Mayesero amene anagwirizanitsa methylene blue ndi kupuma kwa maselo

Magazi a munthu amene achotsedwa fibrin, akasungidwa pa 37 °C kwa maola atatu, amagwiritsa ntchito pafupifupi magawo awiri pa zana a oxygen amene ali nawo. Mukawonjezera methylene blue pang'ono musanawasunge motero, magazi omwewo amagwiritsa ntchito pafupifupi magawo makumi asanu ndi limodzi mphambu asanu pa zana. Palibe chimene chinasintha m'maselowo. Chinasintha ndi madzi amene anali mmenemo okha.

Chiwerengero chimenechi chinachokera m'nkhani ya kafukufuku ya mu 1928 yolembedwa ndi George Harrop ndi E. S. Guzman Barron ku Johns Hopkins, ndipo ndicho chiyambi cha mawu obwerezedwa kwambiri akuti methylene blue imapangitsa kupuma kwa maselo kukhala kwabwino. Mawuwo si abodza, koma tanthauzo lake ndi locheperapo kuposa mmene amamvekera.

Zimene chiwerengero cha patebulo chimayeza kwenikweni

Chimene anayeza pamapeto chinali kuchuluka kwa oxygen amene anatengedwa, pogwiritsa ntchito kusanthula mpweya. Harrop ndi Barron anasefa magazi amene anali atangotengedwa kudzera m'thonje pa 10 °C kuti achotse maselo oyera, anadzaza magaziwo ndi oxygen, anawagawa, anawonjezera utoto ku gawo limodzi, ndipo anasanthula magawo onsewo atawasunga pa kutentha koyenera. Chiwerengero cha maselo oyera sichinkapitirira pafupifupi chikwi chimodzi pa kiyubiki milimita. Kugwiritsidwa ntchito kwa oxygen kunafotokozedwa ngati gawo la oxygen amene anali m'magaziwo pachiyambi koma anali atasowa.

Anayezanso carbon dioxide, koma pamenepa njira yoyezera inawabweretsera vuto. Magazi ochotsedwa fibrin anatulutsa carbon dioxide wofika mamilimolu awiri pa 100 mL m'ola loyamba lowasunga pa kutentha koyenera, pa zifukwa zosagwirizana ndi kusintha kwa mankhwala kumene ankafufuza. Choncho ziŵerengero za chiŵerengero cha carbon dioxide wotuluka poyerekeza ndi oxygen wogwiritsidwa ntchito kuchokera m'magazi athunthu sizinali zothandiza. Maselo otsukidwa okha, oikidwa m'madzi a Locke, ndiwo anapereka ziŵerengero zomveka, ndipo ziŵerengerozo zinali pakati pa 0.73 ndi 0.80 kaya panali utoto kapena panalibe.

Mfundo imeneyi si yopanda pake. “Kupuma” m'nkhani za kafukufukuzi kumatanthauza kusinthana kwa mpweya m'chiwiya chotsekedwa. Kusiyana pakati pa kugwiritsa ntchito oxygen ndi kutulutsa mphamvu zogwiritsidwa ntchito kumafotokozedwa padera mu zimene kugwiritsa ntchito oxygen kungakuuzeni komanso zimene sikungakuuzeni za ATP.

Utotowo unawonjezera kwambiri pamene maselo ankapuma pang'ono kwambiri

Maselo ofiira a magazi a nyama zoyamwitsa amene akula mokwanira sagwiritsa ntchito oxygen pafupifupi konse m'njira imene ingayezedwe. Maselo ofiira a magazi a mbalame, amene ali ndi nyukiliyasi, amagwiritsa ntchito oxygen. Harrop ndi Barron anayesa mitundu yonse iwiriyo, ndipo kusiyana kwake ndiko kunali maziko a mfundo yawo.

M'magazi a nyama zoyamwitsa amene anayesedwa, utotowo unawonjezera kugwiritsidwa ntchito kwa oxygen kuwirikiza makumi awiri mpaka makumi asanu. M'magazi a tsekwe, amene maselo ake anali akupuma kale, liwirolo silinapitirire kuwirikiza kawiri. Kupuma kukakhala kokwera kale pachiyambi, utotowo unkawonjezera pang'ono.

Kusiyana komweku kunaonekeranso mwa zamoyo za mtundu umodzi. Magazi a munthu wodwala polycythemia vera, amene anali ndi maselo osakhwima, anagwiritsa ntchito 11.3 pa zana ya oxygen wake popanda utoto, poyerekeza ndi 2.8 pa zana m'maselo otsukidwa ochokera kwa munthu wathanzi amene anapereka magazi. Utoto unangowafikitsa pa 63.4 pa zana, kutanthauza kuwonjezeka kuwirikiza kasanu ndi kamodzi, pamene maselo abwinobwino anawonjezeka pafupifupi kuwirikiza makumi atatu. Utotowo unachititsa maselo okhwima kuchita ngati osakhwima, ndipo zimenezi n'zimene olembawo ananena kuti unkachita.

Cyanide inayenera kuletsa zimenezi

Zinkadziwika kuti cyanide imaletsa oxidation m'maselo. Komabe, Harrop ndi Barron anaiwonjezera limodzi ndi utotowo.

Zotsatira za magazi a ng'ombe ndi chitsanzo chabwino. Kuchuluka kwa oxygen kunatsika kuchokera pa 22.61 kufika pa 22.03 pa zana mwa kuchuluka kwa mpweya poyerekeza ndi kuchuluka kwa magazi, m'maola atatu popanda chowonjezedwa. Pakakhala methylene blue, kunatsika kufika pa 12.84. Pakakhala methylene blue ndi potassium cyanide wokhala ndi ndende ya gawo limodzi mwa zikwi zisanu la molar, kunatsika kufika pa 12.74. Zimene utotowo unkachita sizinasinthe kwenikweni.

Chithunzi: kujambula kosalekeza kwa kupuma kochepa kwa maselo ofiira a magazi a munthu. Muvi ukusonyeza pamene methylene blue anawonjezedwa. Asanawonjezedwe, mzerewo unali pafupifupi wosasuntha; atawonjezedwa, ukukwera mosalekeza. Chatengedwanso kuchokera kwa Harrop ndi Barron, Journal of Experimental Medicine 48:207–223 (1928), PMID 19869478.

Anamaliza ndi mfundo yakuti utotowo unkachita ngati chonyamulira oxygen, “popereka chinthu chimene chinasowa m'maselo ofiira a magazi opanda nyukiliyasi a nyama zoyamwitsa zazikulu.” Patapita zaka ziwiri, Michaelis ndi Salomon ku Rockefeller Institute anafotokoza mkanganowo m'njira imene yakhalapobe. Mwina zimene utotowo unkachita zinali “katundu wa utotowo amene unangokhalapo mwangozi,” kapena utotowo unali “chitsanzo cha chinthu china chosadziwika m'zamoyo.” Funso la njira ziwirizi silinathetsedwe. Chimene chasintha n'chakuti tsopano maselowo angafotokozedwe molondola kwambiri.

Chinthu chotengedwa m'chiwindi chinachitanso chimodzimodzi

Michaelis ndi Salomon anasonyeza kuti zinthu zotengedwa m'ziwalo pogwiritsa ntchito madzi ozizira zimayambitsa kuwonjezeka komweku. Chochokera m'chiwindi cha khoswe chinali champhamvu kwambiri, chotsatiridwa ndi chochokera mu impso, ndulu, ndi thumba la umuna. Zochokera mu ubongo, minofu, ndi seramu ya magazi zinali ndi mphamvu yochepa kapena zinalibe konse.

Kenako anayesa chinthu chotengedwacho pamaso pa carbon monoxide. Kupuma koyambitsidwa ndi chinthu chotengedwacho kapena utotowo sikunasinthe m'mpweya wosakanikirana wa carbon monoxide wa magawo 98 pa zana ndi oxygen wa magawo 2 pa zana. Mpweya wosakanikirana womwewo unachepetsa kupuma kwa yisiti ndi kwa maselo ofiira a magazi a nkhuku okhala ndi nyukiliyasi ndi pafupifupi magawo 60 mpaka 80 pa zana, mogwirizana ndi kufotokoza kwa Warburg za enzayimu ya kupuma imene imakhudzidwa ndi carbon monoxide. Choncho chinthu chosadziwika cha m'minofucho sichinali enzayimu ya Warburg.

Zinthu zingapo zimene ankaganiza kuti mwina ndi zimenezo zinachotsedwa pamndandanda pamene kafukufukuyo ankapitirira. Glutathione amene walandira maelekitironi ndi cysteine zinangoyambitsa kugwiritsidwa ntchito kwa oxygen wofunikira pa oxidation yawo yokha. Coenzyme ya Harden ndi Young inakanidwa chifukwa minofu imakhala nayo yambiri kwambiri koma inaonetsa pafupifupi mphamvu yochepa kwambiri. Cytochrome ya Keilin, imene inapatsidwa dzina zaka zingapo m'mbuyomo, inakumana ndi kutsutsana komweku. Malingaliro awo enieni, akuti chinthu chogwiracho chinachokera mu nyukiliyasi ya selo, anawatcha malingaliro chabe.

Zotsatirazo zinkafuna mikhalidwe inayake

Maselowo anayenera kukhala athunthu. Kusweka kwa maselo ofiira a magazi chifukwa cha madzi osungunulidwa n'kusonkhanitsidwanso kapena kuziziritsidwa mpaka kuundana mobwerezabwereza kunathetsa mmene ankayankhira ku utoto ndi ku chinthu chotengedwacho. Kusweka kwa maselo ena okha kunachepetsa kuyankhako molingana ndi kuchuluka kwa maselo oswekawo.

Shuga ankafunikanso. Glucose, fructose, ndi sucrose zinathandiza kupuma koyambitsidwa ndi utotowo; mannitol sanatero. Popanda shuga, panalibe kupuma konse, ndipo utotowo unkaoneka kuti ukuwononga maselowo panthawiyo. Choncho glucose amene anawonjezedwa patapita ola limodzi kapena awiri sanabwezeretse kupumako. Olembawo anaganiza kuti utotowo unkachititsa oxidation ya mbali yomanga selo imene selolo linkafunikira.

Kuunikira kunawonjezera kwambiri mphamvu ya utotowo, ngakhale kuti zotsatira zake zinaoneka bwino mumdima. Mitundu ina ya utoto imene ingalandire maelekitironi inachita mosiyana: toluylene blue inafanana ndi methylene blue kapena kuiposa, pamene indigo disulfonate sinachite pafupifupi chilichonse. Panalibe ubale woonekeratu pakati pa mphamvu ya utoto ya oxidation-reduction ndi kukula kwa zotsatira zake. Olembawo anati zimenezi zinkachitika chifukwa cha mmene utotowo umadutsira nembanemba ndi kawopsedwe kake.

Zotsatirazo zinatsatira kuwira, osati kupuma

Kafukufuku wa Barron wa mu 1930 unasamuka pa maselo oyandama m'madzi kupita pa tigawo tating'ono todulidwa ta minofu ya ziwalo zabwinobwino za makoswe ndi zotupa zimene zinali zitaikidwa m'zamoyo zina.

M'minofu yopanda glycolysis imene imachitika pamene oxygen alipo, methylene blue sanachite chilichonse kapena anachepetsa pang'ono kugwiritsidwa ntchito kwa oxygen: mu impso ndi pafupifupi 14 pa zana, mu kapamba ndi pafupifupi 14 pa zana, mu chiwindi ndi pafupifupi 5 pa zana. M'minofu imene imawiritsa pamene oxygen alipo, anawonjezera kugwiritsidwa ntchito kwake: mu ndulu ndi pafupifupi 8 pa zana, mu ubongo ndi pafupifupi 13 pa zana. Kuwonjezeka kwa m'matumbo a zotupa kunachokera pa pafupifupi 27 pa zana mu carcinoma ya bere la munthu kufika pa zoposa 80 pa zana mu sarcoma ya Rous ya nkhuku, ndipo kunali pafupifupi kolingana ndi glycolysis ya minofu iliyonse pamene oxygen alipo.

Chithunzi: dontho lililonse likuimira mtundu umodzi wa minofu. Mzere wopingasa ukuimira glycolysis pamene oxygen alipo; mzere woimirira ukuimira kusintha kwa kugwiritsa ntchito oxygen pambuyo powonjezera methylene blue. Deta yochokera kwa Barron, Journal of Experimental Medicine 52:447–456 (1930), Tebulo 6, PMID 19869777.

Kenako kuyesa ndi cyanide kunatulutsa zotsatira zosiyana ndi zoyambirirazo. Kupuma kwa minofu imene poyamba sinayankhe ku utotowo kutatsekedwa ndi cyanide ndipo kuwira kutayamba kuonekera, utotowo unawonjezeranso kugwiritsidwa ntchito kwa oxygen: mu impso ndi pafupifupi 59 pa zana, mu chiwindi ndi pafupifupi 19 pa zana, mu ndulu ndi pafupifupi 286 pa zana, mu thumba la umuna ndi pafupifupi 200 pa zana.

Barron anapereka lingaliro lakuti utotowo ungagwiritsidwe ntchito poyesa mphamvu ya selo kapena minofu yochita kuwira, ndipo anamaliza ndi lingaliro lina losatsimikiziridwa: mwina kukulitsa zotupa m'madzi okhala ndi utoto kwa mibadwo yambiri kungapangitse kuti kagwiritsidwe ntchito ka zinthu m'chotupa kakhale ngati ka minofu yabwinobwino mpaka kalekale. Limenelo linali funso la kafukufuku lolembedwa mu 1930. Si mawu onena kuti zimenezi ndi mankhwala ochiritsira.

Zimene mayeserowo sakanatha kuyeza

Mu 1928 ndi 1930, “kupuma” kunkatanthauza kugwiritsa ntchito oxygen. Adenosine triphosphate inafotokozedwa koyamba mu 1929, ndipo umboni wakuti mitochondria zochotsedwa m'maselo zimamanga phosphate m'mabondi a ester pamene zikusamutsa maelekitironi unabwera mu 1949. Palibe nkhani yoyambirira ya methylene blue imene ikanatha kuyeza kupanga mphamvu, ndipo palibe imene inanena kuti inachita zimenezo.

Maselowo ndi vuto lachiwiri. Maselo ofiira a magazi a nyama zoyamwitsa amene akula mokwanira alibe mitochondria. Akakhala pa gawo la reticulocyte, amachotsa mitochondria ndi ribosomes mwa kuswa mbali zawo zomwe zasankhidwa. N'chifukwa chake selo lofiira lokhwima limagwiritsa ntchito glycolysis ndipo limadalira njira yake ya pentose phosphate makamaka kuti lipeze NADPH, osati ATP. M'mayesero a mu 1928 munalibe unyolo wosamutsa maelekitironi woti ukonzedwe. Chilichonse chimene chinkagwiritsa ntchito oxygen chinkachita chinthu china.

Tsopano chinthu chinacho chikufotokozedwa bwino ndithu. Methylene blue amalandira maelekitironi kuchokera ku zinthu za m'selo zopereka maelekitironi ndipo amasanduka leucomethylene blue, amene amachitidwanso oxidation ndi oxygen wa mamolekyulu, n'kumamaliza kuzungulirako. M'maselo ofiira a magazi a munthu, flavin reductase yodalira NADPH ndi disulfide reductases ofanana nayo amachita gawo lolandira maelekitironi. Kafukufuku wa mu 1976 wogwiritsa ntchito glucose wokhala ndi chizindikiro chotsatirika unapeza kuti utotowo umafulumizitsa njira ya hexose monophosphate, kuti zotsatira zake pa ndende yochepa zinkadalira oxyhemoglobin, ndipo kuti ndende yapamwamba, ya 0.1 mM, inatulutsa hydrogen peroxide. Utoto umene walandira maelekitironi ukakumana ndi oxygen umatulutsa peroxide, osati mabondi a phosphate.

M'mitochondria, nkhaniyi ikutsutsanidwa kwambiri kuposa mmene mafotokozedwe achidule ofala amavomerezera. Gulu lina la kafukufuku limanena kuti utotowo umatenga maelekitironi pafupi ndi complex I n'kuwapereka ku cytochrome c. Lina linapeza kuti m'mitochondria ya ubongo wa mbewa, utotowo sungabwezeretse kupuma pambuyo poti antimycin watseka njira yake, ndipo m'malo mwake linaika malo olandirira maelekitironi pa malo omangirira ubiquinol a complex III. Lachitatu linapeza kuti ndende yochepa inawonjezera kugwiritsidwa ntchito kwa oxygen panthawi yopuma, koma kupuma kolimbikitsidwa ndi ADP sikunasinthe. Mfundo yofotokozedwa molunjika kwambiri ndi yakuti kugwiritsa ntchito oxygen koyambitsidwa ndi methylene blue sikudalira n'komwe kupanga ATP mwa oxidative phosphorylation: kunapitirirabe pamene unyolo wa kupuma unali utaletsedwa, komanso m'magulu okonzedwa kuti ayesedwe amene analibe unyolo umenewo.

Palinso miyezo yachindunji ya kusiyana pakati pa zinthu ziwirizi. M'mitochondria yochotsedwa m'chiwindi cha khoswe, kuwonjezera ndende ya utoto kunachepetsa ziŵerengero za kulamulidwa kwa kupuma ndipo kunayambitsa kutupa. Olembawo anafotokoza zimenezi ngati kulekanitsa oxidative phosphorylation ndi kusamutsa maelekitironi. M'chiwindi cha khoswe chimene chinkadutsitsidwa madzi oyesera, methylene blue anawonjezera kugwiritsidwa ntchito kwa oxygen pamene chiŵerengero cha ATP poyerekeza ndi ADP chinatsika.

Umboni wa kuchipatala umaperekanso uthenga womwewo. Methemoglobinemia imathandizidwa ndi pafupifupi miligalamu imodzi mpaka ziwiri za methylene blue pa kilogalamu, zoperekedwa kudzera mumtsempha, kudzera mu njira yolandira maelekitironi yodalira NADPH, ndipo milingo ikuluikulu imayambitsa vuto limene likuchiritsidwalo. Nkhani yowunika kafukufuku yomweyo imanena kuti mphamvu yolimbana ndi poizoni imakhala yaikulu kwambiri m'maselo ofiira athunthu ndipo imachepa maselowo akasweka. Zimenezi ndi zomwe zinapezeka mu 1930 pa kusweka kwa maselo ofiira, zomwe zinaonekeranso kuchipatala patapita zaka makumi asanu ndi awiri mphambu zitatu. Chinthu chimene zotsatira zake zothandiza ndi zovulaza zimasiyanitsidwa ndi malire a mlingo si chinthu chimene mlingo wake uyenera kuganiziridwa kuchokera pa kuyeza kugwiritsa ntchito oxygen.

Chifukwa chake gulu lopangidwa nthawi imodzi liyenera kukambidwa

Harrop ndi Barron anaona chinthu chofunika kuchiwerenganso. Methylene blue mwiniwake amapanga mzere m'chida chosanthula kuwala pakati pa mizere iwiri yodziwika ya methemoglobin, “zimene zingasokoneze mosavuta munthu akayang'ana mwachangu chabe.” Utotowo ungafanane ndi chinthu chimene chikufufuzidwa.

Vuto lomweli lilinso pa kapangidwe ka mankhwala. Phenothiazine yofanana nayo, imene ilipo ngati gawo laling'ono, ili ndi khalidwe lake la redox, mphamvu yake yodutsa nembanemba, ndi kawopsedwe kake. Chitsanzo chimodzi cholembedwa chimasonyeza tanthauzo lake momveka: mu kafukufuku wowonjezera iodine ku methylene blue, zitsanzo zokhala ndi pafupifupi 7 mpaka 8 pa zana ya Azure B zinatulutsa makamaka Azure B wowonjezeredwa iodine. Choncho chonyansacho, osati methylene blue, ndicho chinalamulira kusintha kwa mankhwalako.

Aliyense amene amagwiritsa ntchito methylene blue ngati chinthu choyesera, mu labotale, pa tebulo lopaka utoto pa zitsanzo, kapena m'thanki yosungiramo zamoyo zam'madzi, akugwira ntchito ndi chinthu chosadziwika bwino pokhapokha gulu limene linapangidwa nthawi imodzi litakhala litaunika kuti lidziwike. Zinthu zofanana nayo, kutsimikizira kuti ndi chinthu chenicheni, zonyansa za maelementi, zosungunulira zotsala, ndi zotsalira pambuyo powotcha ndi mbali ya kuyesako, osati zolemba za pambali pake. Blupreme imatenga methylene blue wake kwa wopanga mankhwala ndipo imafalitsa satifiketi yathunthu ya kusanthula, poyesa zofunikira zonse za USP m'malo mongoyesa zitsulo zolemera zokha; kalozera wowerenga satifiketi ya kusanthula ndi zimene dzina lakuti mulingo wa USP limatsimikizira komanso zimene silimatsimikizira zimafotokoza mmene mungayang'anire ngati chikalatacho chikugwirizana ndi zonena zake.

Chiwerengerocho chinali cholondola

Mayesero a mu 1928 ndi 1930 anachitidwa mosamala, ndipo zimene anaona zofunika kwambiri zakhalabe zoona: utoto umene ungathe kulandira maelekitironi ungapangitse selo limene silipuma kwenikweni kugwiritsa ntchito oxygen kuwirikiza liwiro lake lanthawi yopuma kangapo, popanda kudutsa pa gawo limene cyanide amatseka.

Cholakwika chimabwera pambuyo pake, pamene “kupuma” kumamveka ndi tanthauzo lake la masiku ano. Kuyeza kusinthana kwa mpweya kumakuuzani kuti maelekitironi anafika ku oxygen. Sikukuuzani kuti ena mwa iwo anagwiritsidwa ntchito kupanga ATP, ndipo m'selo lopanda mitochondria, kusiyana pakati pa mawu awiri amenewa kumakhala kwakukulu kwambiri. Chithunzithunzi chachikulu cha zimene methylene blue amachita m'maselo chimaika kusiyana komweku m'mfundo zambiri, ndipo mbiri ya chinthuchi kuyambira pa utoto kufika pa mankhwala imafotokoza mmene utoto wa nsalu unafikira m'mayesero amenewa poyambirira.