Vietnam Journal of Physiology 19(2), 6/2015 ISSN: 1 8 5 9 - 2 3 7 6 DAP t>NG VIEM TREN BENH NHAN BENH P H O I T A C NGHEN MAN TiNH (COPD)
NHJN TLT GOC DO SINH LY HOC
ThS. Le Quoc T u a n ' ' ' , PGS. TS. N g u y i n Thj Le' TOM T A T : Slf h^p dw&ng th&, tai ciu true, vd khi phi thung trong bpnh phoi tic nghen man tinh (COPD) ddu dugc gdy nen ben tinh trang viem man tinh trong md phoi ngoai vi Tinh trang viem trong COPD dugc ddc trwng b& si/ tang sfi Iwgng dai thwc bao, da nhdn trung tinh. vd lympho T (chu ydu la ddng CD8). Dap img miin djch trong COPD gdm cd mien djch bim sinh vd midn djch mde phdi. Nhiiu hda chdt trung gian cd ngudn gdc tir eac ti bao viim vd cdc ti bdo cau true cQng tdng biiu hipn. Md hinh bpnh I'y nay cQng thay trong nhung ngwai hut thuoc Id khdng tripu chimg. Tuy nhien trong COPD, ddp img viem dwgc khuich da,! len nhiiu lan, nhat Id trong cdc dot cip voi sw tham gia eiia nhiim trung hay nhiim virus. Khdi thudc va cdc chat kich thich khdc tren du&ng hd hip boat hda eae dai thuc bdo vd td bao biiu md gial phdng eac yiu td hda img dpng, ldi keo bach cdu xdm nhpp vdo nhu md phdi. Trong do, ehemokine la nhung chat chiim wu the.
cd vai trd then chdt trong qua trinh viem man tinh cCia COPD.
Tip khda: Bpnh phdi tdc nghen man tinh, lympho T CD8, ehemokine.
1. COPD l i mot benh ly viem man tinh Sinh b i n h hgc ctia COPD lien quan chti y i u d i n eac dufi'ng d i n khi ngoai vi v i nhu mo phli, trong khi a hen suyin, tinh trgng viem xay ra o' tat c i c i c dufi'ng d i n khi ( n h i l la eac dufi'ng d i n khi tmng lam) v i thufi'ng khong lien quan d i n nhu mo phoi [1]. Tren benh nhan COPD cfi sg thu hep cac t i l u p h i quan, xa hfia, pha hiiy nhu mfi phoi, t h i m nhgp cac dgi thuc b i o v i lympho T. Sinh thilt p h i quan tren nhO'ng benh nhan COPD nang cho t h i y co su tang s l lugng neutrophil, Iham nhap dai Ihuc bao v i lympho CD8 tuong ung [2]. Lfi-p b i l u mo tren dufi'ng dan khi trong COPD khong mfing nhu trong hen ma bi chuyin san do i n h hufi'ng tir sg phong thich cac yeu t l tang trufi'ng bilu mfi man tinh EGF (epithelial growth factor). Mfit su khac biit nu'a gitra COPD v i hen chinh la tinh Irang xa hfia. Trong hen suyin
^ Bp mon Sinh ly hpc, Truong Dai hoc Y Dugc Thanh pho Ho Chi Minh
' Tie gia chiu Trach nhigm chinh"
Le Quoc Tuan
Email: iirtuan.phvsioloqv.hcmiai.Qmail.com Ngay nhan bail 2/6/2015
Ngay nhan bai phin bign: 5/6/2015 Ngay chap nhgn dang: 8/6/2015
thufi'ng CO xa hfia dual bieu mfi (subepithelial fibrosis, cfin gpi la s g d i y ming nin), trong khi d l i vfi'i COPD su xa hfia thufi'ng quan sat thiy fi' quanh p h i q u i n (peribronchiolar fibrosis) [1]. Lfi'p co tran dufi'ng d i n khi thu&ng d i y len trong hen suyin, k i t q u i ttr sg phi dai va tang s i n ca tran, trong khi lgi thufi'ng khfing tang trong COPD. Tang tiet chit nhay ia mfit hinh anh thufi'ng gap trong ca hen va COPD, vai su tang s i n cua te bao dai v i tuyen dufi'i niem.
2. Cac te bao viem trong COPD Ttr lau, gifi'i y khoa tin rang ehinh phan irng v i i m xay ra o' nhOng ngufi'i hut thulc l i , vai sg tham gia cua bach cau da nhin, dgi thuc bao va c i c enzyme proteinase, chju trich nhiem eho sg p h i hiiy nhu mfi p h l i trong COPD [3]. G i n diy, nhilu cong trinh da ghi n h i n sg t i m nhugn lympho T uu t h l trong phoi bgnh nhan COPD, nhit l i t l bao TCDS. D i p trng v i i m trong p h l i benh nhin COPD l i i n quan ca d i n m i l n djeh bam sinh (bgch cau da nhan, dgi thuc b i o , bach c i u ua acid, dufi'ng b i o , te bao NK, lympho T yfi, te bao duoi gai), va miln djch dge higu (lympho B, lympho T) [2].
Q u i trinh v i i m dufi'ng d i n khi trong
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Vietnam Journal of Physiology 19(2), 6/2015 ISSN: 1 8 5 9 - 2 3 7 6 COPD dufi'ng nhu khong m i t di, t h i m chl
l i nhieu n i m sau khi cai thulc la [4].
2.1. Cac te bao bieu mfi (epithelial cells)
C i c t l bao bieu mo dugc hogt hfia bai khoi thuoc, san sinh e i e hfia chat trung gian, bae gom: TNF-a (tumor necrosis factor), lL-1 p (Interleukin 1 p), IL-6 (interieukin 6), GM-CSF (granulocyte macrophage colony stimulating factor), IL- 8 (interieukin 8) [4]. T l bao b i l u mfi tren cac duang d i n khi nhfi cfi t h l la nguon g i c ciia TGF- p, hfia chit trung gian d i n den qua trinh xa hfia cyc bp. C i c t l bao bllu mfi eung efi vai trfi quan trpng trong viec bao ve dufi'ng dan khi bang each tilt ra chat nhay ( t l b i o dai), eae chit ching oxy hfia (antioxidants), antriproteases, defensins [2].
Trong v i i m p h i quan man tinh va COPD thuang quan sat thiy hien tugng chuyen san vay (squamous metaplasia), k i t qua ttr su tang sinh eua te b i o b i l u mo day, Thu the ciia y l u tfi lang trufi'ng bieu mfi (EGFR: Epidermal growth factor receptors) tang bilu hiin a nhtrng ngufi'i hilt thulc l i , cfi the gfip phan v i o hign tugng chuyen san v i y , va l i m tang nguy ca ung thu p h i quan [1].
2.2. Cac te bao trung mo (mesenchymal cells)
Cac t l b i o trung mfi bao gom: nguyen b i o sgi (fibroblasts), nguyen b i o sgi ca
(myofibroblasts), v i cac t l bao ca tran.
Day la nhO-ng cau true chinh chju traeh nhiim tao thanh mfi ke, Nhu v i y , chiing cfi vai tro quan trpng trong hien tugng tai c l u triic mfi (tissue remodeling), mpt bieu hien dac trung cOa COPD. Ngoai ra, c i c t l bao nay eOng san sinh nhieu hfia chit trung gian, gfip p h l n vao q u i trinh viem man tinh. Nguyin b i o sgi trong nhu mo phli ciia bgnh n h i n COPD tang sinh c h i m , va it chju t i c dung ciia h i i n tugng hoa irng dfing [5]. Dieu nay d i n d i n sg khilm khuyll q u i trinh sira chO'a, g i y n i n hign tugng khi p h i thiing (emphysema).
2.3. Bach cau da nhan t m n g tinh (neutrophils)
So lugng bgch cau da nhan trung tinh tang len trong dfi'm va djeh rira p h i quan fi- nhu'ng b i n h nhan COPD nhung it tang trong dufi'ng d i n khi v i nhu mo phoi Lugng neutrophil trong dfi'm efi m l i luang quan mat thilt vfi'i dp nang cua COPD va toe dp suy giam chirc nang phli. Hut thuoc l i kich thich true t i l p l i n su san sinh, giai phfing cae tiach cau hgt tir liiy xuang v i e dufi'ng d i n khi, efi le thfing qua GM-CSF va G-CSF (do dai thuc bao nhu mfi p h l i t i l t ra) [6]. Htit thulc la eung cfi t h l lam tang luu giCr neutrophil trong mach mau phoi.
LTB4, C X C L 1 . C X C L 8 N e u t r o p h i l
E m p h y s e m a
iQ M u c u s h y p e r s e c r e t i o n
Hinh 1. Vai trfi ciia da nhan trung tinh Irong COPD [3]
Vietnam Joumal of Physiology 19(2), 6/2015 ISSN: 1 8 5 9 - 2 3 7 6 Bach cau da n h i n tmng tinh dugc thu
hut vao p h l i cua binh nhan COPD bo'i c i c chat hfia irng dfing, nhu: leukotriene B4 (LT B4), ehemokines CXCL1 (con goi l i GRO- a), CXCL8 (efi gpi la IL-8). Da nhan trung tinh dugc hoat hfia g i i i phong nhilu LT 84 va CXCL8 (de thu hitt nhilu bgch c i u han nira), c i c g i c oxy p h i n irng nhu anion superoxide (O2") va myeloperoxidase (MPO). ChtJng cung phfing thich c i c enzyme nhu: serine proteinases NE, cathpsin G, and proteinase-3, MMP-8 (matrix metalloproteinases 8), MMP-9 (matrix metalloproteinases 9). Cae proteinase nay kich thich tang tilt chit nhay va ly g i i i elastin, d i n d i n khi phe thiing.
2.4. Dai t h u c bao
Dai thuc bao dfing vai trfi quan trpng trong ca c h l benh sinh cua COPD, g i y nen h i u h i t cac bilu hien ciia benh. So lugng dai thuc bao tang tir 5-10 l i n hon trong dufi'ng d i n khi, nhu mo phoi, djeh rira p h i quan, va d i m ciia benh nhin. S l lugng nay efi t h l tang d i n 15 l i n han trong nhu mfi phoi fi- nhom benh nhan co khi p h i thung so vfi'i nhtrng nguai hut thulc la khfing bieu hign benh [7]. Dai thgc b i o khu tru nhilu 6' nhu'ng vting cfi thanh phe nang bj pha huy. Nhu v i y , rfi rang co m l i quan h i chal che gitra so lugng dai thgc b i o Irong nhu mo phli va dp nang ciia khi p h i thung.
Cigarette smoke Wood smoke
CTGF TGF-SI • Fibrosis
MMP-9,MMP-12 Cathepsins K,LS
Monocytes CD8~ cells
Hinh 2. Vai trfi ciia dai thuc bao trong COPD [1]
Dai thuc bao khi dugc hoat hoa bo'i khfii t h u l c se e h i l i l t ra nhilu protein viem, la c i c hfia ehat tmng gian loi keo eae bgch c i u khac d i n . Vi dy, c i c bach cau neutrophil cfi t h l dugc thu htit bfi'i CXCL8, CXCL1, va leukotriene B4 (LT B4 ); cac bach c l u dan nhan bfi'i CCL2; lympho
TCD8* bfi'i CXCL10, CXCL11. Dgi thgc bao cung giai phfing cac enzyme g i y ly giai elastin (nhu MMP: matrix metalloproteinases, cathepsin), cac y l u to tang trufi'ng chuyen dang (nhu TGF-|31:
transforming growth factor 31), y l u t l tang truo'ng mfi lien k i t (CTGF:
Vietnam Journal of Physiology 19(2), 6/2015
ISSN: 1859-2376
connective tissue grovrth factor). Ngoii ra,dgi thuc b i o cfin tao ra c i c g i c oxy phan trng (ROS: reactive oxygen species), va NO (nitric oxide), cfi the k i t hgp vfi'i nhau hinh thinh g i e peroxynitrite, cfi t h l gfip phan v i o ca che khang steroid.
Dai thgc bao duge hoat hoa bfi'i khfii thuie la se giai phfing nhilu hoa c h i t trung gian g i y viem nhu: TNF- a , CXCL8, CCL2 (MCP-1), LT B4, g i c oxy phan irng. Chiing cung t i l t ra cac enzyme gay phan hiiy elastin nhu: MMP-2. MMP-9, MMP-12, cathepsin (K, L, S), v i NE [6]. Trong dfi, MMP-9 la enzym huy elastin chilm uu t h l , Dgi thge bao 6' nhO'ng doi tugng hut thulc la ghi nhin cfi sg t i n g d i n g k l protein khang lai sg chit theo chuang trinh BCI-XL va p2i^'^'^'^^'' [7], Nhu vay, dai thge bao cfi thai gian song k i o d i i han fi" nhfim hut thulc la va binh n h i n COPD.
Corticosteroid khong hieu qua trong van de ire c h l viem fi- bgnh nhin COPD.
Tuy nhien, su giai phong CXCL8, TNF- a , va MMP-9 tir dai thgc bao o' ea nhu'ng nguai co hut thuoc va khong hiit thulc deu bj ire c h l bai corticosteroid trong invitro.
Ly do khang corticosteroid t r i n thgc l l fi' benh nhan COPD va hut thulc l i co t h l la do g i i m dang ke hoat dpng ciia enzyme histone deacetylase-2 (HDAC2) [5], Enzym HDAC2 duge huy dfing bo'i thu the glucocorticoid d i n cac gen g i y viem de lam dirng sao ma c i c gen nay. S g giam hoat dpng ciia HDAC2 trong dai thuc bao cfi moi tuang quan chat che vfi'i tang tilt cac cytokine TNF- a, CXCL8, va giam dap irng vfi'i corticosteroid [5], Tren benh nhan COPD, dieu nay co t h l dugc g i y nen bai stress oxy hfia va g i c peroxynitrite.
2.5. Bach cau ai toan (eosinophils) Khac vai hen, bach c i u ai loan cfi r i t it vai tro trong sinh 1^ bgnh COPD, Sg co mgt ciia bach cau ai toan du doan kha
nang d i p irng vfi'i corticosteroid va co the efi su ciing ton tai ciia hen suyen [1].
2.6. Lympho T (T-lymphocytes) Ngufi'i ta ghi nhin cfi su tang tong s l bach c l u lympho T trong nhu mo phli, dufi'ng dan kht trung t i m va ngogi bien a bgnh nhin COPD, nhit la q u i n the CD8.
s l lugng lympho T cfi lien quan chat che vfi'i s l phe nang bj p h i hGy va dp nang ciia hign tugng t i e nghen dufi'ng dan khi [3]. Su gia tang lympho T CDS* la dilm k h i c biit d i n g k l giO'a nhung ngufi'i hiit thulc l i khfing triiu ehirng v i nh&ng benh nhan COPD.
Sg tham nhgp eae l l bao T vao nhu mfi p h l i phy thufic v i o mfit s l y l u t l hoat hfia khfi'i dau. Cae t l b i o lympho T CD4*, va CD8* trong phoi bgnh nhan COPD d i u tang bilu hign CXCR3 - mpt thu t h l dugc hoat hfia bfi'i c i c ehemokine: CXCL9 (Mig), CXCL10 (IP-10), CXCL11 (l-TAC) [7]. T l bao b i l u mfi khi quan tang s i n sinh ehemokine CXCL10 se gfip phin gay tieh ty lympho CD4 va CD8 thong qua thu t h l CXCR3. T l b i o lympho CD8 tang d i l n hinh trong nhilm trting dufi'ng d i n khi. Nhu vgy, eo t h l ton tgi mpt linh trang nhiem triing man tinh bfi'i cac t i c n h i n vi khuan va virus, ehiu traeh nhiim cho dap irng viem tgi dufi'ng ho h i p dufi'i. Nhilu kha nang chinh t i n thuang phli g i y n i n bfi'i khoi thulc da l i m bfic Ip cac t g khang nguyen an trufi'c dfi. Hoac chinh khfii thulc da gay ton thuang cac t l bao c i u triie v i t l b i o ke phli, l i m cho chiing tra nen cfi tinh khang nguyen. Chinh t l bao CD4 nhfim Th (T help) la d i l u kign can d l khfi'i d i u dap irng cua cac t l bao CDS Tc (T cytoxie) de duy tri tri nhfi' miln djch v i bao d i m sg t i n tgi cua chinh t l bao T CD8. Do tri nhfi' miin d|eh nen c i c t i b i o T CD4 efi kha nang duy tri tinh trang v i i m khi ving mat khfii thuoc.
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Emphysema _ , , (apoptosis of type i M ^ P ^ ^ ° " " „
pneumocytes) Granzyme B Hinh 3. Vai tro cua lympho T Irong COPD [1]
Cae t l b i o b i l u mo va dai thue bao dirge kich thich bfi'i interferon- y (IFN- y) se giai phong cac ehemokine: CXCL9 {CXC-chemokine ligand 9), CXCL10, and CXCL11. Cac ehemokine nay t i c dfing vao thy t h l CXCR3 (CXC-chemokine receptor 3) b i l u hien tren t l b i o lympho T h l (T helper 1), v i T d (T eytoxic 1) nham thu hut cae lympho n i y d i n phoi. T l bao T d glai phfing peri'orin va granzyme B gay c h i t cae p h i bao tip I theo chuang trinh, gop p h l n tgo ra khi p h i thiing. IFN- y, do t l b i o Thl va Tel tilt ra, sau do lgi kich thich b i l u mo va dgi thuc bao giai phfing cac ehemokine la p h l i tir ciia thu the CXCR3. Cir nhu vgy, vong xoan b i n h ly nay gay n i n qua trinh v i i m dai d i n g trong COPD.
T I b i o T CD8 * co kha nang gay ly giai va ehit t l bao theo chuang trinh t r i n c i c t l bao b i l u mo p h i nang b i n g phong thich perforins, granzyme B, v i TNF- a, gop p h i n vao benh sinh khi p h i thung. Ngoii ra, t l b i o T CDS con san xuit nhilu cytokine gom: TNF- a . lymphotoxin, v i IFN- Y [3]. Cac cytokine nay gfip p h l n tang
cufi'ng phan ung viem trong phli, ben eanh ca c h l gilt trgc t i l p bfi'i T CD8. Do dfi, COPD dipgc xem nhw Id mpt benh tir mien gay nin boi thudc Id, vfi'i su hien d i i n ci^a dfing t l b i o T hoat hoa eao t r i n binh nhan khi p h i thung.
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SUMMARY
INFLAMMATORY RESPONSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Le Quoc Tuan MSc.\ Nguyen Thi Le MD. PhD.^
'Department of Physiology, University of Medicine and Pharmacy Hochiminh City The narrowed airway, remodeling, and emphysema in chronic obstructive pulmonary disease (COPD) are caused by chronic inflammation in the peripheral lung tissue. The inflammation in COPD is characterized by increased numbers of macmphages, neutrophils, and T lymphocytes (mainly CDS lymphocytes). The immune response in COPD include both innate immunity and acquired immunity, with the expression of many intermediate chemicals derived from inflammatory cells and structural cells. This pathological pattern also seen in asymptomatic smokers. However, in COPD, inflammatory response is amplified many times, especially during exacerbations. Smoke and other irritants on airway activate macrophage, epithelial cells to release the intermediate chemicals. Chemokines play the key role in chronic inflammatory processes of COPD.
Keywords: chronic obstructive pulmonary disease (COPD), CD8 T lymphocytes, chemokines.
