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Previous issue date: 2018 / Funda??o de Amparo ? Pesquisa do Estado de Minas Gerais (FAPEMIG) / A s?ndrome nefr?tica
(SN)
? definida por protein?ria maci?a, edema, hipoalb
uminemia e
hiperlipidemia e desenvolve a partir da les?o
dos
glom?rulos, especialmente
d
os pod?citos.
Pode ser um
a
altera??o prim?ria (idiop?tica), com
o
uma doen?a espec?fica para os rins, ou
secund?ria a
alguma
doen?a sist?mica pr?via. Histologicamente, a
s?ndrome nefr?tica
idiop?tica (
SNI
)
? definida pela combina??o das manifesta??es cl?nicas associadas ?s
anormalidades histol?gicas inespec?ficas do rim, incluindo
glomerulo
esclerose focal e
segmentar (GESF). A SN pode ser estudada, em modelo animal,
por m
eio de
inje??es
locais
de
Cloridrato de doxorrubicina
(
Adriamicina?
)
na dose de 7,5mg/kg
em que,
inje??o
intravenosa ?nica pode
induz
ir
protein?ria grave, semelhante ? observada em humanos.
Embora os mecanismos patog?nicos da SNI persistam obscuros, altera
??es das respostas
imunol?gicas
,
como as respostas at?picas dos linf?citos T e a atua??o de citocinas e
quimiocinas,
parecem estar
envolvidas no dano aos glom?rulos. Neste sentido, a finalidade do
presente estudo
foi
avaliar
a participa??o de citocinas e q
uimiocinas, por meio da express?o
de IL
-
1, IL
-
4, CXCL1,
CCL3/MIP
-
1
e
CCL5/RANTES
em amostras de tecido renal e de
urina,
nos mecanismos de ativa??o e migra??o leucocit?ria,
bem como as altera??es
bioqu?micas, histol?gicas e biom?tricas em ratos com SN indu
zida pela doxorrubicina.
O
protocolo experimental foi devidamente registrado e aprovado pela comiss?o de ?tica no uso
de animais, da Universidade Federal dos Vales do Jequitinhonha e Mucuri (CEUA
-
UFVJM)
sob o protocolo N? 029/2014.
Foram utilizados 25 rato
s machos
(
Wistar
)
,
peso m?dio de 350
gramas e idade m?dia de seis semanas
. Os animais
foram
divididos
em dois grupos: CON
(n=5), que recebeu inje??o endovenosa de
solu??o salina
como grupo controle
e DOXO
(n=25),
que recebeu
inje??o endovenosa de doxorrubi
cina. Os animais do grupo DOXO foram
eutanasiados e avaliados
nos tempos
7, 14, 21 e 28 dias ap?s a inje??o.
Foram
coletadas
amostras urin?rias (24 hs) e
amostras
sangu?neas
(
pun??o card?aca). Ap?s
a
coleta sangu?nea,
os ?rg?os foram perfundidos
com solu??
o salina, sendo
coletados os rins direito e esquerdo,
que foram pesados
e devidamente acondicionados
, para posteriores an?lises biom?tricas,
histol?gicas e imunol?gicas. A contagem total de leuc?citos foi realizada em c?mara de
Neubauer. A avalia??o das am
ostras urin?rias e teciduais para a detec??o de citocinas e
quimiocinas foi realizada por ELISA.
A
nimais do grupo DOXO desenvolveram protein?ria a
partir do
7
? dia ap?s a inje??o de doxorrubicina
, a qual
permaneceu
durante todo o per?odo
experimental. O
bse
rvou
-
se, ainda,
hipercreatininemia, altera??es biom?tricas
,
histol?gicas
e
dos leucogramas neste mesmo grupo
. De modo geral, os animais expressaram maior
concentra??o de citocinas e quimiocinas no tecido renal
do
que
na
s amostras de urina,
sugestivo de um
processo de secre??o relacionad
o
? produ??o tecidual local.
Al?m disso, o
s
resultados
obtidos n
o presente estudo
proporciona
ra
m uma contribui??o in?dita em rela??o
?
participa??o da quimiocina CXCL1
na fisiopatogenia
da SN.
Sua
express?o n
a urina
pode
r?
es
tar r
elacionada com a instala??o das rea??es oxidativas nas fases iniciais da doen?a,
conforme j? demonstrado por nosso grupo, nest
e modelo experimental
.
Podendo, ainda,
sugerir a participa??o de leuc?citos polimorfonucleares (neutr?filos)
na
etiopatogenia
da SN
,
em sua fase inicial
. Contudo, outros estudos ser?o necess?rios a fim de correlacionar
a
express?o tecidual d
a citocina
CXCL1 ? presen?a de neutr?filos
no tecido renal
e,
consequente, produ??o de radicais livres
neste
modelo experimental de nefropat
ia
induzida
pela doxorrubicina. / Disserta??o (Mestrado) ? Programa de P?s-gradua??o em Ci?ncias Farmac?uticas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2018. / Nephrotic syndrome (NS) is defined by massive proteinuria, edema, hypoalbuminemia and
hyperlipidemia and develops from th
e lesion of the glomeruli, especially the podocytes. It can
be a primary (idiopathic) change, as a specific disease for the kidneys, or secondary to some
previous systemic disease. Histologically, idiopathic nephrotic syndrome (NIS) is defined by
the combi
nation of clinical manifestations associated with nonspecific histological
abnormalities of the kidney, including
f
ocal and segmental glomerulosclerosis
(GESF). SN
may be studied in animal models by means of
local injections of doxorubicin hydrochloride
(Adriamycin?) at a dose of 7.5 mg/kg
, in which single intravenous injection may induce
severe proteinuria similar to that seen in humans. Although the pathogenic mechanisms of
NIS persist obscure, changes in immune responses, such as atypical T lymphocyte re
sponses
and cytokine and chemokine activity, appear to be involved in damage to the glomeruli. In
this sense, the purpose of the present study was to evaluate the participation of cytokines and
chemokines through the expression of IL
-
1, IL
-
4, CXCL1,
CCL3/M
IP
-
1
and
CCL5/RANTES
in renal and urine tissue samples in the activation and migration mechanisms as well as the
biochemical, histological and biometric alterations in doxorubicin
-
induced SN rats.
The
experimental protocol was duly registered and approved
by the Ethics Committee on Animal
Use, Federal University of the Jequitinhonha and Mucuri Valleys (CEUA
-
UFVJM) under
protocol No. 029/2014.
Twenty
-
five male rats (Wistar), mean weight of 350 grams and mean
age of six weeks, were used. The animals were divi
ded into two groups: CON (n = 5), who
received intravenous injection of saline as a control group and DOXO (n = 25), who received
intravenous injection of doxorubicin. Animals from the DOXO group were euthanized and
evaluated at times 7, 14, 21 and 28 days
after injection. Urinary samples (24 h) and blood
samples (cardiac puncture) were collected. After the blood collection, the organs were
perfused with saline, and the right and left kidneys were collected, which were weighed and
properly conditioned, for
later biometric, histological and immunological analyzes. Total
leukocyte count was performed in the Neubauer chamber. The evaluation of the urinary and
tissue samples for the detection of cytokines and chemokines was performed by ELISA.
Animals from the D
OXO group developed proteinuria from the 7th day after the injection of
doxorubicin, which remained throughout the experimental period. Hypercreatininemia,
biometric, histological and leukogram changes were also observed in this same group. In
general, the
animals expressed a higher concentration of cytokines and chemokines in the
renal tissue than in the urine samples, suggestive of a secretory process related to the local
tissue production. In addition, the results obtained in the present study provided a
n
unprecedented contribution to the participation of chemokine CXCL1 in the pathophysiology
of NS. Its expression in urine may be related to the establishment of oxidative reactions in the
early stages of the disease, as demonstrated by our group in this e
xperimental model
.
It
may
suggest
the participation of polymorphonuclear leukocytes (neutrophils) in the
etiopathogenesis of NS in its initial phase. However, other studies will be necessary in order
to correlate the tissue expression of cytokine CXCL1 wit
h the presence of neutrophils in the
renal tissue and, consequently, the production of free radicals in this experimental model of
nephropathy induced by doxorubicin.
| Identifer | oai:union.ndltd.org:IBICT/oai:acervo.ufvjm.edu.br/jspui:1/1791 |
| Date | 22 January 2018 |
| Creators | Santos, Adriana Suellen dos |
| Contributors | Pereira, Wagner de F?tima, Melo, Gustavo Eust?quio Brito Alvim de, Carvalho J?nior, ?lvaro Dutra de, Guimar?es, F?bio Tadeu Louren?o, Melo, Gustavo Eust?quio Brito Alvim de, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Pereira, Wagner de F?tima |
| Publisher | UFVJM |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Repositório Institucional da UFVJM, instname:Universidade Federal dos Vales do Jequitinhonha e Mucuri, instacron:UFVJM |
| Rights | A concess?o da licen?a deste item refere-se ao ? termo de autoriza??o impresso assinado pelo autor, assim como na licen?a Creative Commons, com as seguintes condi??es: Na qualidade de titular dos direitos de autor da publica??o, autorizo a Universidade Federal dos Vales do Jequitinhonha e Mucuri e o IBICT a disponibilizar por meio de seus reposit?rios, sem ressarcimento dos direitos autorais, de acordo com a Lei n? 9610/98, o texto integral da obra disponibilizada, conforme permiss?es assinaladas, para fins de leitura, impress?o e/ou download, a t?tulo de divulga??o da produ??o cient?fica brasileira, e preserva??o, a partir desta data., info:eu-repo/semantics/openAccess |
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