https://doi.org/10.52973/rcfcv-e34313
Received: 23/08/2023 Accepted: 08/10/2023 Published: 02/01/2024
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Revista Científica, FCV-LUZ / Vol. XXXIV, rcfcv-e34313
ABSTRACT
White muscle disease (WMD) and/or nutritional muscular dystrophy
is dened as a disease with a generally acute course that results in
degeneration and necrosis of the heart muscle. In this study, it was
aimed to reveal local tissue expressions of acute phase proteins such
as C–reactive protein (CRP), Serum amyloid–A (SAA) and Haptoglobin
(Hp) in lambs with WMD. The study material consisted of 27, one–
six months old lamb heart tissues, 6 of which were healthy and
21 with WMD. The lambs were necropsied, and the relevant heart
samples were taken into neutral formaldehyde. Afterwards, paran
blocks were obtained by going through routine tissue follow–up
processes. Sections were taken from paran blocks and stained
with Hematoxylin–Eosin (H–E) and Immunohistochemical methods.
Histopathologically, control groups exhibited normal histology.
Hyaline degeneration, Zenker necrosis, calcication, inammatory
cell inltration and an increase in connective tissue were detected
in the heart tissues of lambs with WMD. Lambs with WMD had
signicantly increased CRP and SAA proteins compared to control
(P<0.01). However, there was no difference between the groups in Hp
(P>0.05). In conclusion, local tissue expressions of CRP, SAA and Hp in
lambs with WMD were identied immunohistochemically for the rst
time. It is possible to say that CRP and SAA may play important roles
in the pathophysiology of WMD and that CRP and SAA may provide
more sensitive results in the diagnosis and prognosis of the disease.
Key words: White muscle disease; immunohistochemistry; C–
reactive protein; serum amyloid–A; haptoglobin
RESUMEN
La enfermedad del músculo blanco (EMB) y/o distroa muscular
nutricional se dene como una enfermedad con un curso generalmente
agudo que resulta en la degeneración y necrosis del músculo cardíaco.
En este estudio, el objetivo fue revelar la expresion tisular local de
proteínas de fase aguda, como la proteína C–reactiva (PCR), el amiloide
A sérico (SAA) y la haptoglobina (Hp) en corderos con EMB. El material
de estudio estuvo compuesto por 27 tejidos de corazón de cordero
de uno a seis meses de edad, 6 sanos y 21 con EMB. Se realizó la
necropsia de los corderos y las muestras de corazón correspondientes
se pusieron en formaldehído neutro. Posteriormente, se obtuvieron
bloques de parana mediante los procesos de seguimiento tisular
rutinarios. Se tomaron secciones de bloques de parana y se tiñeron
con los métodos de Hematoxilina–Eosina (H–E) e Inmunohistoquímico.
Histopatológicamente, los grupos de control presentaron una
histología normal. En los tejidos cardíacos de corderos con EMB
se detectó degeneración hialina, necrosis de Zenker, calcicación,
inltración de células inamatorias y aumento del tejido conectivo.
En comparación con el control, los corderos con EMB mostraron un
aumento signicativo de las proteínas PCR y SAA (P<0,01). Sin embargo,
no hubo diferencia entre los grupos en la tinción de HE (P>0,05). En
conclusión, las expresiones tisulares locales de PCR, SAA y Hp en
corderos con EMB se identicaron inmunohistoquímicamente por
primera vez. Es posible armar que PCR y SAA pueden desempeñar
papeles importantes en la siopatología de la EMB, y que PCR y SAA
pueden proporcionar resultados más sensibles en el diagnóstico y
pronóstico de la enfermedad.
Palabras clave: Enfermedad del músculo blanco; inmunohistoquímica;
proteína C–reactiva; amiloide–A sérico; haptoglobina
Evaluation of local expressions of acute phase proteins in white muscle
disease in lambs by the immunohistochemical method
Evaluación inmunohistoquímica de expresiones locales de proteínas de
fase aguda en la enfermedad del músculo blanco en corderos
Ozhan Karatas
1
, Gokhan Akcakavak
2
*
1
Sivas Cumhuriyet University, Faculty of Veterinary Medicine, Department of Pathology. Merkez, Sivas, Türkiye.
2
Yozgat Bozok University, Faculty of Veterinary Medicine, Department of Pathology. Sorgun, Yozgat, Türkiye.
*Corresponding Author: gokhan.akcakavak@bozok.edu.tr
Acute phase proteins in white muscle disease in lambs / Karatas and Akcakavak ___________________________________________________
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INTRODUCTION
White muscle disease (WMD) and/or nutritional muscular dystrophy
is dened as a disease with a generally acute course that results in
degeneration and necrosis of the heart muscle. The etiology of the
disease is vitamin E (VitE) and/or Selenium (Se) deciency [1, 2].
WMD causes heart failure–related death in young animals that tend
to grow rapidly. Pathomorfologically, it manifests with degeneration,
paleness, brosis, necrosis and calcication in the heart muscle [2,
3, 4]. WMD is usually seen in kids (Capra aegagrus hircus), lambs (Ovis
aries), calves (Bos taurus) and camels (Camelus) [5, 6, 7]. WMD shows
a global incidence of around 1%. Its incidence is around 20–30% in
Türkiye and New Zeland [8].
Selenium (Se) is normally included in the structure of the
glutathione peroxidase (GSH–Px) enzyme [9]. GSH–Px neutralizes
the effects of hydrogen peroxide and lipid hydroperoxide, which
cause cell protein destruction and necrosis. Vitamins E (Vit E) plays
a major role in inhibiting excessive peroxide formation and prevents
hyaline degeneration [9, 10]. The metabolic function of Se is closely
related to vitamin E. Both agents act to protect biological membranes
from oxidative damage [11]. While Se deciency is seen in animals
grazing on pastures, Vit E deciency is more common in animals fed
with forage. Deciencies of these two agents cause lipoperoxidation,
muscle degeneration and calcication in various tissues [3, 12, 13].
Some free radicals formed after the decrease of antioxidant defense
as a result of Vit E and Se deciency cause oxidative stress. As free
oxygen radicals play a major role in the pathogenesis of the disease
by causing very important pathological changes such as degeneration
of proteins in tissues, lipid peroxidation and necrosis of heart muscle
[4, 12, 14]. In Se and vit E deciencies, lipid peroxidation and hydrogen
peroxide cannot be cleared from the muscles due to the decrease in
GSH–Px activity. In addition, increased reactive oxygen species (ROS)
levels serve as markers for oxidative stress, and lipid peroxidation and
instability of the redox system are associated [13]. In many studies,
it has been reported that oxidative stress plays a very important role
in the pathogenesis of WMD [4, 13, 14, 15]. In this context, oxidative
stress is seen as an important cause of degenerative and necrotic
changes in related tissues.
Inaccurate results can be obtained due to the fact that the GSH–
Px enzyme is affected by some factors and the detection of Se and
Vit E in body uids is dicult and does not always give accurate
results [16, 17, 18]. In addition, it is dicult to reach a clear WMD
diagnosis based solely on clinical symptoms because it can be
confused with many infections and mineral balance disorders such
as cerebrocortical necrosis (CCN), listeriosis, borna disease, enzootic
ataxia, polyarthritis [19, 20, 21]. Therefore, diagnosis based on autopsy
ndings is frequently preferred today [3, 4].
Acute phase response (APR) is known as a series of inammatory
responses of the host in conditions such as infection, trauma and
tissue damage. Pyrogen cytokines are mediators of APR. APR is
induced by a series of pro–inammatory cytokines (IL–1, IL–6, TNF–α)
released by inammatory cells to produce Acute Phase Protein (APP)
in response to tissue damage [22, 23, 24]. APR is crucial in ensuring
that homeostatic mechanisms quickly regain normal physiological
function by isolating and neutralizing pathogens, minimizing tissue
damage and initiating repair [25]. Proteins whose blood levels
uctuate markedly at the onset of inammation are called Acute
Phase proteins (APP). APP are blood proteins that assess the response
of the immune system in cases of trauma, infection or inammation.
The main production site of APP is the liver [22, 23]. In conditions
such as infection, trauma, and tissue damage, some blood proteins
decrease over time and are called negative APPs, while those with
increased blood protein amounts are called positive APPs. C–reactive
protein (CRP), Serum amyloid–A (SAA) and Haptoglobin (Hp) are in the
group of positive APPs [22, 26, 27].
CRP is a highly important phylogenetically conserved plasma
protein that participates in the systemic response to inammation.
CRP constitutes an important part of APR, and its values in the blood
increase in many infectious processes [28, 29]. It plays a role in many
processes, such as chemotaxis, inhibition of cytokine production,
and modulation of monocytes and macrophages. In cases such as
infection and tissue damage, its value in the blood can increase up
to 50,000 times [30, 31].
SAA consists of 2 different groups of apolipoproteins: acute phase
SAA (A–SAA) and structural SAAs (C–SAA) [32]. It has effects such as
SAA, inducing chemotaxis and anti–inammatory effects. In addition, it
has functions such as fat metabolism and transport and stimulation of
enzymes that break down the extracellular matrix [31, 33]. SAA secretion
is observed in the acute phase of inammation, and therefore it is often
preferred to differentiate between acute and chronic inammation.
SAA levels can increase 1000 times during APR [32, 33, 34].
Hp is known as a very important APP in ruminants. Hp plays an
important role in many biological processes, such as bacteriostatic
effect, stimulation of angiogenesis and binding to haemoglobin [22,
31]. Normally, its amount in the blood is quite low, whereas when the
immune system is stimulated, it may increase 100 times [26, 31]. It has
been stated in many studies that it is useful to evaluate the severity
of the inammatory response in natural or experimental infections
such as endometritis, enteritis, pneumonia, mastitis, endocarditis
and abscess [23, 31, 35].
In recent years, APPs have been frequently preferred in both
human and veterinary elds as markers of inammation, infection
and trauma. Not enough studies are available in the literature for
the detection and evaluation of APPs in WMD. This study aimed to
evaluate local tissue expressions of acute phase proteins such as
Hp, CRP and SAA in heart tissue in WMD, a metabolic disease, by
immunohistochemistry.
MATERIAL AND METHODS
Animal materials
The material of the study consisted of heart samples from 21 WMD
positive male lambs (Ovis aries, merino, 1–6 months) and 6 healthy male
lambs (Ovis aries, merino, 1–6 months), a total of 27 heart samples.
Heart tissues were obtained from different farms suffering from
WMD disease in Sivas and Yozgat provinces. Additionally, Musculus
gracilis and intercostal muscles were examined in all VMD positive
animals. Heart tissues of the necropsied lambs were taken into neutral
formalin for histopathological and immunohistochemical examination.
The study was approved by the Sivas Cumhuriyet University HADYEK
ethics committee (31.07.2023, Decision no; 616).
Histopathological and Immunohistochemical examination
After 24–48 h neutral formalin xation of heart tissues, routine
tissue follow–up procedures were performed. Afterwards, they were
embedded in paran and paran blocks were obtained. 4–5 µm
FIGURE 1. A. Hyaline degeneration and Zenker necrosis in the endocardium (arrows), VMD groups, B–C. Calcication areas in the epicardium, endocardium and
myocardium (arrows), VMD groups
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sections were taken from paran blocks onto ground slides with
a microtome (Leica RM 2255, Germany), stained with Hematoxylin–
Eosin and examined under light microscopy (Olympus BX51, Tokyo,
Japan) [36, 37].
For the immunohistochemical examination, 4–5 µm thickness
sections were taken on adhesive slides. Immunohistochemical
staining was performed following the procedure with a commercial
kit (UltraVision Detection System Anti–Polyvalent, HRP (Horseradish
Peroksidaz) (Ready–To–Use, TP–060–HL, Lab Vision, USA) [38].
The antigen retrieval process was performed by (microwave oven–
UTD–1420, Utest, Turkey) in Tris–Ethylenediaminetetraacetic acid
(EDTA) (pH 9, 10x) solution at 750 watts for 20 min. Rabbit Anti–Hp
(Polyclonal antibody, Proteintech, USA, Cat No:16665–1–AP, 1/200
dilution), Rabbit Anti–SAA (Polyclonal antibody, Proteintech, USA,
Cat No: 20398–1–AP, 1/200 dilution) and Rabbit Anti–CRP (Polyclonal
antibody, Proteintech, USA, Cat No: 24175–1–AP, 1/200 dilution)
primers were used. Primers were incubated for 90 min. As chromogen,
3.3 diaminobenzidine (DAB) was used and counterstained with
Mayer's–Hematoxylin. The sections were then examined under a light
microscope at 20X magnication by a blinded pathologist (Olympus
BX51, Tokyo, Japan). Immunohistochemical scoring none;0, little;1,
moderate;2, severe;3 was evaluated [38].
Statistical analysis
SPSS (Inc., Chicago, USA 25.0) statistical program was used to
evaluate the data between groups. Immunohistochemical scores were
evaluated using the t–test. The group mean was given as Mean±SE.
The accepted signicance limit was P<0.05.
RESULTS AND DISCUSSION
Macroscopic Results
The cardiac muscle tissues of the animals in the control group had
a normal macroscopic appearance.
Hyaline degeneration, Zenker necrosis and areas of calcication
were seen in the heart tissue of WMD animals (FIG 1). Areas with
hyaline degeneration and Zenker necrosis were usually pale and
similar to sh and/or chicken meat. In addition, calcication areas
were found in the cardiac tissue in 12 cases.
In addition, pallor was detected macroscopically in the Musculus
gracilis in 5 cases and in the intercostal muscles in 3 cases in cadavers.
No calcication was observed in non–cardiac muscles.
Microscopic Results
Histopathologically, control animals showed normal histology (FIG
2, A). In the WMD group, degenerative and necrotic muscle bers were
found, citration was lost, and these bers had a pinkish and swollen
appearance (FIG 2, B–C). In this group, calcication areas were found
disseminated (FIG 2, E). In addition, mononuclear cell ltration and
increased connective tissue were observed in places (FIG 2, D–E).
In the immunohistochemical examination, immunohistochemical
scores in the Control and WMD groups are given in TABLE I. Mild or
no immunoreactivity was found with the primers Hp, CRP, and SAA
in the control group. Moderate and severe staining was found in CRP
and SAA in the WMD group compared to the control group (P<0.01).
In particular, immunopositivity was observed in degenerative and
necrotic muscle bres and inammatory cell inltrations (FIG 3). Hp
in the WMD group presented similar immunopositivity compared to
the control group and was not signicant (P>0.05).
WMD shows two different clinical forms, acute (cardiac) and
subacute. The acute form is characterized by cardiac muscle
degeneration and sudden death, especially in young animals, while
the subacute form usually presents with skeletal muscle degeneration
TABLE I
Immunohistochemical scores of CRP, SAA, Hp in healthy and WMD animals
Groups CRP SAA Hp
Control 0.67 ± 0.21
b
0.83 ± 0.16
b
0.50 ± 0.21
a
WMD 2.23 ± 0.16
a
2.07 ± 0.21
a
0.69 ± 0.13
a
P<0.01 P<0.01 P>0.05
Group averages are given as Mean + SE.
a,b
: Indicates statistical signicance between
values in the same column (C: Control, WMD: White muscle disease, CRP: C–reactive
protein, SAA: Serum amyloid–A, Hp: Haptoglobin)
FIGURE 2. Histopathological examination of the Control (A) and WMD (B–E) groups, Hematoxylin–Eosin, A. Normal histological appearance of the control group, 100X.
B–C. Hyaline degeneration and zenker necrosis (arrows), WMD groups, 400X. D. Inammatory cell inltration (arrows), VMD groups, 200X. E.Calcication areas (arrows)
and brosis (arrowheads), WMD groups, 100X
Control
CRP SAA Hp
VMD
FIGURE 3. Microscopic view of immunohistochemical staining between groups (WMD; White muscle disease, Relevant expressions in degenerative and
necrotic cells (arrows), CRP; C–reactive protein, SAA; Serum amyloid–A, Hp; Haptoglobin)
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[4, 20]. The main clinical forms of the disease are inability to stand
up, loss of appetite, weakness, diculty in standing, short and steep
steps, shortness of breath, and curvature of the back [3, 4, 20]. Most
of the clinical ndings mentioned in this study were recorded in lambs.
In the study, lesions were generally located in heart tissue. In the
cadavers, paleness was detected macroscopically in the Musculus
gracilis in 5 cases and in the intercostal muscles in 3 cases. It was
stated that treatment procedures were applied to the lambs in our
study by the patient owners, but no positive results were obtained.
This situation can be explained by the fact that it is not possible to
treat patients with acute heart failure.
Previous studies have reported that the disease mostly affects
the heart, legs and other muscles [3, 21]. Macroscopically, hyaline
degeneration, Zenker necrosis and areas of calcication have been
reported [3, 4].Histopathologically, degenerative and necrotic changes
in the heart muscle have been reported. In particular, these muscle
bres are stated to be irregular, swollen and homogeneously pink. In
addition, dystrophic calcication areas, connective tissue increases
and inammatory cell inltrations in the interstitium are reported in
these necrotic parts [3, 14, 21]. In this study, macroscopically, similar
to previous study ndings, hyaline degeneration, Zenker necrosis
and calcication areas were detected in the heart tissue of lambs
with WMD (FIG 1). In particular, areas with hyaline degeneration
and Zenker necrosis were generally pale in color and had a fish
and/or chicken meat–like appearance. Although this appearance
is seen macroscopically in WMD, it is necessary to support it with
histopathological examination. Because it is reported that the skeletal
muscles of lambs normally appear whitish, gross ndings alone are
not sucient for diagnosis [3, 10]. Microscopically, degenerative
and necrotic muscle bers (FIG 2 B–C) were found in lambs with
WMD, citration was lost, and these bers had a pinkish and swollen
appearance. Additionally, an increase in mononuclear cell ltration
and connective tissue was observed in some places (FİG 2 D–E), and
our ndings were consistent with the literature [3, 4].
In recent years, CRP protein is frequently evaluated in the
veterinary eld for diagnosis and prognosis in many infectious and
inflammatory conditions [26, 35]. No studies were found in the
literature to detect CRP in WMD. In the related study, a signicant
level of CRP immunoreactivaty was found in the WMD group compared
to the control group (P<0.01, FIG 3). This study on WMD revealed
that CRP can accumulate locally, although we have no evidence of
blood concentrations. It also seems to play an important role in the
pathophysiology of WMD.
The high activity of CRP protein has been reported in studies on
many cardiovascular diseases in human medicine. In addition, some
studies have reported a positive correlation between oxidative stress
and CRP levels [39, 40, 41, 42]. It has been reported in a study that
oxidative stress may be a determinant of CRP levels [40]. Therefore, it
can be concluded that high immunoreactivity in lambs with WMD may
be related to possible oxidative stress. Immunoreactivity, especially
in degenerative and necrotic muscle bres strengthens this idea.
SAA, another acute phase protein, has been evaluated in the
veterinary eld in the diagnosis and prognosis of many infections
or inammatory conditions in recent years [26, 35]. No study was
found in the literature to detect any SAA in WMD. In this study, there
was a signicant increase in SAA protein in the WMD group compared
to the control group (P<0.01, FIG 3). Local production of biologically
SAA in different tissue damage has been reported in different studies
and has been attributed to the role of host immunity [43, 44]. In
particular, in a study conducted in dairy calves with bovine respiratory
disease, it was predicted that the increase in SAA concentrations was
associated with host immunity [44]. The current study revealed that
SAA accumulated locally, although it did not have any ndings about
blood concentrations associated with systemic APR. Although we
cannot say for sure because the study material consisted of lambs
(1–6 monthly), the increased local expression of SAA in WMD may result
from the host's immunity and/or accumulate as a result of systemic
APR. In this context, more comprehensive studies are needed in the
future. Our ndings suggest that SAA protein plays an important role
in the pathophysiological process of WMD.
In this study, Hp protein was similar in the WMD group compared to
the control group (P>0.05). These ndings suggested that Hp does not
play an active role in the pathophysiological process of WMD in lambs.
When the ndings of this study are evaluated, the accumulation
of locally relevant APPs in WMD, which is a metabolic disease, shows
that the acute phase reaction is not only a systemic reaction but an
important part of the possible local immune response. In particular,
CRP and SAA show that they may play an important role in the
pathophysiology of WMD. The most important limitation of the present
study is the lack of relevant blood concentrations. It was suggest that
more detailed information about APR can be obtained in future studies
by evaluating blood concentrations of relevant APPs in WMD.
CONCLUSION
Our results show that the cardiac (acute) form is more effective
in the Sivas and Yozgat regions of Turkey. In addition, local tissue
expressions of CRP, SAA and Hp in lambs with WMD were determined
immunohistochemically for the rst time. It is possible to say that
CRP and SAA may play an important role in the pathophysiology of
WMD, and that CRP and SAA may give more sensitive results in the
diagnosis and prognosis of the disease.
Conict of interest
There is no conict of interest between the authors.
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