologous
EPO in patient blood was investigated in anemia
after thermal trauma [23]. In particular, it was
noticeable that patients with burns below 30%
TBSA generally had normal EPO blood values
on the one hand and were not subject to transfusion on the other hand. In contrast, patients with
burns above 30% TBSA were usually found to
have markedly low EPO levels in the blood. In
addition, these patients were usually anemic. It is
also striking that patients with pronounced bacterial wound infections had even lower EPO and
pronounced anemia values, and therefore all
patients in these two groups were subject to
transfusion [23].
In the 80s and 90s followed a series of publications, the aim of which was the anemia
correction in severely burned patients by EPO
16 Erythropoietin: AnInnovative Therapeutic Approach inThermal Trauma
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167
application. In none of the publications a signicant reduction of the number of transfused blood
products required could be detected; an effective
increase in erythropoiesis, which had been
intended, could also not be demonstrated. Effects
on wound healing are not described, as they were
not the subject of the investigations [24, 25].
It is now known that erythropoiesis is not likely
to be increased by EPO administration in critically
ill patients. In a mouse model, it could be shown
that after an adequate thermal trauma a general
depletion of the bone marrow occurs whereby the
erythropoiesis and the lymphpectoris are more
affected than the myelopoiesis. This depletion is
refractory to EPO therapy [26]. However, this fundamentally undesirable effect could be a benet
for patients injured by serious burns, as this would
make the feared complications of excessive erythropoiesis very unlikely, and the pro-regenerative
effects of EPO could be exploited.
16.6 Pro-Regenerative EPO
Eects in Burn Injury
Animal Models
mals. The blood count changes were not statistically signicant, but on day 14, there was a slight
increase in erythrocyte and reticulocyte counts in
the animals treated with EPO.
After standardized water vapor scalding, the
effect of topically applied EPO was investigated
in a mouse model. It showed that the deep dermal
scalding in the treated with EPO hydrogel animals healed much faster, the re-epithelialization
was completed earlier. Increased epithelial proliferation, faster formation, and maturation of the
extracellular matrix, as well as marked angiogenesis induction and consequent higher capillary
densities were also demonstrated with high
CD31, VEGF, and eNOS levels [28]. In another
work, the combined presence of EPOR and the
EPO hetero receptor could be detected in both
healthy and scalded mouse skin. In the healthy
skin, a clear reduction of the EPOR expression
after EPO application could be detected, in the
thermally injured not, here the expression rate
remains high. Likewise, a faster and higherquality wound healing (dermis /epidermis papillae, maturity of the extracellular matrix) could be
demonstrated by EPO application [29].
In 2006, Galleano [26] published the rst work
investigating the pro-regenerative effects of
rhEPO after thermal trauma in the mouse model
[27]. Three groups were formed: Verum group:
rhEPO 400 IU/kgBW/d for 14 days, placebo
group: distilled water, control group: they were
previously passively immunized against rhEPO
and given rhEPO 400 IU/kg/d for 14 days.
Signicantly faster wound closure was associated
with faster re-epithelialization in the verum group
compared to the other two groups. Wound healing
in the immunized group (control) was again signicantly delayed compared to the placebo group
(distilled water). In the respective comparison, the
verum group showed signicantly better epithelial proliferation, a considerably more mature
extracellular matrix and pronounced angiogenesis
[27]. This was demonstrated in particular by the
higher microvascular density in the histological
sections, which also had a corresponding
increased CD31 expression, as well as increased
VEGF and NO values in the samples of these ani-
16.7 Experiences inLow-Grade
and Severely Burned Patients
A pilot study for topical use was performed on 11
low-grade burned patients. In this project, EPOhydrogel was applied locally to split skin donor
sites or placebo hydrogel was used in the controls. A faster healing of the split skin donor sites
in the verum group could be observed. For example, complete healing of the split skin donor sites
treated with EPO hydrogel was observed after
7days in 85% of patients [30]. Further healing
attempts with topically applied EPO were carried
out in pediatric scalding injuries. Complete healing of the affected areas within 10 days was
observed in mixed 2a–2b scalding injuries.
To translationally review the promising
results, hoping for a possible improvemend of
wound healing in severely burned patients, a
nationwide multi-center study funded by the
Federal Ministry of Education and Research was
168
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C. I. Günter and H.-G. Machens
being carried out with systemically administered
low-dose EPO (EPO in Burns, EuraCT Number:
2006-002886-38, Protocol Number: 0506,
ISRCT Number: ISRCTN95777824) [31]. The
objective of the original trial “EPO in Burns” was
to demonstrate faster wound healing through the
pro-regenerative and cytoprotective effects of
systemic applied, low-dose recombinant EPO in
thermally injured adult patients. Unfortunately,
the results of “EPO in Burns” regarding the reepithelialization of the study wound did not show a
conclusive result. A potential advantage in reaching the 100% re-epithelialization could be seen in
the EPO group within the rst ten days. Thereafter
this trend changed into the contrary. Regarding
results of several secondary endpoints, such as
ABSI Score results the EPO group showed much
better values and therefore a more positive prognosis, than the control group. ICH-GCP conform
clinical trials are needed to investigate this ndings more thorrowly [1, 2].
16.8 EPO Treatment
forPrevention ofSecondary
Burn Progression
Further interesting reports on EPO effects in thermal trauma relate to the possibility that a “lowdose” EPO application can prevent the secondary
burn progression of wounds within the rst few
minutes to a maximum of hours after trauma. In the
animal model (rat), intraperitoneal administration
of low dose EPO signicantly reduced secondary
burn progression within 45 min of standardized
trauma. In the following days, the wounds also
healed signicantly faster. This promising approach
is worth pursuing and, given sufcient positive data,
performing ICH-GCP- compliant clinical trials.
16.9 EPO inSecondary
Reconstruction
EPO may also play a role in secondary, reconstructive operations in patients with severe burn
injuries, especially in the free microvascular tissue transfer. Based on the assumption that EPO
could be tissue-protective in ischemic damage.
The investigation required experimental aps,
which are designed to develop a zone of persistent ischemia with subsequent necrosis.
As early as 2003, Rezaeian etal. [
the rst paper dealing with the use of EPO to
improve ap survival in randomly perfused aps
in the rat model. On the one hand, the ap survival
was investigated, on the other hand possible EPOinduced undesired side effects, such as hematocrit
and blood pressure increase, were evaluated.
Short-term low-dose and high-dose EPO was
associated with statistically signicantly improved
ap survival [
increase in hematocrit and blood pressure could
only be detected in animals that had received highdose EPO for three weeks. This signicant increase
correlated with a statistically worse ap survival.
Harder etal. [33] developed a mouse model that
integrates a randomly perfused, laterally pedunculated musculocutaneous ap into a dorsal skin
chamber. Untreated, this ap developed partial
necrosis of approximately 50% due to persistent
ischemia. Using intravital uorescence microscopy, it is possible to repeatedly examine both morphological and dynamic changes in the tissue and
vasculature of the ap at the same localization in
the chamber window [33, 34]. A rst study examined the efcacy of recombinant human EPO rst
detected in two different dosages 24h prior to ap
elevation, before induction of ischemic stress and
following, repeated over 4days. The administration of rhEPO showed signicant, dose-dependent
anti-inammatory (i.e., decreased leukocyte-endothelial interaction, impaired cell apoptosis), and
pro-angiogenic effect (i.e., microvascular neovascularization). The lower dose resulted in signicantly improved ap survival compared to the
untreated animals, whereas the ten-fold higher
dose only marginally improved ap survival.
Administration of rhEPO maintained perfusion in
the capillaries of critically perfused ap areas. The
signicant increase in hematocrit, which could
only be detected in the high-dose EPO group starting on the fourth day after rst administration, led
to a signicant worsening of the ow properties in
the ap, and thus poorer survival despite rapid and
strong abolition of the EPO-induced anti-ammatory effect characterized by a decrease in cell apoptosis and leukocyte-endothelial interaction [33].
32]. A statistically signicant
32] published
16 Erythropoietin: AnInnovative Therapeutic Approach inThermal Trauma
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169
Having demonstrated that EPO is dosedependently protective of critically perfused ap
tissue, Contaldo et al. [35] investigated in the
same mouse model the optimal time of EPO
administration for ap elevation, the induction of
persistent ap ischemia. For this purpose, lowdose EPO was administered over a period of 48h
either before (preconditioning) or after (post-conditioning) the ap elevation. In a third group, the
mice received EPO overlapping both 30 min
before and after ap elevation and 24h (perioperative treatment) after ap elevation. Both preconditioning and perioperative treatment resulted
in a signicant improvement in ap survival as a
result of maintaining capillary perfusion in the
critically perfused portion of the ap. This, in
turn, results from a very early EPO- mediated upregulation of inducible nitric oxide synthase
(iNOS) [34], which leads to dilatation of the afferent ap vessels. If EPO is administered only after
ischemia induction (post-conditioning), this
iNOS-mediated maintenance of ap perfusion
cannot be induced in a timely manner. In addition,
a VEGF-mediated angiogenic reaction associated
with de novo formation of functional capillaries
was demonstrated [34, 35].
In another work, Contaldo etal. [36] also demonstrated in a murine model that persistent vasodilations, and thus improved ap survival after
perioperative EPO administration, are not only
mediated by iNOS, but also due to more than ve
days of prolonged up-regulation of endothelial
NOS (eNOS). In this work, it was also investigated whether EPO-induced and VEGF-mediated
angiogenesis is indeed involved in improved ap
survival. The co-administration of rhEPO and
bevacizumab, i.a., VEGF receptor inhibitor acting
as an angiogenesis inhibitor led to a failure of the
EPO-induced angiogenic response. Interestingly,
there was no change in ap survival after EPO
alone. The authors concluded that EPO-mediated
angiogenesis is not involved in ap survival under
these modes of administration. This is probably
because of the time delay, as the newly formed
capillaries are functional only vedays after ap
elevation. This period is beyond the ischemia tolerance of the tissue or the demarcation of necrosis
[36]. In analogy to microvascular ap scans,
Contaldo and coworkers investigated the efcacy
of EPO on musculocutaneous tissue undergoing a
3-h ischemic phase, followed by reperfusion.
High-dose EPO were systemically administered
either 1 or 24h before ischemia [37]. The animals
treated with EPO showed an increased expression
of both the EPO receptors in skin and muscle tissue, as well as the NOS.These aps and the animals showed less reperfusion injury than untreated
animals, resulting in maintenance of capillary
perfusion, decreased hyperpermeability of the
vessels, and less inammatory response [37].
Lindenblatt etal. [38] investigated NO-mediated
tissue protection after systemic EPO administration on a collateralized island ap on the hamster.
For this purpose, rhEPO alone or rhEPO was
administered together with a non-specic
NO-blocker L-nitro-L-arginine methyl ester
(L-NAME). The rhEPO application led to a signicant improvement of the ap perfusion, as well
as to a weakening of the inammatory reaction
and the apoptosis rate. As the co-administration of
rhEPO and L-NAME led to a complete abolition
of tissue protection, the authors concluded that the
protective effect is primarily mediated via NO
[39]. An implementation of the ndings obtained
in the clinic would be very desirable, in particular
the use of non- hematocrit- effective EPO dosages
or the short- term use of higher EPO dosages
before they become hematocrit effective to a problematic extent. Here, the local EPO application,
possibly also high-dose or alternatively the use of
modied non-erythropoietic EPO molecules is of
particular importance [40].
16.10 Summary andConclusions
The results of the presented, animal experimental investigations on thermal injuries are promising. Unfortunately ICH-GCP compliant clinical
trials for EPO as a therapeutic agent to optimize
wound healing could not show positive results.
This so called “EPO-Paradox” was discribed
before by Steppich [3]. In the animal model,
damage to the ap caused by acute persistent
ischemia, as well as ischemia/reperfusion injury,
can be reduced by EPO application. This shows
both a time dependence with regard to ap elevation (ischemia induction), as well as a dose
170
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C. I. Günter and H.-G. Machens
a
b
Fig. 16.1 (a) Scalding injury, 4 days after injury (2a°to
3°) First Treatment with EPO Hydrogel. (b) Result after
4x EPO Hydrogel Treatements
dependency of EPO. A signicant increase in
hematocrit, as observed in these models following repeated dosing of high-dose EPO, may
worsen the ow of the blood, leading to thromboembolic complications [41], thus abolishing
EPO- mediated protective, anti-ischemic effects.
On the other hand, an anti-thrombotic effect of
EPO applications has already been demonstrated
in the mouse model [42], so that the scientic
discussion is far from complete [43]. The tissueprotective effect of EPO appears to exist in ischemic tissue, e.g., ap models to be primarily
NO-associated, in which with persistent ischemia, perfusion can be maintained in the critically perfused ap (area). Angiogenesis does not
seem to play the crucial role, as the newly formed
vessels are functional only after about vedays,
a time when the necrosis of the ap has already
been irreversibly demarked.
For a possible individual use of EPO in the
context of healing attempts in burn-injured
patients, a very careful patient evaluation in the
individual case must be advised. In particular,
with regard to problematic pre-existing conditions
such as hypertension, thromboembolic events or
known malignancies, a particularly careful history-taking and consideration of the risk-benet
ratio must be ensured [44] (Fig.16.1). The use of
EPO as a routine therapy in the proregenerative
eld is not possible jet, as so far no clinical trial
could demonstrate positive results. A possible
alternative would be the further development and
testing of non-hematopoietic EPO derivatives.
Here, however, a longer time can be expected
until they have overcome the hurdles of the necessary approval studies and other preconditions and
are available for widespread clinical use [12, 45].
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42. Meistrell ME, Botchkina GI, Wang H, Di Santo E,
Cockroft KM, Bloom O, Vishnubhakat JM, Ghezzi
P, Tracey KJ. Tumor necrosis factor is a brain
damaging cytocine in cerebral ischemia. Shock.
1997;8:34–8.
43. Yazihan N, Karakurt O, Ataoglu H. Erythropoietin
reduces lopopolysaccharide-induced cell damage and
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44. Cuzzocrea S, Mazzon E, di Paola R, Genovese T, Patel
NS, Britti D, de Majo M, Caputi AP, Thiemermann
C. Erythropoietin reduces the degree of arthritis
caused by type II collagen in the mouse. Arthritis
Rheum. 2005;52:949–50.
45. Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals
JA. Recombinant human erythropoietin increases
survival and reduces neuronal apoptosis in a murine
model of malaria. Malar J. 2008;7:3.
Further Readings
Gunter CI, Machens H-G, Ilg FP, Hapfelmeier A,
Jelkmann W, Egert-Schwender S, et al. A randomized controlled trial: regenerative effects, efcacy and
safety of erythropoietin in burn and scalding injuries.
Front Pharmacol. 2018;9:951. https://doi.org/10.3389/
fphar.2018.00951.
Günter CI, Ilg FP, Hapfelmeier A, Egert-Schwender S,
Jelkmann W, Giri S, Bader A, Machens HG.Post hoc
subgroup-analysis of the placebo-controlled, randomized clinical trial “EPO in burns” relation between
gender, concomitant medication and comorbidity with
erythropoietin-treatment on wound healing in burn
patients. Front Pharmacol. 2019; under revision.
Steppich B, Groha P, Ibrahim T, Schunkert H, Laugwitz
KL, Hadamitzky M, etal. Effect of erythropoietin in
patients with acute myocardial infarction: ve-year
results of the REVIVAL-3 trial. BMC Cardiovasc
Disord. 2017;17(1):38. https://doi.org/10.1186/
s12872-016-0464-3.
Targeting C-Reactive Protein
https://t.me/medicina_free
inInammatory Disease
JohannesZeller andSteenU.Eisenhardt
17
17.1 C-Reactive Protein (CRP)
Despite extensive studies since CRP was rst discovered and named by Tillett and Francis in 1930
[1], the exact role and mechanism of action of
this prototypical acute phase reactant [2] has not
yet been dened satisfactorily. Here, we try to
give a brief overview of C-reactive protein as a
major factor in physiological and pathological
processes, and discuss its potential role as a
rewarding therapeutic target.
C-reactive protein (CRP) is a member of the
phylogenetically ancient and highly conserved
pentraxin protein family. As such, it serves as a
pattern recognition molecule in innate immunity.
CRP production is evoked by the increase of circulating proinammatory cytokines in plasma as
a response to most forms of infection, inammation, or tissue injury.
Interleukin-6 (IL-6) is the principal inducer of
the CRP gene and regulates the expression
through the activation of C/EBP transcription
factors [3]. Additionally, interleukin-1β (IL-1β)
and tumor necrosis factor-α (TNF-α) potentiate
the IL-6 effects, act synergistically and enhance
the CRP expression at the transcriptional level [4,
J. Zeller · S. U. Eisenhardt (*)
Division of Reconstructive Microsurgery,
Department of Plastic and Hand Surgery, Medical
Center—University of Freiburg Faculty of Medicine,
University of Freiburg, Freiburg, Germany
e-mail: steffen.eisenhardt@uniklinik-freiburg.de
5]. The CRP gene is located on the long arm
(q-arm) of human chromosome 1 among other
host protective genes. With a size of 2263 nucleotides, it extends from 1q21 to 1q23 with one single intron [6].
Although the main regulation of CRP gene
expression happens on a transcriptional level,
further post-transcriptional mechanisms have
been reported. CRP is constantly synthesized at
low rates and retained in the endoplasmic reticulum under physiological conditions [7]. However,
during the acute phase response, the rate of secretion becomes more efcient, resulting in an
acceleration of the CRP secretion, thus presenting a post-transcriptional regulation [8, 9].
The concentrations of circulating CRP in
serum may therefore rise dramatically in a
cytokine- mediated response from undetectable
levels in healthy individuals up to 1000-fold and
more within one to three days [10].
The hepatic synthesis is the predominant origin of CRP, and hepatocytes start with secretion
of the acute phase reactant 6–8h after the onset
of inammation or infection, while the inducing
IL-6 levels rise within 1h in conditions of tissue
damage (Fig. 17.1) [11, 12]. Although CRP
expression has been reported in various other
cell types as well, e.g., neuronal cells in
Alzheimer’s disease [13], renal cortical tubular
epithelial cells after inammatory stimuli [14],
arterial tissue, respiratory epithelium [15], adipocytes, and leukocytes [16–20], extrahepatic
© Springer Nature Switzerland AG 2019
D. Duscher, M. A. Shiffman (eds.), Regenerative Medicine and Plastic Surgery,
https://doi.org/10.1007/978-3-030-19958-6_17
173
174
https://t.me/medicina_free
J. Zeller and S. U. Eisenhardt
Fig. 17.1 Model of the genesis and the effects of CRP in ischemia/reperfusion injury
17 Targeting C-Reactive Protein inInammatory Disease
https://t.me/medicina_free
175
synthesis of CRP is not considered to affect
plasma levels signicantly.
The plasma half-life of CRP is about 19–24h
and it is cleared from circulation and catabolized
by the hepatocytes. Plasma concentrations of circulating CRP remain unaffected by any physiological or pathological condition, and circulating
CRP concentrations stable are solely dependent
on synthesis rates [21, 22].
Therefore, CRP is an inammation marker
widely appreciated and extensively used in clinical practice. As the plasma levels are solely
determined by the induction stimuli and synthesis rates, CRP conveniently serves in diagnosis
and monitoring as a surrogate parameter for the
intensity of tissue damage in trauma, inammation, and infection [22]. To date, a plethora of
studies have suggested that even slightly elevated CRP serum levels in apparently healthy
humans, as measured with high sensitivity assays
(hsCRP), are directly associated with an
increased risk of coronary events [23–26].
Moreover, hsCRP may predict future clinical
events among patients suffering various atherothrombotic syndromes [27–29]. In concentrations generally achieved during inammation,
CRP induces tissue-factor production in peripheral blood monocytes (PBM). The subsequent
increased pro-coagulant activity may contribute
to the development of thrombo- occlusive complications, as disseminated intravascular coagulation and thrombosis in inammatory states
[30, 31].
These studies suggested that CRP might have
not only a predictive but also causal role in vascular disease. This sparked an interest of the role of
CRP in perturbances of the microcirculation and
in microsurgery. The wide distribution of CRP’s
main ligand phosphocholine (PC) as a constituent in pathogens (e.g., teichoic acid and lipopolysaccharides of bacteria) and apoptotic or necrotic
cellular membrane [32–34], the conservation of
its structure and the failure to detect any deciency or mutation of this protein in human additionally suggests a pivotal physiological role of
CRP in innate host defense [10]. While membranes of viable cells conceal the phosphocholine
head groups, this major cell surface ligand of
CRP comes accessible if cells undergo apoptosis
and necrosis [32]. Therefore, CRP binds only to
damaged or activated plasma membranes and
promotes benecial scavenging and host-defense
functions [22, 35, 36]. Kaplan and Volanakis [28]
were the rst to describe the activation of the
classical complement pathway by CRPopsonized microbial polysaccharides. CRP mediates clearance by opsonization. CRP-opsonized
particles can then be directly bound by Fcγ receptors [37, 38] and besides, CRP regulates the complement activation of the classical pathway
commencing at complement C1q [39, 40], leading to phagocytosis by phagocytic cells [41, 42].
Further binding sites for other receptors on
phagocytic cells have been suggested as well [43,
44]. The assumption of CRP enhancing the clear-
ance of apoptotic cells appears even more likely
as CRP also binds specically to small nuclear
ribonucleoprotein particles [45–47].
17.2 The Relevance ofC-Reactive
Protein inPlastic Surgery
17.2.1 Ischemia/Reperfusion Injury
In 1954, an innovative group around Plastic
Surgeon Dr. Joseph Murray [48] performed the
rst successful kidney transplantation in history,
a breakthrough in organ transplantation later
honored with the 1990 Nobel Prize in Physiology
or Medicine. Earlier attempts failed, inter alia,
due to an ischemia-evoked inammatory cascade
[49]. Among the rst to describe the common and
relevant problem of ischemia/reperfusion injury
(IRI) was Cerra etal. in 1975. IRI as a clinical
phenomenon is of importance in a broad range of
pathological conditions as myocardial infarction
or stroke [50, 51] and describes an inammatory
reaction to reperfusion of previously ischemic
tissue [52, 53]. In the pathogenesis, recovered
blood ow subsequently to the ischemic period
brings leukocytes into the area of impaired tissue
and initiates pathologic leukocyte-endothelium
interaction [54, 55]. In these conditions, the tissue damage is aggravated by the accumulation of
activated white blood cells producing reactive
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