Ubushakashatsi bwahuje methylene blue n'ihumeka ry'uturemangingo

Amaraso y'umuntu yakuwemo fiburine, ashyuhijwe kuri 37 °C mu gihe cy'amasaha atatu, akoresha hafi bibiri ku ijana bya ogisijeni arimo. Iyo hongewemo methylene blue nke mbere yo kuyashyira muri ubwo bushyuhe, ayo maraso akoresha hafi mirongo itandatu na bitanu ku ijana. Nta cyahindutse ku turemangingo. Igisubizo cy'amazi twarimo ni cyo cyonyine cyahindutse.

Uwo mubare ukomoka mu nyandiko yasohowe mu 1928 na George Harrop na E. S. Guzman Barron bo muri Johns Hopkins, kandi ni wo nkomoko y'imvugo ikunze gusubirwamo ivuga ko methylene blue ituma ihumeka ry'uturemangingo rirushaho kugenda neza. Iyo mvugo si ikinyoma, ariko icyo isobanura kiragufi kurusha uko yumvikana.

Icyo umubare uri mu mbonerahamwe upima koko

Icyapimwaga ku musozo ni ogisijeni yakoreshejwe, bikagenwa hifashishijwe isesengura rya gaze. Harrop na Barron bayungururaga amaraso akimara gukurwa mu mubiri bakoresheje ipamba kuri 10 °C kugira ngo bakuremo uturemangingo twera, bakuzuza icyitegererezo ogisijeni kugeza kitagishobora kwakira indi, bakakigabanya, bakongeramo irangi mu gice kimwe, maze bagasesengura ibice byombi nyuma yo kubishyira mu bushyuhe bwagenwe. Umubare w'uturemangingo twera ntiwakundaga kurenga hafi igihumbi kuri milimetero kibe. Ikoreshwa rya ogisijeni ryatangazwaga nk'umugabane wa ogisijeni yari iri mu cyitegererezo mbere, wari wabuze.

Banapimye diyogiside ya karubone, ariko aho uburyo bwo gupima bwabateje ingorane. Amaraso yakuwemo fiburine yarekura diyogiside ya karubone igera kuri milimole ebyiri kuri 100 mL mu isaha ya mbere yo gushyirwa mu bushyuhe bwagenwe, kubera impamvu zidafitanye isano n'imyitwarire ya shimi yigwaga. Bityo, ibipimo by'igereranya ry'ihumeka byakuwe ku maraso yose ntibyashoboraga gukoreshwa. Uturemangingo twogejwe dushyirwa mu gisubizo cya Locke ni two twonyine twatanze imibare yashoboraga gusobanurwa, kandi iyo mibare yari hagati ya 0.73 na 0.80, haba harimo irangi cyangwa ritarimo.

Ibyo si amakuru y'ubusabusa. Muri izi nyandiko, “ihumeka” risobanura ihanahana rya gaze mu gikoresho gifunze. Itandukaniro hagati yo gukoresha ogisijeni no gutanga ingufu zikoreshwa risuzumwa ukwaryo mu nyandiko ivuga icyo ikoreshwa rya ogisijeni rikubwira n'icyo ritakubwira kuri ATP.

Irangi ryongereye byinshi aho uturemangingo twahumekaga gake cyane

Uturemangingo dutukura tw'amaraso y'inyamabere twakuze neza dukoresha ogisijeni nke cyane, hafi ku buryo itapimika. Uturemangingo dutukura tw'amaraso y'inyoni dufite intima two turayikoresha. Harrop na Barron bakoze ubushakashatsi kuri twombi, kandi iryo tandukaniro ni ryo shingiro ry'ibyo bashyigikiraga.

Mu byitegererezo by'inyamabere, irangi ryatumye ikoreshwa rya ogisijeni ryiyongera inshuro makumyabiri kugeza kuri mirongo itanu. Mu maraso y'ingagi, uturemangingo twayo twari dusanzwe duhumeka, ntiryigeze rirenza gukuba kabiri umuvuduko w'ihumeka. Uko ihumeka ryo ku ntangiriro ryabaga rinini, ni ko irangi ryongeragaho bike.

Uko kugenda guhinduka kunagaragara mu bwoko bumwe bw'ibinyabuzima. Icyitegererezo cy'amaraso y'umuntu wari urwaye polycythemia vera, cyarimo uturemangingo tutarakura neza, cyakoresheje 11.3 ku ijana bya ogisijeni yacyo nta rangi ririmo, ugereranyije na 2.8 ku ijana by'uturemangingo twogejwe twakuwe ku muntu muzima watanze amaraso. Irangi ryazamuye uwo mubare kugera kuri 63.4 ku ijana gusa, ryihutisha ikoreshwa inshuro esheshatu, mu gihe uturemangingo dusanzwe twaryihutishaga hafi inshuro mirongo itatu. Irangi ryatumaga uturemangingo twakuze neza twegera imyitwarire y'ututarakura neza, ari na cyo abanditsi bavugaga ko ryakoraga.

Siyanide yagombye kuba yarabihagaritse

Siyanide yari izwiho guhagarika okisidasiyo mu turemangingo. Harrop na Barron barayongeyeho nubwo bari babizi, bayishyirana n'irangi.

Ibyavuye ku maraso y'inka bigaragaza neza uko byagenze. Mu masaha atatu, ogisijeni yarimo yagabanutse iva kuri 22.61 igera kuri 22.03 by'ingano kuri ijana, nta kintu cyongeweho. Hari methylene blue, yagabanutse igera kuri 12.84. Hari methylene blue na siyanide ya potasiyumu ifite ubukomere bwa kimwe mu bihumbi bitanu bya molar, yagabanutse igera kuri 12.74. Ingaruka y'irangi ntiyahindutse mu buryo bugaragara.

Igishushanyo: iyandikwa rikomeza ry'ihumeka ku rugero ruto ry'uturemangingo dutukura tw'amaraso y'umuntu. Umwambi werekana aho methylene blue yongerewe. Mbere yaho, umurongo uri hafi gutambika; nyuma yaho uzamuka ubudatuza. Cyakuwe muri Harrop na Barron, Journal of Experimental Medicine 48:207–223 (1928), PMID 19869478.

Banzuye ko irangi ryakoraga nk'iritwara ogisijeni, “ritanga ikinyabutabire cyabuze mu turemangingo dutukura tw'amaraso y'inyamabere twakuze neza tudafite intima.” Nyuma y'imyaka ibiri, Michaelis na Salomon bo muri Rockefeller Institute bashyize iryo tandukaniro ry'ibitekerezo mu buryo bwakomeje gukoreshwa. Ingaruka y'irangi yashoboraga kuba “umutungo w'irangi utunguranye,” cyangwa irangi rikaba “icyitegererezo cy'ikinyabutabire kitazwi kiri mu binyabuzima.” Ayo mahitamo yombi ntararangizwa. Icyahindutse ni uko ubu uturemangingo dushobora gusobanurwa neza kurushaho.

Umushongi wakuwe mu mwijima wakoze ikintu kimwe

Michaelis na Salomon berekanye ko imishongi y'ingingo ikuwe hifashishijwe amazi akonje itera ukwiyongera nk'uko. Umwijima w'imbeba ni wo wagize ingaruka ikomeye kurusha iyindi, ukurikirwa n'impyiko, urwagashya n'ibya. Ubwonko, imikaya na serumu y'amaraso byagize ingaruka nke cyangwa ntibyayigira.

Nyuma bapimye uwo mushongi hari monogiside ya karubone. Ihumeka ryatewe n'umushongi cyangwa n'irangi ntiryahindutse mu ruvange rwa monogiside ya karubone ingana na 98 ku ijana na ogisijeni ingana na 2 ku ijana. Urwo ruvange rwa gaze rwahagaritse ihumeka ry'umusemburo n'iry'uturemangingo dutukura tw'amaraso y'inkoko dufite intima ku rugero rwa hafi 60 kugeza kuri 80 ku ijana, bihuye n'ibisobanuro bya Warburg ku nzima y'ihumeka ibangamirwa na monogiside ya karubone. Bityo, icyo kinyabutabire cyo mu ngirangingo kitari cyamenyekana nticyari inzima ya Warburg.

Ibinyabutabire byinshi byakekwagaho byagiye bivanwa ku rutonde. Glutathione na cysteine biri mu miterere ya redugisiyo byateje gusa ikoreshwa rya ogisijeni ryari rikenewe kugira ngo byo ubwabyo bikorerwe okisidasiyo. Koenzima ya Harden na Young yaranzwe kuko imikaya ari yo iyifite ku bwinshi, nyamara ikagaragaza ingaruka iri hafi kuba ntoya kurusha izindi. Sitokorome ya Keilin, yari yarahawe izina imyaka mike mbere yaho, na yo yahuye n'uko kuvuguruzanya. Igitekerezo cyabo bwite cy'uko ikinyabutabire gikora cyaturukaga mu ntima y'akaremangingo, bavuze ko ari igitekerezo gusa.

Hari ibisabwa kugira ngo ingaruka igaragare

Uturemangingo twagombaga kuba tudangiritse. Isenyuka ry'uturemangingo dutukura tw'amaraso ryatewe n'amazi yatunganyijwe hifashishijwe kubira no gukonjesha umwuka wayo, cyangwa no gukonjeshwa inshuro nyinshi kugeza dukomeye, ryakuyeho igisubizo cyabaga ku rangi no ku mushongi. Iyo uturemangingo tumwe gusa twasenyukaga, icyo gisubizo cyagabanukaga hakurikijwe urugero rw'isenyuka.

Isukari na yo yari ikenewe. Glucose, fructose na sucrose byashyigikiraga ihumeka ryatewe n'irangi; mannitol ntiyabikoraga. Iyo nta sukari yabaga irimo, nta humeka na rito ryabaga, kandi irangi ryasaga n'iryangiza uturemangingo muri icyo gihe. Bityo, glucose yongeweho nyuma y'isaha imwe cyangwa ebyiri ntiyagaruraga ihumeka. Abanditsi bakekaga ko irangi ryakoraga okisidasiyo ku gice cy'imiterere akaremangingo kari gakeneye.

Umucyo wongeraga cyane ingaruka y'irangi, nubwo iyo ngaruka yanagaragaraga mu mwijima. Andi marangi ashobora gukorerwa redugisiyo yitwaraga mu buryo butandukanye: toluylene blue yageraga ku rugero rwa methylene blue cyangwa ikarurenga, mu gihe indigo disulfonate hafi nta cyo yakoraga. Nta sano isobanutse yabonetse hagati y'ubushobozi bw'irangi bwa okisidasiyo-redugisiyo n'ubunini bw'ingaruka yaryo. Abanditsi babisobanuye bashingiye ku bushobozi bwaryo bwo kunyura mu gihu cy'akaremangingo no ku burozi bwaryo.

Ingaruka yagendanaga n'isembura, atari ihumeka

Ubushakashatsi bwa Barron bwo mu 1930 bwavuye ku turemangingo twari mu bisubizo by'amazi bujya ku duce tw'ingirangingo twaciwe mu ngingo zisanzwe z'imbeba no mu bibyimba byatewe ahandi.

Mu ngirangingo zitagira gikolize ibaho hari ogisijeni, methylene blue nta cyo yakoze cyangwa yagabanyije gato ikoreshwa rya ogisijeni: mu mpyiko hafi 14 ku ijana, mu rwagashya hafi 14 ku ijana, mu mwijima hafi 5 ku ijana. Mu ngirangingo zikora isembura hari ogisijeni, yongereye ikoreshwa ryayo: mu mpindura hafi 8 ku ijana, mu bwonko hafi 13 ku ijana. Ukwiyongera mu bibyimba kwavuye kuri hafi 27 ku ijana muri kanseri y'ibere y'umuntu kugera ku kurenga 80 ku ijana muri sarcoma ya Rous y'inkoko, hafi bikurikije urugero rwa gikolize ibaho hari ogisijeni muri buri ngirangingo.

Igishushanyo: buri kadomo ni ubwoko bumwe bw'ingirangingo. Umurongo utambitse werekana gikolize ibaho hari ogisijeni; umurongo uhagaze werekana ihinduka ry'ikoreshwa rya ogisijeni nyuma ya methylene blue. Amakuru yakuwe muri Barron, Journal of Experimental Medicine 52:447–456 (1930), Imbonerahamwe 6, PMID 19869777.

Nyuma, igerageza rya siyanide ryatanze ishusho ihabanye n'iya mbere. Iyo ihumeka muri za ngirangingo zitari zabanje kugira igisubizo ryahagarikwaga na siyanide maze isembura rikigaragaza, irangi ryongeraga ikoreshwa rya ogisijeni na none: mu mpyiko hafi 59 ku ijana, mu mwijima hafi 19 ku ijana, mu mpindura hafi 286 ku ijana, mu bya hafi 200 ku ijana.

Barron yatanze igitekerezo cy'uko irangi ryashoboraga gukoreshwa mu gupima ubushobozi bw'akaremangingo cyangwa bw'ingirangingo bwo gukora isembura, maze asoza avuga ibishoboka: gukomeza korora ibisekuru byinshi by'uturemangingo tw'ikibyimba mu bikoresho birimo irangi byashoboraga kuzatuma imihindurire y'ibinyabutabire mu kibyimba iba nk'iyo mu ngirangingo zisanzwe burundu. Icyo cyari ikibazo cy'ubushakashatsi cyanditswe mu 1930. Si ikirego cy'uko hari ubuvuzi bukora.

Icyo ubwo bushakashatsi butashoboraga kuba bwarapimye

Mu 1928 no mu 1930, “ihumeka” ryasobanuraga ikoreshwa rya ogisijeni. Adenosine triphosphate yatangajwe bwa mbere mu 1929, kandi kwerekana ko mitokondiriya zatandukanijwe n'uturemangingo zikora esterifikesiyo ya fosifate mu gihe zihererekanya elegitoroni byabaye mu 1949. Nta nyandiko n'imwe ya mbere kuri methylene blue yashoboraga kuba yarapimye ikorwa ry'ingufu, kandi nta n'imwe yavugaga ko yabikoze.

Uturemangingo ni ikibazo cya kabiri. Uturemangingo dutukura tw'amaraso y'inyamabere twakuze neza ntiturimo mitokondiriya. Mu cyiciro cya retikulocyte, dukuramo mitokondiriya na ribozome binyuze mu kwisenya gutoranya ibice by'akaremangingo. Ni yo mpamvu akaremangingo gatukura kakuze neza kabeshwaho na gikolize kandi kakishingikiriza ku nzira yako ya fosifate ya pentose ahanini kugira ngo kabone NADPH aho kubona ATP. Mu bushakashatsi bwo mu 1928, nta ruhererekane rwo gutwara elegitoroni rwari ruhari ngo rusanwe. Icyakoreshaga ogisijeni icyo ari cyo cyose cyakoraga ikindi kintu.

Ubu icyo kindi kintu gisobanuwe ku rugero rwiza. Methylene blue yakira elegitoroni zituruka ku binyabutabire bitanga ubushobozi bwa redugisiyo mu turemangingo, igahinduka leucomethylene blue. Iyo na yo yongera gukorerwa okisidasiyo na ogisijeni iri mu buryo bwa molekile, bigasoza uruziga. Mu turemangingo dutukura tw'amaraso y'umuntu, flavin reductase ishingiye kuri NADPH n'inzima za disulfide reductase bifitanye isano na yo ni byo bikora icyiciro cya redugisiyo. Ubushakashatsi bwo mu 1976 bwakoresheje glucose yashyizweho ikimenyetso bwabonye ko irangi ritera ukwiyongera kw'imikorere y'inzira ya monofosifate ya hexose, ko ingaruka yaryo ku bukomere buke yashingiraga kuri oxyhemoglobin, kandi ko ubukomere bwinshi kurushaho, bwa 0.1 mM, bwabyaraga perogiside ya hidirojeni. Irangi ryakorewe redugisiyo rihuye na ogisijeni ribyara perogiside, ntabwo ribyara imiyoboro ya fosifate.

Muri mitokondiriya, uko ibintu bimeze kuracyaganirwaho cyane kurusha uko incamake zikunzwe zibivuga. Icyerekezo kimwe cy'ubushakashatsi kivuga ko irangi rifata elegitoroni mu gice cya kompleksi I rikaziha sitokorome c. Ikindi cyabonye ko muri mitokondiriya z'ubwonko bw'imbeba ridashobora kugarura ihumeka nyuma yo guhagarikwa na antimycin, ahubwo gishyira aho elegitoroni zakirwa ku mwanya ubiquinol ifatiraho muri kompleksi III. Icya gatatu cyabonye ko ubukomere buke bwongeraga ikoreshwa rya ogisijeni mu gihe cyo kuruhuka, ariko ihumeka ryatewe na ADP ntirihinduke. Imvugo ibivuga mu buryo butaziguye kurusha izindi ni uko ikoreshwa rya ogisijeni ritewe na methylene blue ridashingira na gato ku ikorwa ry'imiyoboro ya fosifate rijyana na okisidasiyo: ryakomeje igihe uruhererekane rw'ihumeka rwari rwahagaritswe, no mu byitegererezo bitarufite.

Hari n'ibipimo bitaziguye by'itandukaniro hagati y'izo ngano zombi. Muri mitokondiriya zatandukanijwe n'umwijima w'imbeba, kongera ubukomere bw'irangi byagabanyije ibipimo by'igereranya ry'igenzura ry'ihumeka kandi bitera kubyimba. Abanditsi babisobanuye nk'ugutandukana kw'ikorwa ry'imiyoboro ya fosifate na okisidasiyo. Mu mwijima w'imbeba wanyuzwagamo amazi yabugenewe, methylene blue yongereye ikoreshwa rya ogisijeni mu gihe igipimo cya ATP ugereranyije na ADP cyagabanukaga.

Amakuru yo mu buvuzi atanga ubutumwa bumwe. Methemoglobinemia ivurwa hakoreshejwe hafi miligarama imwe kugeza kuri ebyiri za methylene blue kuri buri kirogirama, zitanzwe mu mutsi, binyuze mu nzira ya redugisiyo ishingiye kuri NADPH, kandi ingano nini kurushaho zitera iyo ndwara iri kuvurwa. Isesengura rimwe rivuga ko ingaruka yo kurwanya uburozi iba nini kurusha izindi mu turemangingo dutukura tw'amaraso tudangiritse, kandi ikagabanuka iyo hari isenyuka ryatwo. Ibyo ni ibyabonetse mu 1930 ku isenyuka ry'uturemangingo dutukura byongeye kugaragara nyuma y'imyaka mirongo irindwi n'itatu, noneho mu bitaro. Ikinyabutabire gifite ingaruka z'ingirakamaro n'izangiza ku mpande zitandukanye z'urugero runaka rw'ingano si ikinyabutabire ingano yacyo ikwiye kugenwa hakurikijwe igipimo cy'ikoreshwa rya ogisijeni.

Impamvu icyiciro cy'umusaruro gifite umwanya muri iki kiganiro

Harrop na Barron babonye ikintu gikwiye kongera gusomwa. Methylene blue ubwayo itanga umurongo mu gikoresho cyo kureba urusobe rw'umucyo, hagati y'imirongo ibiri iranga methemoglobin, “ibyo bikaba byatera kwitiranya mu buryo bworoshye iyo birebwe hutihuti.” Irangi rishobora kwigana ikinyabutabire kirimo gushakishwa.

Icyo kibazo kinafite uruhande rwa shimi. Phenothiazine ifitanye isano na yo, iboneka nk'ikigize gito, ifite imyitwarire yayo ya okisidasiyo-redugisiyo, ubushobozi bwayo bwo kunyura mu gihu cy'akaremangingo n'uburozi bwayo. Urugero rumwe rwanditswe rugaragaza neza uburemere bw'ikibazo: mu bushakashatsi ku kongeramo iyode muri methylene blue, ibyitegererezo byarimo hafi 7 kugeza kuri 8 ku ijana bya Azure B byabyaye ahanini Azure B yongewemo iyode. Bityo, umwanda aho kuba methylene blue ni wo wagize uruhare rwiganje mu myitwarire ya shimi.

Umuntu wese ukoresha methylene blue nk'ikinyabutabire cyo mu bushakashatsi, muri laboratwari, aho basigira irangi ku byitegererezo, cyangwa mu kigega kirimo amafi, aba akoresha ikigize kitasobanuwe neza keretse icyiciro cy'umusaruro cyarakorewe isuzuma riranga ibikirimo. Ibinyabutabire bifitanye isano na yo, umwirondoro wayo, imyanda y'ibinyabutabire shingiro, ibisigazwa by'ibishongesha n'ibisigazwa nyuma yo gutwikwa ni ibice by'igerageza, si impapuro ziriherekeza gusa. Blupreme ibona methylene blue yayo ku ruganda rukora imiti kandi igatangaza icyemezo cyuzuye cy'isesengura, igapima ibisabwa byose bya USP aho gupima ibyuma biremereye gusa; amabwiriza yo gusoma icyemezo cy'isesengura n'icyo kwitwa icyiciro cya USP kwemeza n'icyo kutemeza bisobanura uko wagenzura inyandiko ukayigereranya n'ibivugwa ku gicuruzwa.

Umubare wari wo

Ubushakashatsi bwo mu 1928 no mu 1930 bwakozwe bwitondewe, kandi icy'ingenzi bwabonye cyakomeje kwemezwa: irangi rishobora gukorerwa redugisiyo rishobora gutuma akaremangingo gahumeka gake cyane gakoresha ogisijeni inshuro nyinshi kurusha umuvuduko wako mu gihe cyo kuruhuka, katanyuze mu cyiciro siyanide ihagarika.

Ikosa rigaragara nyuma, iyo “ihumeka” risomwe mu gisobanuro cyaryo cy'ubu. Igipimo cy'ihanahana rya gaze kikubwira ko elegitoroni zageze kuri ogisijeni. Ntikikubwira ko hari izakoreshejwe mu gukora ATP, kandi mu karemangingo kadafite mitokondiriya, intera iri hagati y'izo mvugo zombi iba nini bishoboka. Incamake yagutse y'ibyo methylene blue ikora mu turemangingo ishyira iryo tandukaniro mu rwego rwagutse, naho amateka y'icyo kinyabutabire kuva ku irangi kugera ku muti asobanura uko irangi ry'imyenda ryageze muri ubwo bushakashatsi bwa mbere.