| Abstract | Astma je kronična opstruktivna bolest dišnih puteva karakterizirana simptomima: teškog disanja („zviždanja“), gubitka daha, kašalja, stezanja u prsima i proizvodnji sputuma. Astma je globalna bolest koja neravnomjerno pogađa ljude neovisno o rasi, dobi, spolu etničkoj pripadnosti ili geografskoj lokaciji. Procjenjuje se da između 2-18% populacije u svijetu boluje od astme.
ISAAC program je prva globalna studija prevalencije astme čiji su zabrinjavajući podaci doveli do stavljanja velikog fokusa na astmu početkom 21.st. Etiologija astme ovisi o dva glavna čimbenika: genetici i okolišu. Njihovo preplitanje daje široku vanjsku i unutarnju fenotipizaciju bolesti kao i kompliciranu kasifikaciju težine kliničke slike. Postoji niz obrazaca GINA-e za dijagnosticiranje pojedinog tipa astme kao i propisane dozirane terapije. Današnja dijagnostika astme temelji se na funkcijskim plućnim testovima i širokom spektru bronhoprovokacijskih testova uz korištenje modernih alata poput biomarkera i OMIC metoda u identificiranju specifičnog patofiziološkog mehanizma upale. Najčešći vanjski uzročnici astme su: alergeni, polutanti te mikroorganizmi (posebno virusi i bakterije). Alergijska astma najrašireniji je tip astme s najvećim trendom rasta oboljelih (osobito djece). Genetika astme proučavana je: studijama povezanosti, asocijacijskim studijama (GWAS) i epigenetskim studijama. Astmatska upala dijeli se na Th1 i Th2 tip odgovora. Dok Th1 odogovor nije toliko poznat, Th2 odgovor je proučen s etiološke i
terapeutske strane. U Th2 odgovoru sudjeluje mnoštvo imunoloških stanica, a najveći utjecaj imaju: T-limfociti, eozinofili i mastociti. Stanice glatkog mišićja, epitela i subepitela dišnih puteva najpogođenija su tkiva u astmatskoj upali u kojima sudjeluju proupalni citokini što za posljedicu ima zatvaranje dišnih puteva i limitirani protok zraka. JAK/STAT signalni put je od iznimne
važnosti u astmatskim upalama. Vezanjem liganda za receptor pokreće se inicijacijski signal-multimerizacijom receptora, pokreće se kaskadni signalni put fosforilacije JAK kinaze koji uzrokuje aktivaciju STAT transkripcijskog čimbenika ključnog u transkripcijskoj ekspresiji citokin-inducirajućih gena. Poremećaj ovog signala u astmi dovodi do snažne migracije imunoloških
stanica i proizvodnje citokina u bronhima. Jak-inhibitorima nastoji se spriječiti inicijacija upale uzrokovane aktivacijom JAK/STATsignalnog puta. Taj pristup je drugačiji, od dosadašnjih terapija koje su uglavnom riješavale simptome.
Trenutno poznati Jak inhibitori u kliničkim, pretkliničkim ili patentnim aplikacijama su: Theravance: TD-8236, Rigel/AstraZeneca: R256/AZD0449, AstraZeneca: „Example 35“, Almirall: LAS194046 , Vectura: VR588, Merck: iJAK-001 i IJC-1, Genentech: iJAK-381 i GDC-0214 te PM-43I kao jedini STAT inhibitor. |
| Abstract (english) | Asthma is a chronic obstructive airways disease characterized by symptoms: shortness of breath ("whistling"), loss of breath, coughing, chest tightness and sputum production. Asthma is a global disease that affects people unevenly
regardless of race, age, gender, ethnicity, or geographic location. It is estimated that between 2-18% of the world's population suffers from asthma. The ISAAC program is the first global study of asthma prevalence whose worrying data led to a major focus on asthma in the early 21st century. The etiology of asthma depends on two main factors: genetics and the
environment. Their intertwining gives a broad external and internal phenotyping of the disease as well as a complicated classification of the severity of asthma. There are a number of GINA patterns for diagnosing a particular type of asthma as well as the prescribed dosage therapy for it. Today’s diagnosis of asthma is based on functional lung tests and a wide range
of bronchoprovocation tests with the assistance of modern tools such as biomarkers and OMIC methods in identifying the specific pathophysiological mechanism of inflammation. The most common external causes of asthma are: allergens, pollutants and microorganisms (especially viruses and bacteria). Allergic asthma is the most common type of asthma with the highest growth trend in patients (especially children). Asthma genetics have been studied in: association studies, association studies (GWAS), and epigenetic studies. Asthmatic inflammation is divided into Th1 and Th2 type responses.
While the Th1 response is not so well known, the Th2 response has been studied from the etiological and therapeutic side. Many immune cells participate in the Th2 response, and the most influential are: T-lymphocytes, eosinophils and mast cells. Smooth muscle, epithelial, and subepithelial cells of the airways are the most affected tissues in asthmatic inflammation,
mediated by proinflammatory cytokines, causing airway closure and limited airflow.
The JAK / STAT signaling pathway is crucial for asthmatic inflammation. The receptor-ligand initiation signal initiates receptor multimerization, consequetnly activating a cascade pathway of JAK kinase phosphorylation that causes activation of the STAT transcription key in the transcriptional expression of cytokine-inducing genes. Disruption of this signal in asthma leads to strong migration of immune cells and production of cytokines in the bronchi. Jak-inhibitors in asthma aim to prevent the very initiation of JAK / STAT inflammation, unlike previous symptomatic therapies. Currently known strong inhibitors in clinical, preclinical or patent applications are: Theravance: TD-8236, Rigel / AstraZeneca: R256 / AZD0449, AstraZeneca: "Example 35", Almirall: LAS194046, Vectura: VR588, Merck: iJAK-001 and IJC- 1, Genentech: iJAK-381 and GDC-0214 and PM-43I as the sole STAT inhibitor. |
