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Eko Poerwanto

Respon Tubuh Terhadap Pajanan Panas: Kajian Ekspresi Transient Receptor Potential Vanilloid Vanilloid 1, Heat Shock Factor1 dan Heat Shock Protein 70 pada Jantung Tikus = Body Response To Heat Exposure: Overview of Expression Transient Receptor Potential Vanilloid 1, Heat Shock Factor1 and Heat Shock Protein 70 in Rats Heart

"Latar belakang: Peningkatan suhu tubuh ekstrim menyebabkan denaturasi protein,

terhentinya reaksi enzimatik, hilangnya aktivitas dan integritas membran, serta

memicu terjadinya kerusakan sel. Peningkatan suhu tubuh juga mempengaruhi

terjadinya efek inotropik dan kronotropik positif pada jantung. Diperkirakan bahwa

pajanan panas dapat meningkatkan ekspresi protein Transient Receptor Potential

Vanilloid 1 (TRPV1), Heat Shock Factor 1 (HSF1) dan Heat Shock Protein 70

(Hsp70) pada kardiomiosit berperan penting dalam proses termotoleran dan

aklimatisasi terhadap panas serta berguna sebagai mekanisme adaptasi secara sistemik

dan seluler. Tujuan dari penelitian adalah untuk menganalisis ekspresi TRPV1, HSF1,

dan Hsp70 pada jantung sebagai respons protektif terhadap pajanan panas.

Metode: Penelitian bersifat eksperimental in vivo menggunakan hewan coba tikus

jenis Sprague Dawley (SD) berumur 12 minggu dengan berat badan 200-300 gram di

laboratorium hewan Balitbangkes Kemenkes RI, pada Oktober-Desember 2014.

Sebanyak 28 ekor tikus jantan dengan n=4 pada tiap kelompoknya, dibagi dalam

kelompok Kontrol (K) dan kelompok Perlakuan (P). Kelompok perlakuan terdiri dari

6 subkelompok (kelompok hari ke-1,3,7,10,14 dan 21) mendapatkan pajanan panas di

dalam hyperthermic chamber bersuhu (45oC ± 0.3oC) dan kelembaban relatif (70% ±

3%) selama 60 menit. Dilakukan pengukuran berat badan, suhu kulit, suhu rektal dan

frekuensi denyut jantung. Perubahan morfologi kardiomiosit diamati menggunakan

pewarnaan Hematoksilin-Eosin. Ekspresi TRPV1, HSF1 dan Hsp70 diperiksa

menggunakan metode imunohistokimia dan ELISA.

Hasil: Penelitian menunjukan pajanan panas 45oC; kelembaban relative 70% selama

60 menit menyebabkan penurunan berat badan sejak hari ke-1 hingga hari ke-21

perlakuan. Terjadi peningkatan suhu kulit, suhu rektal dan heart rate yang puncaknya

terjadi pada hari ke-7, dan menurun mulai pada hari ke-10 sampai pada hari ke-21

meskipun intensitas pajanan panas tetap sama. Hal tersebut menandakan mekanisme

aklimatisasi dan proses termotoleransi telah terjadi pada hari ke-7 perlakuan. Terjadi

penambahan ukuran lebar kardiomiosit dan peningkatan berat pada jantung seiring

lamanya pajanan panas, Hasil ini menunjukkan terjadinya hipertrofi jantung namun

tidak disertai adanya fibrosis. Secara molekuler melalui pemeriksaan Imunohistokimia

dan ELISA pada kardiomiosit menunjukkan ekspresi TRPV1, HSF1 dan Hsp70 yang

bersifat sebagai protein protektif dan kardioprotektor cenderung mengalami

peningkatan sejak hari ke-1 sampai pada hari ke-7 perlakuan dan cenderung menurun

pada hari ke-10 sampai dengan hari ke-21. Perubahan kadar ekspresi TRPV1, HSF1

dan Hsp70 sejalan dengan perubahan yang terjadi pada suhu kulit, suhu rektal dan

heart rate.

Kesimpulan: Pajanan panas pada tubuh memberikan pengaruh pada jantung berupa

terjadinya hipertrofi konsentris disertai adanya peningkatan ekspresi TRPV1, HSF1

dan Hsp70 yang berperan penting sebagai protein protektif dan kardioprotektor

Background: Increased extreme body temperature causes protein denaturation,

cessation of enzymatic reactions, loss of membrane activity and integrity, and triggers

cellular damage. Increased body temperature also affects the occurrence of positive

inotropic and chronotropic effects on the heart. It is postulated that increase in

expression Transient Receptor Potential Vanilloid 1 (TRPV1), Heat Shock Factor 1

(HSF1), Heat Shock Protein 70 (Hsp70) in cardiomyocytes is activated by extreme

temperatures and has an important role in thermotolerance and heat acclimatization

processes -and as a mechanism of systemic and cellular adaptation. The aim of the

study was to analyze the expression of TRPV1, HSF1, and Hsp70 on cardiac muscle

as a protective response to heat exposure.

Methods: This in vivo experimental research was conducted using Sprague-Dawley

(SD) rats (age 12 weeks, 200-300 gram) in animal laboratory National Institute of

Health Research and Development, Indonesian Ministry of Health, October-December

2014. A total of 28 male rats with n = 4 in each group, divided into Control group (K)

and Treatment group (P). The treatment group consisted of 6 sub-groups (i.e.

1,3,7,10,14 and 21 days) received heat exposure in hyperthermic chamber at (45oC ±

0.3oC) and (70% ± 3%) with relative humidity of 60 minutes. Body weight, skin

temperature, rectal temperature and heart rate were measured. Changes in

cardiomyocyte morphology were observed using Hematoxylin-Eosin staining.

Expressions of TRPV1, HSF1 and Hsp70 were examined using immunohistochemical

and ELISA methods.

Results: The results of this study showed that heat exposure at 45oC;70% RH for 60

minutes resulted in weight loss from day 1st to day 21st of the treatment. Peaks

elevation in skin temperature, rectal temperature and heart rate were reached at day

7th, and decreased gradually from day 10th to day 21st even though the intensity of

heat exposure was unchanged. This indicated the mechanism of acclimatization and

thermotolerance process had occurred on the 7th day of heat treatment. There was

increased in the size of the cardiomyocyte width and heart weight along with the

duration of heat exposure. These results indicated the occurrence of heart hypertrophy

but not accompanied by fibrosis. Molecular aspects on cardiomyocytes through

Immunohistochemistry and ELISA showed TRPV1, HSF1 and Hsp70 expression as

protective proteins and cardioprotectors, which tended to increase from day 1st to 7th

day of treatment and decrease gradually on day 10th to day 21st. Changes in

expression levels of TRPV1, HSF1 and Hsp70 coincided with changes in skin

temperature, rectal temperature and heart rate.

Conclusion: Heat exposure to the body induced the development of heart hypertrophy

and coincided with the increased expression of TRPV1, HSF1 and Hsp70 which act as

a protective protein and cardioprotector."

Depok: Fakultas Kedokteran Universitas Indonesia, 2017

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Ari Fahrial Syam

Patofisiologi molekuler perkembangan lesi mukosa gaster tikus pada hipoksia sistemik kronis : tinjauan eksprersi hypoxia inducible factor-Ia heat shock faktor 1 dan heat shock protein 70

Depok: Universitas Indonesia, 2010

D1736

UI - Disertasi Open Universitas Indonesia Library

Sulfiana

Pengaruh Hipoksia Hipobarik Intermiten terhadap Heat Shock Protein 70 dan Produksi Sitokin TNF-?, IL-1? dan IL-10 pada Jaringan Hepar Tikus = The Effect of Intermittent Hypobaric Hypoxia on Heat Shock Protein 70 and Production of TNF-Î±, IL-1Î², and IL-10 Cytokines in Rat Liver Tissue

"Kondisi hipoksia hipobarik dapat mengganggu kesehatan manusia dan menjadi risiko keselamatan di dunia penerbangan. Berbagai jalur pensinyalan sensitif oksigen pada tingkat seluler, dapat diaktifkan selama paparan hipoksia hipobarik intermiten (HHI). HSP sebagai chaperokine berperan dalam transduksi sinyal dan modulasi sistem imun serta terkait dengan produksi sitokin pro-inflamasi atau anti-inflamasi. Penelitian ini bertujuan menganalisis efek HHI terhadap HSP70 dan produksi sitokin pro dan anti-inflamasi. Penelitian ini merupakan penelitian eksperimental dengan menggunakan jaringan hepar tikus Sprague-Dawley yang disimpan pada suhu -20°C. Tikus dibagi menjadi 5 kelompok yaitu kontrol (C), HHA, HHI1, HHI2, dan HHI3 dan diberikan paparan HHI pada ketinggian 25.000 kaki selama 5 menit. Analisis konsentrasi protein dan sitokin ditentukan dengan metode sandwich ELISA. Hasil penelitian menunjukkan terdapat perbedaan bermakna ekspresi protein HSP70 pada hepar tikus pada kelompok HHA dan HHI terhadap kontrol (p<0.05), terdapat perbedaan bermakna konsentrasi IL-10 antara kelompok HHI3 terhadap kontrol (p = 0,018), dan adanya korelasi positif dengan kekuatan korelasi sedang antara HSP70 dengan TNF-Î± dan IL-1Î², serta korelasi positif sedang HSP70 dengan IL-10. HHI menginduksi peningkatan HSP70 sebagai mekanisme adaptasi dan memodulasi sistem imun tubuh untuk meningkatkan konsentrasi IL-10.

Hypobaric hypoxic conditions can disrupt human health and become a risk for safety of aviation. Various signaling oxygen-sensitive pathways at the cellular level can be activated during intermittent hypobaric hypoxia (IHH) exposure. HSP as a chaperokine plays a role in signal transduction and modulation of the immune system and it is associated with the production of pro-inflammatory or anti-inflammatory cytokines. This study aims to analyze the effect of IHH on HSP70 and the production of pro- and anti-inflammatory cytokines. This study was an experimental study using Sprague-Dawley rat liver tissue stored at -20°C. Rats were divided into 5 groups, they are control (C), AHH, IHH1, IHH2, and IHH3. They were exposed to IHH at altitude of 25,000 feet for 5 minutes. Analysis of protein and cytokines concentrations was determined by the sandwich ELISA method. The results showed that there was a significant difference in HSP70 protein expression in the liver of rats in the HHA and IHH groups compared to the control (p<0.05), there was a significant difference in IL-10 concentration between the IHH3 group compared to the control (p = 0.018), a positive correlation with moderate correlation strength between HSP70 with TNF-Î± and IL-1Î², and a moderate positive correlation between HSP70 with IL-10. HHI produces an increase in HSP70 as an adaptive mechanism and modifies the immune system to raise the levels of IL-10."

Jakarta: Fakultas Kedokteran Universitas Indonesia, 2023

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UI - Tesis Membership Universitas Indonesia Library

Mutia Syadewi

Studi ekspresi gen heat shock protein (HSP 70) pada emilia sonchifolia l. dan sphagneticola trilobata l. di lingkungan Universitas Indonesia-Depok dan Kebun Raya Cibodas = Study of heat shock protein (HSP) 70 gene expression of emilia sonchifolia l. and sphagneticola trilobata l. in Universitas Indonesia Depok and Kebun Raya Cibodas

"Suhu permukaan bumi umumnya berbeda sesuai lokasi geografis, salah satunya dipengaruhi oleh ketinggian wilayah. Wilayah Universitas Indonesia UI terletak pada ketinggian 50--140 m dpl dengan suhu rata-rata 28,6 C, sementara wilayah Kebun Raya Cibodas KRC terletak pada ketinggian 1.300--1.425 m dpl dengan suhu rata-rata 20,06oC. Perbedaan suhu diduga dapat memengaruhi respons tumbuhan seperti ekspresi gen heat shock protein Hsp 70. Penelitian bertujuan untuk mengetahui ekspresi gen Hsp70 pada Emilia sonchifolia dan Sphagneticola trilobata yang berasal dari UI dan KRC.

Penelitian dilakukan dengan mengisolasi RNA dari daun muda Emilia sonchifolia dan Sphagneticola trilobata UI dan KRC, diubah menjadi complementary DNA cDNA dengan tektik reverse transcription, dan diamplifikasi dengan teknik polymerase chain reaction PCR menggunakan primer Hsp70 Arabidopsis thaliana.

Hasil amplifikasi kemudian di-sequencing dan dianalisis dengan teknik in-silico. Hasil amplifikasi menunjukkan bahwa terdapat produk parsial gen Hsp70. Penyejajaran urutan basa nukleotida antara keempat sampel yang diteliti dengan gen Hsp70 dari spesies referensi Arabidopsis thaliana menunjukkan adanya kesamaan secara parsial, dan perbedaan satu basa nukleotida posisi ke-65 yang tidak berpengaruh pada perubahan asam amino. Hasil penelitian mengindikasikan bahwa gen Hsp70 terekspresi pada Emilia sonchifolia dan Sphagneticola trilobata yang tumbuh di UI dan KRC.

The temperature of earth surface is generally different according to geographical location, one of which is influenced by the altitude. Universitas Indonesia UI is located at an altitude of 50 140 m amsl with an average temperature of 28.6 C, while Kebun Raya Cibodas KRC located at an altitude of 1.300 1.425 m amsl with an average temperature of 20,06 C. Temperature differences are thought to affect plant responses, such as the expression of heat shock protein Hsp 70 genes. The research aims to find out the expression of Hsp70 genes on Emilia sonchifolia and Sphagneticola trilobata derived from UI and KRC.
The study was conducted by isolating RNA from young leaves of Emilia sonchifolia and Sphagneticola trilobata collected from UI and KRC, then converted into complementary DNA cDNA. The cDNA product was further amplified by polymerase chain reaction PCR using Hsp70 Arabidopsis thaliana primer. The amplification products then sequenced and analyzed by in silico techniques.
The results of amplification show that there is partial product of the Hsp70 gene. The sequencing results show a nucleotide variation in the 65th base which has no effect on amino acid changes. The results indicate Hsp70 gene is expressed in Emilia sonchifolia and Sphagneticola trilobata grown in UI and KRC."

Depok: Fakultas Matematika dan Ilmu Pengetahuan Alam Universitas Indonesia, 2018

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Citra Karina Windarti

Studi ekspresi gen heat shock protein (HPS) 70 pada ageratum conyzoides l. dan synedrella nodiflora l. di Universitas Indonesia-Depok dan Kebun Raya Cibodas = The study of heat shock protein (HPS) 70 gene expression on ageratum conyzoides l. and synedrella nodiflora l. in Universitas Indonesia Depok and Kebun Raya Cibodas

"Asteraceae merupakan salah satu famili tumbuhan yang bersifat invasif. Tumbuhan dengan sifat invasif dapat lebih mentoleransi suhu tinggi akibat adanya peran mekanisme Hsp70. Gen Hsp70 merupakan gen yang terkonservasi didalam sel sebagai bentuk adaptasi terhadap beberapa cekaman lingkungan, salah satunya adalah cekaman suhu. Perbedaan suhu rata-rata antara Universitas Indonesia-Depok yaitu 28,6oC dan Kebun Raya Cibodas dengan suhu rata-rata 20,06 oC menjadi dasar dilakukannya penelitian untuk melihat tingkat ekspresi gen Hsp70 pada Ageratum conyzoides dan Synedrella nodiflora. Penelitian diawali dengan isolasi RNA dari organ daun dengan metode CTAB yang telah dimodifikasi dan dilanjutkan dengan sintesis cDNA.

Hasil dari cDNA diamplifikasi dengan PCR menggunakan primer Hsp70 yang digunakan oleh Sung 2001 pada Arabidopsis thaliana. Hasil penelitian menunjukkan adanya amplifikasi gen Hsp70 secara parsial, serta adanya variasi basa nukleotida pada sampel lokasi Universitas Indonesia dan Cibodas pada posisi basa ke 110 dan 108 yang mengakibatkan adanya perbedaan pembacaan asam amino. Namun perbedaan asam amino tersebut tidak membuat perubahan prediksi struktur protein pada sampel.

Asteraceae is one of the invasive plant family. Invasive plants have more ability to tolerating high temperatures with the role of the Hsp70 mechanism. The Hsp70 gene is conserved in cells as a form of adaptation to some environmental stresses, one of which is temperature stress. The difference of average temperature between Universitas Indonesia Depok which is 28,6oC and Cibodas Botanical Garden with average temperature 20,06oC become the basis of this research to see the level of Hsp70 gene expression in Ageratum conyzoides and Synedrella nodiflora plants at two locations with different temperature. The research begins with RNA isolation from the leaf tissues with modified CTAB method followed by cDNA synthesis. The cDNA then amplified by PCR using a Hsp70 primer used by Sung 2001 in Arabidopsis thaliana.
The results showed that there is a partial amplification of the Hsp70 gene, as well as the presence of nucleotide base variations in Universitas Indonesia Depok and Cibodas at base positions number 110 and 108 which resulted in differences in amino acid readings. However, these amino acid differences do not make a change in protein structure prediction of the samples. "

Depok: Fakultas Matematika dan Ilmu Pengetahuan Alam Universitas Indonesia, 2018

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Peran heat shock protein (HSP) terhadap penyakit rongga mulut

"Indonesian Journal of Dentistry 2006; Edisi Khusus KPPIKG XIV: 435-438

Heat Shock Protein (HSP) is a molecular chaperone that prevents stress induced aggregation of partially denatured proteins and promotes their return to native confimations when the condition is favorable. As

molecular chaperones, the HSP protect protein structure and activity, thereby preventing disease, but they may contribute to cell malfunction if they are perturbed. In inracellular quantities and cellular localizalion of HSP was changed in response to anoxia/hypoxia, heat and oxidation, and in relation to pathological status. This review discuses the role of HSP in several human medical condition particularly in oral mucosa."

Fakultas Kedokteran Gigi Universitas Airlangga, 2006

pdf

Artikel Jurnal Universitas Indonesia Library

The Role of heat shock proteins in pathogenesis of oral squamous cell carcioma.

"Cell in the distress situation, denaturation of proteins may occur, and may also respond by expressing stress proteins. However, such homeostatis effort does not always succeed and even may lead to disease, including cancer. In distress situation also ensue much protein misfolding. Objective: This research were to explain the role of heat shock protein 40 (Hsp40) and HSP20 in pathogenesis of occured oral squamous cell carcinoma (OSSC) patient which realized human papiloma virus (HPV) infection. Material and method: Tissue biopsy frozen section were taken from BOSC and OSCC patients was cut into three part. Parrafin blocks were made from cutting I, which was subsequently stains with HE to ascertain the type of neoplasm. Cutting II was subjected to DNA isolation. The DNA isolation results were subjected to PCR to amplify L1-HPV gene for fixed the HPV stressor. Protein isolation was treated from cutting III, followed with Blottdot test by using anibody monoclonal anti Hsp40 and Hsp 70 and continued with measurement using densitometer to find the concentration of Hsp40 and Hsp70. The collected data were analyzed with F Test (Manova) and discriminant analysis. Result: This experiment showed the differences in concentration of Hsp40 (p<=0,070) and Hsp70 (p<=0,006) between benign oral squamous cell (BOSC) and OSCC patients which realized HPV infection. Conclusion: This experiment proved that OSCC patients which realized HPV infection indicated an up regulated of Hsp70 concentration, so that there was occurs misfolding of the proteins cell. The misfolding was ensue obstacle of apoptosis and to raise cell poliferation which to storm carcinogenesis. An up regulated of Hsp40 was role as co-chaperone."

[Universitas Airlangga, Journal of Dentistry Indonesia], 2009

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Artikel Jurnal Universitas Indonesia Library

Ocktariyana

Analisis genetik dan epigenetik gen pengkode faktor nyeri Nerve Growth Factor (NGF), Transient Receptor Potential Cation Channel Subfamily Ankyrin Member 1 (TRPA1), dan Purinergic Receptor P2x Ligand-Gated Ion Channel 3 (P2RX3) pada endometriosis = Genetic and epigenetic analyses of Nerve Growth Factor (NGF), Transient Receptor Potential Cation Channel Subfamily Ankyrin Member1 (TRPA1), and Purinergic Receptor P2x Ligand-Gated Ion Channel 3 (P2RX3) as a pain protein coding in endometriosis

"Endometriosis sering dikaitkan dengan nyeri menstruasi dan nyeri pelvis. Penyakit ini terjadi sekitar 10-15% pada perempuan usia reproduksi . NGF, TRPA1 dan reseptor P2RX3 aktivitas gen terlibat dalam respon nyeri. Penelitian ini bertujuan untuk menganalisis tingkat ekspresi mRNA gen NGF, reseptor TRPA1 dan reseptor P2RX3 yang diduga disebabkan oleh perubahan tingkat metilasi DNA promoter gen tersebut, serta hubungannya pada intensitas nyeri subjek endometriosis.Sampel jaringan endometrium dan susukan endometriosis peritoneum diperoleh dari 20 subjek endometriosis, sementara jaringan endometrium kontrol diperoleh dari 20 subjek nir endometriosis. Metode yang digunakan untuk analisis metilasi DNA yaitu metode MSP dan perangkat lunak Image-J digunakan untuk menganalisis intensitas pita metilasi dari gen NGF, reseptor TRPA1 dan reseptor P2RX3R, selanjutnya digunakan metode qRT-PCR untuk analisis tingkat mRNA gen-gen tersebut. Penilaian intensitas nyeri dilakukan dengan menggunakan kuesioner standar skala penilaian numerik (NRS) melalui wawancara dengan pasien. Pada penelitian ini didapatkan hasil terdapat hubungan yang bermakna antara intensitas nyeri dan kejadian endometriosis (p>0,001). Hasil tersebut dibuktikan dengan terdapat perbedaan yang bermakna tingkat ekspresi relatif mRNA gen NGF, reseptor P2RX3 antara jaringan endometrium endometriosis dibandingkan dengan subjek nir endometriosis masing-masing nilai p= <0,05. Terdapat juga perbedaan yang bermakna tingkat metilasi DNA promotor gen NGF dan reseptor P2RX3 antara jaringan endometrium endometriosis dengan endometrium nir endometriosis (p<0,05). Selanjutnya, terdapat hubungan yang bermakna antara ekspesi mRNA NGF dan reseptor Reseptor P2RX3 dengan intensitas nyeri pada endometriosis (p<0,05), namun tidak terdapat hubungan antara tingkat metilasi DNA dengan ekspresi relatif mRNA gen NGF, reseptor reseptor TRPA1 pada endometriosis begitupun antara metilasi DNA dengan intensitas nyeri pada ketiga gen tersebut (p>0,05). Terjadi perubahan ekspresi relatif mRNA gen NGF, reseptor TRPA1 dan reseptor P2RX3 pada subjek endometriosis yang berhubungan dengan peningkatan intensitas nyeri pada endometriosis, namun mekanisme epigenetik metilasi DNA pada penelitian tersebut tidak berhubungan pada intensitas nyeri endometriosis.

Endometriosis is often associated with both cyclic menstrual pain and pelvic pain. It affects 10% of reproductive age women. NGF, TRPA1 and P2RX3 receptors gene activity are found to be involved in pain response. This study aims to analyze the methylation level of NGF gene, TRPA1 and P2RX3 receptors that might alter the mRNA expression in peritoneal endometriosis and endometrial tissue, as well as its correlation to the pain level in endometriosis patients.20 endometrial tissues and 20 peritoneal endometriosis tissues were obtained from patients, while 20 endometrium tissues as control were obtained from healthy women. First, each participant was given informed consent before the research begin. We used methylation specific PCR (MSP) and Image-J software to analyze the methylation level of NGF gene, TRPA1 and P2RX3 receptors; electrophoresis to analyze the band intensity; qRT-PCR to evaluate the mRNA level in each gene. Finally, we evaluated the pain level using the standardized questionnaire of numeric rating scale (NRS) by doing interviews with patients. In this study, it was found that there is a significant relationship between pain intensity and the incidence of endometriosis (p> 0.001). This results is proven by a significant difference in the mRNA expression level of NGF gene and P2RX3 receptor between endometrial endometriosis and endometrial non-endometriosis tissues, with each p value = <0.05. There is also a significant difference in the DNA methylation level of NGF gene and P2RX3 receptor between endometrial endometriosis and endometrial non-endometriosis tissues (p <0.05). There is a significant relationship between the mRNA expression level of NGF gene, P2RX3 receptor and pain intensity in endometrial endometriosis tissues (p <0.05). However, the results showed that there is no correlation between the DNA methylation level and the mRNA expression of NGF gene, TRPA1 and P2RX3 receptors. There is also no correlation between the DNA methylation level of NGF gene, TRPA1 and P2RX3 receptors and pain intensity in endometriosis tissue. There is an alteration of mRNA expression of NGF gene, TRPA1 and P2RX3 receptors which correlates to pain intensity in endometriosis patients. However, there is no correlation between DNA methylation level and pain intensity in endometriosis patients."

Jakarta: Fakultas Kedokteran Universitas Indonesia, 2019

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Dicky Fakhri

Peran polimorfisme toll like receptor 2 dan toll interacting protein terhadap kejadian sepsis dan respons imun pada anak di bawah 1 tahun yang menjalani operasi jantung terbuka = Role of toll like receptor 2 and toll interacting protein polymorphism in the development of sepsis and immunology response in children less than 1 year old undergoing open heart surgery

"[ABSTRAK

Latar Belakang: Pada anak dengan penyakit jantung bawaan (PJB) yang

menjalani operasi jantung terbuka, sepsis merupakan salah satu komplikasi

pascaoperasi. Lama prosedur pintas jantung paru, usia, status gizi, timektomi, dan

variasi genetik, seperti polimorfisme toll-like receptor (TLR) 2 dan tollinteracting

protein (TOLLIP) dapat memengaruhi respons imun. Informasi

mengenai peran faktor tersebut terhadap kejadian sepsis dan respons imun

pascaoperasi jantung terbuka masih terbatas.

Tujuan: Mengetahui peran polimorfisme TLR2, TOLLIP, dan faktor lainnya

terhadap kejadian sepsis dan respons imun pascaoperasi jantung terbuka untuk

memperoleh strategi paling tepat dalam penanganan kasus bedah jantung pada

anak.

Metodologi: Studi longitudinal dengan non-probability consecutive sampling

dilakukan pada anak <1 tahun yang menjalani operasi jantung terbuka.

Pemeriksaan polimorfisme TLR2 Arg677Trp, TLR2 N199N, TOLLIP rs5743867,

sel CD4 dan CD8 yang menyekresikan IFN-γ intraselular, sel Dendritik yang

mengekspresikan TLR2, dan sel NK. Pasien menjalani operasi jantung terbuka.

Setelah operasi, pasien dimonitor untuk menilai sepsis dan respons imun

pascaoperasi.

Hasil: Dari 108 subjek yang terlibat, 21,3% diantaranya mengalami sepsis.

Seluruh subjek adalah mutan TLR2 Arg677Trp, 92,6% pasien adalah mutan TLR2

N199N, dan 52,8% pasien adalah mutan TOLLIP rs5743867. Polimorfisme TLR2

N199N dan timektomi total tidak diikutkan dalam model analisis multivariat.

Polimorfisme TOLLIP rs5743867 (p = 0,358) menurunkan resiko sepsis, lama

prosedur pintas jantung paru ≥90 menit (p = 0,002), usia neonatus (p = 0,032), dan

gizi buruk (p = 0,558) meningkatkan risiko sepsis pascaoperasi. Jumlah respons

imun bervariasi antara kategori, namun secara umum komponen respons imun

lebih rendah pada pasien yang mengalami sepsis dibanding pada pasien yang tidak

mengalami sepsis.

Simpulan: Lama prosedur pintas jantung paru dan usia neonatus secara signifikan

memengaruhi risiko dan kecepatan sepsis pascaoperasi. Peran polimorfisme TLR2

N199N dan TOLLIP rs5743867 terhadap kejadian sepsis dan respons imun

pascaoperasi memerlukan studi komprehensif lebih lanjut.

ABSTRACT

Background: Sepsis is one of the complications in children with congenital heart

defect who underwent open heart surgery. Cardiopulmonary bypass (CPB) time,

age, nutritional status, thymectomy, and genetic variants, such as toll-like receptor

(TLR) 2 and toll-interacting protein (TOLLIP) polymorphism affect immune

response. Information regarding those factors in the development of sepsis and

immune response after open heart surgery is still limited.

Objectives: To understand the role of TLR 2 and TOLLIP polymorphism, as well

as other risk factors, in the development of sepsis and immune response following

open heart surgery to develop the best strategy in open heart surgery in children.

Methods: Longitudinal study with consecutive sampling were done in children <1

year old who underwent open heart surgery. Blood sample was obtained to check

for TLR2 Arg677Trp polymorphism, TLR2 N199N polymorphism, TOLLIP

rs5743867 polymorphism, the numbers of intracellular interferon γ CD4 and CD8,

TLR2 expression in Dendritic cells, and NK cells. Patient then underwent open

heart surgery. Thymectomy was done as indicated and CPB time was recorded.

After surgery, patient was monitored for signs of sepsis and immune response was

checked.

Results: Out of 108 patients involved in this study, 21.3% developed

postoperative sepsis. TLR2 Arg677Trp polymorphism was found in all patients,

TLR2 N199N polymorphism was found in 92.6% of the patients, and TOLLIP

rs5743867 polymorphism was found in 52.8% of the patients. TLR2 N199N

polymorphism and thymectomy were not included in multivariate analysis.

TOLLIP rs5743867 polymorphism (p = 0.358) reduced the risk of sepsis, CPB

time ≥90 menit (p = 0.002), neonates (p = 0.032), and severe malnutrition (p =

0.558) increased the risk of postoperative sepsis. Immune response?s counts vary

in each category, but were generally lower in patients who developed

postoperative sepsis.

Conclusion: Cardiopulmonary bypass time and neonates significantly influenced

the risk and hazard of postoperative sepsis. Further investigation on the role of

TLR2 N199N and TOLLIP rs5743867 polymorphism are necessary to provide

more comprehensive explanation on the development of postoperative sepsis and

the immune response after open heart surgery;Background: Sepsis is one of the complications in children with congenital heart