{"id":3497,"date":"2022-06-15T10:00:59","date_gmt":"2022-06-15T07:00:59","guid":{"rendered":"https:\/\/tatd.org.tr\/toksikoloji\/?p=3497"},"modified":"2022-06-14T21:15:42","modified_gmt":"2022-06-14T18:15:42","slug":"akicger_hasarinda_makrofaj","status":"publish","type":"post","link":"https:\/\/tatd.org.tr\/toksikoloji\/2022\/06\/15\/akicger_hasarinda_makrofaj\/","title":{"rendered":"Pulmoner Toksik Maddelerin Neden Oldu\u011fu Akut Akci\u011fer Hasar\u0131 ve Kronik Fibrozisde Makrofajlar\u0131n Rol\u00fc"},"content":{"rendered":"

Hasar b\u00f6lgelerinde biriken makrofajlar\u0131n, ksenobiyotiklere verilen patojenik yan\u0131tta rol oynad\u0131\u011f\u0131 g\u00f6r\u00fc\u015f\u00fc 100 y\u0131ldan daha uzun bir s\u00fcre \u00f6nce Eli Metchnikoff taraf\u0131ndan ortaya konmu\u015ftur. \u0130nflamatuar yan\u0131t\u0131 “baz\u0131 zararl\u0131 etkilere kar\u015f\u0131 faydal\u0131 bir reaksiyon” olarak tan\u0131mlayarak, inflamasyon b\u00f6lgesindeki h\u00fccreler taraf\u0131ndan sal\u0131nan “fermentlerin” doku hasar\u0131na katk\u0131da bulunabilece\u011fi hipotezini de \u00f6ne s\u00fcrm\u00fc\u015ft\u00fcr (1). O zamandan bu yana bu kavram\u0131 destekleyen \u00e7ok say\u0131da yay\u0131n yap\u0131lm\u0131\u015ft\u0131r.<\/p>\n

Bu yaz\u0131m\u0131zda; akut ve kronik akci\u011fer hasar\u0131nda ve pulmoner toksik maddelerin neden oldu\u011fu hastal\u0131k patogenezinde makrofajlar\u0131n ve makrofajlar taraf\u0131ndan sal\u0131nan inflamatuar medyat\u00f6rlerin rol\u00fcne odaklanan bir derlemeden<\/a> bahsedece\u011fiz.<\/p>\n

\u0130nflamatuar Makrofajlar<\/h1>\n

\u0130nflamatuar makrofajlar, konak savunmas\u0131nda ve zararl\u0131 uyaranlara kar\u015f\u0131 do\u011fal ba\u011f\u0131\u015f\u0131kl\u0131k sistemi yan\u0131t\u0131nda \u00f6nemli bir rol oynayan monon\u00fckleer fagositlerdir. Embriyonik \u00f6nc\u00fcllerden kaynaklanan yerle\u015fik doku makrofajlar\u0131n\u0131n (\u00f6rn. alveolar makrofajlar) aksine, b\u00fcy\u00fck \u00f6l\u00e7\u00fcde kan ve kemik ili\u011fi \u00f6nc\u00fclerinden elde edilirler. CCR2 veya CX3CR1 gibi spesifik kemokin resept\u00f6rlerini eksprese ederler ve hasarl\u0131 h\u00fccre ve dokulardan sal\u0131nan kemokinlere yan\u0131t olarak dokularda birikirler (2-4). Doku hasar\u0131n\u0131n oldu\u011fu b\u00f6lgelerde lokalize olduktan sonra, bu makrofajlar, doku mikro\u00e7evresinde kar\u015f\u0131la\u015ft\u0131klar\u0131 medyat\u00f6rler taraf\u0131ndan aktive edilip de\u011fi\u015fen seviyelerde proinflamatuar\/sitotoksik (M1) veya anti-inflamatuar\/yara onar\u0131m\u0131 (M2) aktivitesi sergileyen alt s\u0131n\u0131flara d\u00f6n\u00fc\u015f\u00fcrler (5-7). Makrofajlar\u0131n M1 ve M2\u2019ye d\u00f6n\u00fc\u015f\u00fcm\u00fc s\u0131k\u0131 bir \u015fekilde kontrol edilen, spesifik sinyal yollar\u0131n\u0131, transkripsiyon fakt\u00f6rlerini ve posttranslasyonel d\u00fczenleyici ba\u011flant\u0131lar\u0131 i\u00e7eren bir s\u00fcre\u00e7tir (Tablo 1) (8, 9).<\/p>\n

Tablo 1:<\/strong> Makrofaj Aktivasyonu ve Polarizasyonunun Reg\u00fclat\u00f6rleri<\/p>\n

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Reg\u00fclat\u00f6r<\/strong><\/td>\nM1<\/strong><\/td>\nM2<\/strong><\/td>\n<\/tr>\n
Ekstrasel\u00fcler<\/strong><\/td>\n<\/td>\n<\/td>\n<\/tr>\n
Sitokinler<\/td>\nIL-1\u03b2, IL-6, IL-12,<\/p>\n

IL-23, IFN\u03b3,<\/p>\n

TNF\u03b1, MIP-1\u03b1<\/td>\n

IL-4, IL-13, IFN\u03b1,<\/p>\n

IL-1 RA<\/td>\n<\/tr>\n

B\u00fcy\u00fcme Fakt\u00f6rleri<\/td>\nGM-CSF<\/td>\nM-CSF, TGF\u03b2<\/td>\n<\/tr>\n
Eikozanoidler\/ biyoaktif lipidler<\/td>\nLTB4; 12-HETE,<\/p>\n

5- HETE<\/td>\n

Lipoxins, Resolvins,<\/p>\n

Thromboxane, PGI2<\/td>\n<\/tr>\n

TLR-4 agonistleri<\/td>\nDAMPs, PAMPs,<\/p>\n

LPS<\/td>\n

<\/td>\n<\/tr>\n
NOD agonistleri<\/td>\nPeptidoglycans<\/td>\n<\/td>\n<\/tr>\n
\u0130ntrasel\u00fcler<\/strong><\/td>\n<\/td>\n<\/td>\n<\/tr>\n
Oksidatif stres<\/td>\nROS, RNS<\/td>\n<\/td>\n<\/tr>\n
Metabolizma<\/td>\nAnaerobik glikoliz, glikoz al\u0131m\u0131, ya\u011f asidi sentezi<\/td>\nOksidatif glikoz metabolzimas\u0131, ya\u011f asidi oksidasyonu ve al\u0131m\u0131<\/td>\n<\/tr>\n
Sinyal yolaklar\u0131<\/td>\nAKT2, NOTCH \u00bd<\/td>\nAKT1, RTKs<\/td>\n<\/tr>\n
N\u00fckleer<\/strong><\/td>\n<\/td>\n<\/td>\n<\/tr>\n
Transkripsiyon fakt\u00f6rleri<\/td>\nNF\u03baB, AP-1,<\/p>\n

STAT1, IRF1,<\/p>\n

IRF5, IRF8,<\/p>\n

HIF-1\u03b1<\/td>\n

IRF4, KLF-4, c-myc,<\/p>\n

PPAR\u03b3, RXRs,<\/p>\n

LXRs, STAT3,<\/p>\n

STAT6, IRF3, IRF4,<\/p>\n

HIF2\u03b1<\/td>\n<\/tr>\n

Epigenetik<\/strong><\/td>\n<\/td>\n<\/td>\n<\/tr>\n
MikroRNA\u2019lar ve histon modifikasyonlar\u0131<\/td>\nmiRNA-155,<\/p>\n

miRNA-125b,<\/p>\n

miRNA-27b,<\/p>\n

miRNA-127,<\/p>\n

miRNA-223,<\/p>\n

miRNA-106a<\/p>\n

HDAC3<\/td>\n

miRNA-146a\/b<\/p>\n

miRNA-21,<\/p>\n

miRNA-511-3p,<\/p>\n

miRNA-124,<\/p>\n

miRNA-125a\/b,<\/p>\n

miRNA-24,<\/p>\n

miRNA-34a, let-7c<\/td>\n<\/tr>\n

DNA metilasyonu<\/td>\nDNMT3b, DNMT1<\/td>\nH3K27<\/p>\n

demethylase<\/p>\n

DNMT3a, DNMT3al<\/td>\n<\/tr>\n<\/tbody>\n<\/table><\/div>\n

 <\/p>\n

Proinflamatuar\/sitotoksik M1 makrofajlar; tek ba\u015f\u0131na interferon (IFN) \u03b3\u2018ya yan\u0131t olarak veya toll-like resept\u00f6r (TLR) 4 agonistleri (\u00f6rn., lipopolisakkarit [LPS]; y\u00fcksek mobilite grup i\u00e7eren protein ailesi \u00fcyesi olan HMGB1) ya da di\u011fer sitokinler (\u00f6rn., t\u00fcm\u00f6r nekroz fakt\u00f6r\u00fc [TNF] \u03b1 ve gran\u00fclosit makrofaj-koloni uyar\u0131c\u0131 fakt\u00f6r [GM-CSF]) ile birlikte geli\u015firler.<\/p>\n

Aktive M1 makrofajlar proinflamatuar sitokinleri (TNF \u03b1, interl\u00f6kin (IL)-1\u03b2, IL-6, IL-12, IL-15, IL-23) salg\u0131lay\u0131p, sitotoksik reaktif oksijen t\u00fcrlerini (ROS), reaktif nitrojen t\u00fcrlerini (RNS), proteolitik enzimleri ve biyoaktif lipidleri \u00fcretirler.<\/p>\n

M1 makrofajlar\u0131n\u0131n aktivitesi, inflamasyonu azaltan ve yara onar\u0131m\u0131n\u0131 ba\u015flatan M2 makrofajlar\u0131 ile dengelenmi\u015f durumdad\u0131r. Bu s\u00fcrece, anti-inflamatuar sitokinler (IL-4, IL-10, IL-13), baz\u0131 eikosanoidler (lipoksinler, resolvinler) ve b\u00fcy\u00fcme fakt\u00f6rleri (TGF\u03b2, vask\u00fcler endotelyal b\u00fcy\u00fcme fakt\u00f6r\u00fc [VEGF], epidermal b\u00fcy\u00fcme fakt\u00f6r\u00fc [EGF], ba\u011f dokusu b\u00fcy\u00fcme fakt\u00f6r\u00fc [CTGF], fibroblast b\u00fcy\u00fcme fakt\u00f6r\u00fc [FGF], trombosit kaynakl\u0131 b\u00fcy\u00fcme fakt\u00f6r\u00fc [PDGF]) arac\u0131l\u0131k eder.<\/p>\n

Akut akci\u011fer hasar\u0131 ve persistan inflamasyon, M1 makrofajlar\u0131n\u0131n uzun s\u00fcreli veya a\u015f\u0131r\u0131 bir imm\u00fcn yan\u0131ta ek olarak kusurlu M2 makrofaj arac\u0131l\u0131 doku onar\u0131m\u0131n\u0131 i\u00e7erirken, fibrozis ve kanser gibi kronik hastal\u0131klar\u0131n geli\u015fiminin, M2 makrofajlar\u0131n\u0131n alt gruplar\u0131n\u0131n a\u015f\u0131r\u0131 duyarl\u0131l\u0131klar\u0131n\u0131n bir sonucu oldu\u011fu d\u00fc\u015f\u00fcn\u00fclmektedir.<\/p>\n

M1 ve M2 makrofaj aktivasyonu olduk\u00e7a dinamik bir s\u00fcre\u00e7tir. Sinyal molek\u00fclleri, transkripsiyon fakt\u00f6rleri, epigenetik d\u00fczenleyiciler ve h\u00fccresel metabolizma patofizyolojik ko\u015fullara yan\u0131t olarak de\u011fi\u015ftik\u00e7e, makrofajlar fenotiplerini ve i\u015flevlerini kolayca de\u011fi\u015ftirirler. \u00d6rne\u011fin ba\u015flang\u0131\u00e7ta proinflamatuar ve sitotoksik reaksiyonlar\u0131 kolayla\u015ft\u0131ran h\u00fccreler, fenotipik de\u011fi\u015fime u\u011frayabilir ve b\u00f6ylece inflamasyon ve hasar\u0131n \u00e7\u00f6z\u00fcnmesinde rol oynayabilirler (10, 11). Sonu\u00e7 olarak, makrofajlar\u0131n, proinflamatuar bir M1’den bir anti-inflamatuar\/yara onar\u0131m\u0131 M2 fenotipine ge\u00e7i\u015fi, normal yara iyile\u015fmesi ve doku rejenerasyonunun ilerlemesi i\u00e7in \u00e7ok kritik bir durumdur. Hipoksinin de M1\u2019den M2\u2019ye fenotipik ge\u00e7i\u015fi bozdu\u011funa dair bulgular s\u00f6z konusudur (12).<\/p>\n

\"\"<\/p>\n

\u015eekil 1:<\/strong> Akut yaralanma ve fibroziste proinflamatuar\/sitotoksik\u00a0 (M1) ve anti-inflamatuar\/yara onar\u0131m\u0131 (M2) makrrofajlar. Olgunla\u015fmalar\u0131ndan pek \u00e7ok fakt\u00f6r sorumludur ve ind\u00fckleyen maddelere g\u00f6re birbirlerine ge\u00e7i\u015f g\u00f6sterebilirler.<\/p>\n

Akut Akci\u011fer Hasar\u0131 ve Onar\u0131m\u0131nda \u0130nflamatuar Makrofajlar<\/h1>\n

Akci\u011ferde akut hasar, endotelyal ve epitelyal bariyerlerin bozulmas\u0131 ile ili\u015fkilidir (13, 14). Proteinden zengin \u00f6dem s\u0131v\u0131s\u0131n\u0131n birikmesi, bron\u015f epitelinin d\u00f6k\u00fclmesi, nekrotik veya apoptotik Tip I h\u00fccrelerin g\u00f6r\u00fcn\u00fcm\u00fc, a\u015f\u0131nm\u0131\u015f bazal membran, geni\u015flemi\u015f \u00f6demat\u00f6z interstisyum, hasarl\u0131 endotelyal h\u00fccreler ve dokuda h\u00fccresel art\u0131klar\u0131n birikmesi ile karakterizedir. H\u00fccresel \u00f6zellikler, alveolar-kapiler membran b\u00fct\u00fcnl\u00fc\u011f\u00fcn\u00fcn kayb\u0131n\u0131, n\u00f6trofillerin ve makrofajlar\u0131n transepitelyal g\u00f6\u00e7\u00fcn\u00fc ve proinflamatuar\/sitotoksik proteinlerdeki art\u0131\u015flar\u0131 i\u00e7erir. Akut akci\u011fer hasar\u0131n\u0131n sonucu, toksik maddenin do\u011fas\u0131na, maruz kalma dozuna, s\u00fcresine ve spesifik doku konumuna ba\u011fl\u0131d\u0131r. Baz\u0131 maruziyetlerden sonra akci\u011fer yap\u0131s\u0131 ve fonksiyonu normale d\u00f6nerken, di\u011fer durumlarda, pulmoner vask\u00fcler y\u0131k\u0131ma, fibrozan alveolite, \u00e7oklu organ yetmezli\u011fine ve \u00f6l\u00fcme yol a\u00e7an hasar\u0131n kal\u0131c\u0131l\u0131\u011f\u0131 veya ilerleyicili\u011fi s\u00f6z konusudur.<\/p>\n

Akut akci\u011fer hasar\u0131nda makrofajlar\u0131n rol\u00fc oldu\u011funu \u00f6ne s\u00fcren ilk kan\u0131tlar, hayvanlar\u0131n \u00e7e\u015fitli pulmoner toksik maddelere (asbest, radyasyon, bleomisin, endotoksin, silika, vb.) maruz kalmas\u0131n\u0131n ard\u0131ndan dokuda bu h\u00fccrelerin say\u0131s\u0131n\u0131n artt\u0131\u011f\u0131na dair bulgulara dayanmaktad\u0131r (6, 15-17). Ek olarak, pulmoner toksik maddeler taraf\u0131ndan ind\u00fcklenen hasardan hemen sonra akci\u011ferde biriken makrofajlar\u0131n, proinflamatuar\/sitotoksik makrofajlar\u0131n prototipik g\u00f6stergeleri olan; artan boyut ve vakuolizasyon, ind\u00fcklenebilir nitrik oksit sentaz (iNOS) ve TNF \u03b1 ekspresyonu dahil morfolojik de\u011fi\u015fikliklerle kan\u0131tland\u0131\u011f\u0131 gibi, proinflamatuar bir M1 fenotipine do\u011fru aktive oldu\u011fu g\u00f6r\u00fclm\u00fc\u015ft\u00fcr. (6, 18-20).<\/p>\n

Akut akci\u011fer hasar\u0131nda proinflamatuar\/sitotoksik M1 makrofajlar\u0131n\u0131n rol\u00fcne ili\u015fkin do\u011frudan kan\u0131t, doku hasar\u0131n\u0131n makrofaj fonksiyonel durumu ile do\u011frudan ili\u015fkili oldu\u011fu bulgular\u0131ndan gelir. \u00c7e\u015fitli yakla\u015f\u0131mlar\u0131n kullan\u0131ld\u0131\u011f\u0131 bir dizi deneysel modelde (\u00f6rne\u011fin, farmakolojik, genetik veya makrofaj eksikli\u011fi olan fareler), makrofajlar\u0131 bask\u0131layarak veya azaltarak pulmoner hasar\u0131n d\u00fczeldi\u011fi veya \u00f6nlendi\u011fi g\u00f6sterilmi\u015ftir. \u00d6rne\u011fin, yap\u0131lan baz\u0131 \u00e7al\u0131\u015fmalarda M1 makrofaj sitotoksik\/proinflamatuar aktivite, anti-inflamatuar steroidler ile bloke edildi\u011finde, ozon, silika, bleomisin, hardal gaz\u0131, endotoksin, oleik asit veya hidrojen s\u00fclf\u00fcr\u00fcn neden oldu\u011fu akci\u011fer hasar\u0131n\u0131n azald\u0131\u011f\u0131 g\u00f6r\u00fclm\u00fc\u015ft\u00fcr (6, 21-24). Benzer \u015fekilde, M1 makrofaj aktivasyonunu engelleyen gadolinyum klor\u00fcr ya da inflamatuar makrofajlar\u0131n say\u0131s\u0131n\u0131 azaltan klodronat lipozomlar\u0131 \u00f6n tedavi olarak uyguland\u0131\u011f\u0131nda akci\u011ferde makrofaj birikimi ve ard\u0131ndan geli\u015fen ozon, sigara duman\u0131, radyasyon ve silikan\u0131n toksik etkilerinin azald\u0131\u011f\u0131 g\u00f6r\u00fclm\u00fc\u015ft\u00fcr (6, 25-28).Yap\u0131lan ba\u015fka bir \u00e7al\u0131\u015fmada, bleomisin kaynakl\u0131 akut akci\u011fer hasar\u0131 ve iNOS ekspresyonu, M1 makrofajlar\u0131 olu\u015fturamayan CCR4 eksik farelerde g\u00f6r\u00fclmemi\u015ftir (29). Radyasyon, ozon ve bleomisine yan\u0131t olarak geli\u015fen toksisitede art\u0131\u015flar; homeostatik ko\u015fullar alt\u0131nda akci\u011fer proinflamatuar makrofaj aktivitesini bask\u0131lama i\u015flevi g\u00f6ren pulmoner kolektin, s\u00fcrfaktan protein D’den yoksun farelerde g\u00f6zlenmi\u015ftir (20, 30, 31).<\/p>\n

Akut hasar\u0131n \u00e7\u00f6z\u00fclmesi, normal akci\u011fer yap\u0131s\u0131na ve i\u015flevine d\u00f6n\u00fc\u015f, aktif ve koordineli bir s\u00fcre\u00e7tir. Kan\u0131tlar, proinflamatuar medyat\u00f6rlerin sal\u0131n\u0131m\u0131n\u0131 bask\u0131layan ve doku onar\u0131m s\u00fcre\u00e7lerini aktive eden kar\u015f\u0131 d\u00fczenleyici mekanizmalar\u0131 uyaran M2 makrofajlar\u0131n\u0131n b\u00fcy\u00fck \u00f6l\u00e7\u00fcde bu s\u00fcre\u00e7lere arac\u0131l\u0131k etti\u011fini g\u00f6stermektedir. Hayvanlar\u0131n ozon, hardal gaz\u0131, bleomisin, radyasyon, endotoksin, sigara duman\u0131 ve asbeste maruz kalmas\u0131n\u0131n ard\u0131ndan akci\u011ferde anti-inflamatuar\/yara onar\u0131m\u0131 M2 makrofajlar\u0131n\u0131n artt\u0131\u011f\u0131 bildirilmi\u015ftir (6, 7, 20, 32, 33). Ancak ortaya \u00e7\u0131kmalar\u0131, M1 makrofajlar\u0131na k\u0131yasla daha ge\u00e7 olmaktad\u0131r.<\/p>\n

Ozon, endotoksin, hardal gaz\u0131, dizel egzozu, asbest, silika veya hiperoksiye maruz kalmay\u0131 takiben akci\u011ferdeki M2 makrofajlar\u0131ndaki art\u0131\u015flar, IL-4, IL-10 ve IL-13’\u00fcn yukar\u0131 reg\u00fclasyonu ile ili\u015fkilidir (5, 6, 33). Bu sitokinler, proinflamatuar\/sitotoksik medyat\u00f6rlerin makrofaj \u00fcretimini azalt\u0131r ve h\u00fccre d\u0131\u015f\u0131 matriks proteinlerinin ve yara iyile\u015fmesinde \u00f6nemli olan b\u00fcy\u00fcme fakt\u00f6rlerinin olu\u015fumunu uyar\u0131r (3, 4). \u00d6zellikle, M2 makrofaj geli\u015fimi i\u00e7in anahtar olan IL-13’\u00fcn uygulanmas\u0131, fareleri \u00f6l\u00fcmc\u00fcl endotoksemiden korurken, anti-IL-13 antikorlar\u0131, bu farelerin hayatta kalmas\u0131n\u0131 \u00f6nemli \u00f6l\u00e7\u00fcde azalt\u0131r (34).<\/p>\n

\u0130nflamatuar Makrofajlar ve Pulmoner Fibrozis<\/h1>\n

Kronik pulmoner fibrozis, kollajen ve di\u011fer h\u00fccre d\u0131\u015f\u0131 matriks bile\u015fenlerinin a\u015f\u0131r\u0131 birikiminin bir sonucu olarak ortaya \u00e7\u0131kan akci\u011fer yap\u0131s\u0131n\u0131n geri d\u00f6n\u00fc\u015f\u00fcms\u00fcz y\u0131k\u0131m\u0131 ve remodelling ile karakterize bir dizi hastal\u0131\u011f\u0131 ifade eder. Bu, solunum yollar\u0131nda skar doku geli\u015fimine ve nefes almada zorlu\u011fa yol a\u00e7ar. Kan\u0131tlar, d\u00fczensiz yara onar\u0131m\u0131n\u0131n pulmoner fibrozise katk\u0131da bulunan kilit bir fakt\u00f6r oldu\u011funu ve bunun, en az\u0131ndan k\u0131smen, uzun s\u00fcreli inflamasyon veya pn\u00f6monit sonras\u0131 M1 ve M2 makrofajlar\u0131n\u0131n aras\u0131ndaki dengesizli\u011fe ba\u011fl\u0131 oldu\u011funu g\u00f6stermektedir (35-37). Bu dengesizlik, skar dokunun \u00e7\u00f6z\u00fcnmesini ve matriksin par\u00e7alanmas\u0131n\u0131 destekleyen, M1 makrofajlar taraf\u0131ndan \u00fcretilen anti-fibrotik sitokinler (CXCL10) ve MMP’lerin azalmas\u0131 ve fibroproliferatif doku remodellingini ind\u00fckleyen, M2 makrofajlar taraf\u0131ndan sal\u0131nan profibrotik mediat\u00f6rlerin (TGF \u03b2,CTG F) a\u015f\u0131r\u0131 sal\u0131n\u0131m\u0131 ile ili\u015fkilidir. Fibrotik doku alanlar\u0131ndaki M2 makrofajlar\u0131ndaki art\u0131\u015flar, idiyopatik pulmoner fibrozis, KOAH ve kistik fibrozlu hastalar\u0131n akci\u011ferlerinde kaydedilmi\u015ftir; dahas\u0131, dokudaki bu h\u00fccrelerin say\u0131s\u0131, k\u00f6t\u00fcle\u015fen bir prognoz ile do\u011frudan ili\u015fkilidir.<\/p>\n

Hem insanlarda hem de kemirgenlerde fibrogenez s\u0131ras\u0131nda akci\u011ferde biriken M2 makrofajlar\u0131, fibroblast proliferasyonunu ve kollajen sentezini uyaran bir dizi \u00f6nemli profibrotik medyat\u00f6r\u00fcn (TGF \u03b2, CTG F ve CCL 18) ana kayna\u011f\u0131 olarak tan\u0131mlanm\u0131\u015ft\u0131r (38, 39). M2 makrofajlar\u0131n\u0131n ayr\u0131ca TNF \u03b1, IL-1, IL-10, IL-13, IL-33, trombosit kaynakl\u0131 b\u00fcy\u00fcme fakt\u00f6r\u00fc (PDG F), fibroblast b\u00fcy\u00fcme fakt\u00f6r\u00fc (FGF) ve fibronektin sal\u0131n\u0131m\u0131 yoluyla fibrozu artt\u0131rd\u0131\u011f\u0131 d\u00fc\u015f\u00fcn\u00fclmektedir ki bu mediat\u00f6rlerin fibrotik akci\u011fer hastal\u0131\u011f\u0131 olan insanlarda ve hayvanlarda artt\u0131\u011f\u0131 g\u00f6sterilmi\u015ftir (3, 4). Pulmoner fibroz geli\u015fiminde hiperaktif M2 makrofajlar\u0131n\u0131n rol\u00fcn\u00fc destekleyen en g\u00fc\u00e7l\u00fc kan\u0131t, fibrojenik toksik maddelere (\u00f6rn. bleomisin, radyasyon, silika) yan\u0131t\u0131n, IL-10 veya IL-13’\u00fc a\u015f\u0131r\u0131 eksprese eden hayvanlarda veya M2 makrofaj aktivasyonunu kolayla\u015ft\u0131ran IL-33’\u00fcn egzojen uygulamas\u0131yla \u015fiddetlendi\u011fine dair bulgulardan gelir (6, 8, 40). Aksine M-CSF’si olmayan veya M2 makrofajlar\u0131n\u0131 t\u00fcketen klodronat lipozomlar\u0131 ya da anti-CSF1R antikoru ile tedavi edilen hayvanlarda kollajen \u00fcretimi ve fibroz azal\u0131r (41-43).<\/p>\n

Akut Akci\u011fer Hasar\u0131 ve Fibroziste Yerle\u015fik Alveolar Makrofajlar<\/h1>\n

Makrofajlar\u0131n fenotipik ve i\u015flevsel olarak farkl\u0131 alt pop\u00fclasyonlar\u0131, sa\u011fl\u0131kl\u0131 bireylerin ve deney hayvanlar\u0131n\u0131n akci\u011ferleri boyunca lokalizedir; bu yerle\u015fik doku makrofajlar\u0131 alveolar makrofajlar, interstisyel makrofajlar, plevral makrofajlar, intravask\u00fcler makrofajlar ve hava yolu makrofajlar\u0131 olarak tan\u0131mlanm\u0131\u015ft\u0131r (6). En b\u00fcy\u00fck ve en geli\u015fmi\u015f olanlar\u0131, s\u00fcrfaktan\u0131n geri d\u00f6n\u00fc\u015f\u00fcm\u00fcnde kilit rol oynayan alveolar makrofajlard\u0131r. Yerle\u015fik alveolar makrofajlar ayr\u0131ca, patojenlere ve solunan toksik maddelere yan\u0131t vermek i\u00e7in stratejik olarak yerle\u015ftirilmi\u015f pulmoner ba\u011f\u0131\u015f\u0131kl\u0131k savunmas\u0131n\u0131n merkezindedir. Di\u011fer yerle\u015fik makrofajlar gibi, homeostaz\u0131 sa\u011flama, hasara ve enfeksiyona kar\u015f\u0131 koruma rollerinin anahtar\u0131 olan M2-benzeri fenotipe sahiptirler (36). Sa\u011fl\u0131kl\u0131 akci\u011ferde, alveolar makrofajlar, alveolar epitelyum ve s\u00fcrfaktan protein D, CD200, IL-10, TGF \u03b2 ve bir transmembran glikoproteini MUC-1 gibi molek\u00fcller ile TLR4, CD200R gibi makrofaj resept\u00f6rleriyle etkile\u015fimleri ile kontroll\u00fc bir ortamda bulunurlar (35). Alveolar makrofaj-epitel temas\u0131ndaki bozukluklar, erken inflamatuar sinyalle\u015fmede kritik olay olarak kabul edilir (36). Yerle\u015fik alveolar makrofajlar\u0131n, zararl\u0131 uyaranlara kar\u015f\u0131 akut inflamatuar yan\u0131t\u0131 tetiklemede rol oynad\u0131\u011f\u0131 g\u00f6sterilmi\u015ftir.<\/p>\n

Zararl\u0131 uyaranlara maruziyeti takiben yerle\u015fik alveolar makrofaj aktivasyonu, inflamazomlar (\u00f6rn., NLRP3) yoluyla da meydana gelebilir. Bunlar, inflamasyonu tetikleyen IL-1 ve IL-18 sal\u0131n\u0131m\u0131na sebep olan kaspaz-1’i oligomerize ve aktive eden sitozolik multiprotein kompleksleridir. Steril inflamasyonda NLRP3 aktivasyonu, kristallerin (\u00f6rn., kolesterol, \u00fcrat), partik\u00fcllerin (\u00f6rn., silika, titanyum) veya nanomateryallerin (\u00f6rn., karbon nanot\u00fcpler) fagositozunu takiben meydana gelir (44, 45). \u00c7al\u0131\u015fmalar, NLRP3 inflamazomunun ozon, titanyum nanopartik\u00fcller, asbest, silika ve partik\u00fcl madde taraf\u0131ndan ind\u00fcklenen akut akci\u011fer hasar\u0131na katk\u0131da bulundu\u011funu g\u00f6stermektedir (46, 47).<\/p>\n

Yerle\u015fik alveolar makrofajlardan sal\u0131nan inflamazom ve inflamazom ba\u011flant\u0131l\u0131 sitokinlerin ast\u0131m, KOAH ve fibrozis gibi kronik akci\u011fer hastal\u0131klar\u0131n\u0131n geli\u015fiminde rol oynad\u0131\u011f\u0131n\u0131 g\u00f6steren veriler de mevcuttur (48). Bu g\u00f6z \u00f6n\u00fcne al\u0131nd\u0131\u011f\u0131nda, akut pulmoner fibrotik de\u011fi\u015fiklikler, idiyopatik pulmoner fibrozlu hastalarda ve ayr\u0131ca asbest kaynakl\u0131 fibrozda alveolar makrofajlarda artan IL-1\u03b2 ve IL-18 seviyeleri ile ili\u015fkilidir (46). Sigara duman\u0131, asbest, silika, karbon nanot\u00fcpler, nanomateryaller ve bleomisin gibi fibrojenik toksik maddelerin t\u00fcm\u00fcn\u00fcn, IL-1\u03b2 salg\u0131lanmas\u0131na yol a\u00e7an alveolar yerle\u015fik makrofajlar\u0131nda NLRP3 inflamazomunu do\u011frudan aktive etti\u011fi g\u00f6sterilmi\u015ftir (46). IL-1\u03b2, epitel h\u00fccrelerinin ve fibroblastlar\u0131n kollajen \u00fcreten miyofibroblastlara d\u00f6n\u00fc\u015f\u00fcm\u00fcn\u00fc, \u00e7o\u011falmas\u0131n\u0131 ve aktivasyonunu tetikleyen TGF \u03b2 sal\u0131n\u0131m\u0131n\u0131 uyar\u0131r (49). Son \u00e7al\u0131\u015fmalar, bleomisin kaynakl\u0131 fibrozun ba\u015flang\u0131c\u0131ndan hemen \u00f6nce, yerle\u015fik makrofajlar\u0131n t\u00fckenmesinin patolojinin \u015fiddetini de\u011fi\u015ftirmedi\u011fini g\u00f6stermi\u015ftir (50). Bu veriler, yerle\u015fik makrofajlar\u0131n fibrogeneze katk\u0131s\u0131n\u0131n, hastal\u0131k s\u00fcrecinin erken evrelerinde daha belirgin oldu\u011funu g\u00f6stermektedir.<\/p>\n

Yerle\u015fik alveolar makrofajlar\u0131n toksik maruziyet veya enfeksiyonlardan sonra d\u00fczenlenmi\u015f h\u00fccre \u00f6l\u00fcm\u00fcne (piroptoz, nekroptoz, METosis) maruz kalmaya e\u011filimli olduklar\u0131n\u0131 g\u00f6steren \u00e7al\u0131\u015fmalar s\u00f6z konusudur (51). Bu s\u0131k\u0131 bir \u015fekilde d\u00fczenlenmi\u015f h\u00fccre \u00f6l\u00fcm\u00fc yollar\u0131, y\u00fcksek oranda inflamatuar ve imm\u00fcnojeniktir. TLR4 ligandlar\u0131 (\u00f6rne\u011fin, LPS, HMGB1), RAGE aktivasyonu, IL-1\u03b2 ve TNF \u03b1 gibi inflamatuarlar ve sitokinler dahil olmak \u00fczere \u00e7e\u015fitli fakt\u00f6rler taraf\u0131ndan ind\u00fcklenebilirler (52). Yerle\u015fik alveolar makrofaj \u00f6l\u00fcm\u00fcn\u00fcn, dola\u015f\u0131mdaki monositlerin ve n\u00f6trofillerin hasarl\u0131 alana ve enfeksiyon b\u00f6lgelerine g\u00f6\u00e7\u00fcn\u00fc ve inflamatuar yan\u0131tlar\u0131 ba\u015flatmada anahtar oldu\u011fu d\u00fc\u015f\u00fcn\u00fclmektedir (53). Makrofaj \u00f6l\u00fcm\u00fc ve inflamasyonun kar\u015f\u0131l\u0131kl\u0131 olarak birbirini etkiledi\u011fi ve inflamasyonun artmas\u0131na neden olan bir oto-amplifikasyon d\u00f6ng\u00fcs\u00fc olu\u015fturdu\u011funa dair artan \u00e7al\u0131\u015fmalar s\u00f6z konusudur (54).<\/p>\n

Sonu\u00e7<\/h1>\n

Solunum yolu d\u0131\u015f ortamla do\u011frudan temas halinde oldu\u011fundan, solunan patojenlerin ve toksik maddelerin olumsuz etkilerine kar\u015f\u0131 \u00f6zellikle hassast\u0131r. Makrofajlar, bu zararl\u0131 ksenobiyotiklere kar\u015f\u0131 temel bir konak\u00e7\u0131 ba\u011f\u0131\u015f\u0131kl\u0131k savunma mekanizmas\u0131n\u0131 temsil eder. Ancak, etkili konak savunmas\u0131, yara iyile\u015fmesi ve homeostaz\u0131n tekrar sa\u011flanmas\u0131, makrofajlar\u0131n aktivitesinin dikkatli bir \u015fekilde kontrol edilmesini gerektirir. Kontrol mekanizmalar\u0131n yoklu\u011funda, makrofajlar a\u015f\u0131r\u0131 aktive olur ve bu da akut hasar\u0131n alevlenmesine veya kronik akci\u011fer hastal\u0131\u011f\u0131n\u0131n geli\u015fmesine neden olur. Bu, makrofajlar\u0131n tek bir homojen h\u00fccre pop\u00fclasyonundan olu\u015fmamas\u0131; daha ziyade benzersiz fenotipik ve fonksiyonel \u00f6zelliklere sahip alt pop\u00fclasyonlardan olu\u015ftu\u011fu ger\u00e7e\u011fi ile daha da karma\u015f\u0131k bir hal al\u0131r. Ayr\u0131ca, fenotiplerini h\u0131zla de\u011fi\u015ftirme kapasitesine de sahiptirler. Kar\u0131\u015f\u0131k bir pop\u00fclasyon i\u00e7inde tek tek makrofajlar\u0131n tan\u0131mlanmas\u0131na ve karakterizasyonuna izin veren yakla\u015f\u0131mlar\u0131n (tek h\u00fccreli RNAseq veya western blotlama) kullan\u0131m\u0131 ve ayr\u0131ca patojenik s\u00fcre\u00e7 s\u0131ras\u0131nda farkl\u0131 zamanlarda makrofajlar\u0131n ko\u015fullu y\u0131k\u0131m\u0131na izin veren yakla\u015f\u0131mlar\u0131n (Cre-lox)\u00a0 kullan\u0131m\u0131, bu h\u00fccrelerin akci\u011fer hastal\u0131\u011f\u0131n\u0131n geli\u015fimindeki rol\u00fcn\u00fc de\u011ferlendirmede \u00f6zellikle de\u011ferli olacakt\u0131r.<\/p>\n

Toksik maddelere yan\u0131t olarak akci\u011fer makrofajlar\u0131 ve epitel h\u00fccreleri aras\u0131ndaki etkile\u015fimlere odaklanmak da \u00f6nemlidir. Bu ba\u011flamda, hiperoksi veya toksik madde kaynakl\u0131 akci\u011fer hasar\u0131n\u0131 takiben olu\u015fan epitelyal h\u00fccre kaynakl\u0131 mikrovezik\u00fcllerin makrofajlar\u0131n proinflamatuar aktivasyonunda anahtar oldu\u011funu g\u00f6steren son \u00e7al\u0131\u015fmalar, yeni bir ara\u015ft\u0131rma alan\u0131 olu\u015fturmaktad\u0131r. Gelecekteki ara\u015ft\u0131rmalar i\u00e7in ba\u015fka bir ilgi alan\u0131, pulmoner toksik maddelere kar\u015f\u0131 patojenik yan\u0131tta ROS, proteazlar ve TNF \u03b1 ‘ya yan\u0131t olarak inflamatuar makrofajlardan sal\u0131nan h\u00fccre d\u0131\u015f\u0131 tuzaklar\u0131n (DNA ve proteinlerden olu\u015fan lifler) rol\u00fcd\u00fcr. Makrofaj aktivasyonunu d\u00fczenleyen yolaklar\u0131 ve salg\u0131lad\u0131klar\u0131 mediyat\u00f6rleri anlamak, akci\u011fer hastal\u0131klar\u0131n\u0131n ve solunan toksik maddelerin neden oldu\u011fu hastal\u0131klar\u0131n tedavisinde daha etkili yakla\u015f\u0131mlara yol a\u00e7abilir.<\/p>\n

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    Hasar b\u00f6lgelerinde biriken makrofajlar\u0131n, ksenobiyotiklere verilen patojenik yan\u0131tta rol oynad\u0131\u011f\u0131 g\u00f6r\u00fc\u015f\u00fc 100 y\u0131ldan daha uzun bir s\u00fcre \u00f6nce Eli Metchnikoff taraf\u0131ndan ortaya…<\/p>\n","protected":false},"author":3162,"featured_media":3499,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"_lmt_disableupdate":"","_lmt_disable":"","footnotes":""},"categories":[1,10014,10019],"tags":[10035,10036,10022,406],"class_list":["post-3497","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-genel","category-akademik-blog-yazisi","category-tft","tag-makrofaj","tag-pulmoner","tag-tft","tag-toksikoloji"],"acf":[],"_links":{"self":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts\/3497","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/users\/3162"}],"replies":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/comments?post=3497"}],"version-history":[{"count":0,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts\/3497\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/media\/3499"}],"wp:attachment":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/media?parent=3497"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/categories?post=3497"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/tags?post=3497"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}