PMID- 34777398
OWN - NLM
STAT- MEDLINE
DCOM- 20220214
LR  - 20220214
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Ruxolitinib Ameliorates Airway Hyperresponsiveness and Lung Inflammation in a 
      Corticosteroid-Resistant Murine Model of Severe Asthma.
PG  - 786238
LID - 10.3389/fimmu.2021.786238 [doi]
LID - 786238
AB  - Asthma prevalence has increased considerably over the decades and it is now 
      considered as one of the most common chronic disorders in the world. While the 
      current anti-asthmatic therapies are effective for most asthma patients, there 
      are 5-10% subjects whose disease is not controlled by such agents and they 
      account for about 50% of the asthma-associated healthcare costs. Such patients 
      develop severe asthma (SA), a condition characterized by a dominant Th1/Th17 
      cytokine response that is accompanied by Type 2 (T2)-low endotype. As JAK (Janus 
      Kinase) signaling is very important for the activation of several cytokine 
      pathways, we examined whether inhibition of JAKs might lessen the clinical and 
      laboratory manifestations of SA. To that end, we employed a recently described 
      murine model that recapitulates the complex immune response identified in the 
      airways of human SA patients. To induce SA, mice were sensitized with house dust 
      mite extract (HDME) and cyclic (c)-di-GMP and then subsequently challenged with 
      HDME and a lower dose of c-di-GMP. In this model, treatment with the JAK 
      inhibitor, Ruxolitinib, significantly ameliorated all the features of SA, 
      including airway hyperresponsiveness and lung inflammation as well as total IgE 
      antibody titers. Thus, these studies highlight JAKs as critical targets for 
      mitigating the hyper-inflammation that occurs in SA and provide the framework for 
      their incorporation into future clinical trials for patients that have severe or 
      difficult-to manage asthma.
CI  - Copyright (c) 2021 Subramanian, Hashem, Bahal, Kammala, Thaxton and Das.
FAU - Subramanian, Hariharan
AU  - Subramanian H
AD  - Department of Physiology, College of Human Medicine, Michigan State University, 
      East Lansing, MI, United States.
FAU - Hashem, Tanwir
AU  - Hashem T
AD  - College of Natural Science, Michigan State University, East Lansing, MI, United 
      States.
FAU - Bahal, Devika
AU  - Bahal D
AD  - College of Veterinary Medicine, Michigan State University, East Lansing, MI, 
      United States.
FAU - Kammala, Ananth K
AU  - Kammala AK
AD  - Department of Physiology, College of Human Medicine, Michigan State University, 
      East Lansing, MI, United States.
FAU - Thaxton, Kanedra
AU  - Thaxton K
AD  - College of Natural Science, Michigan State University, East Lansing, MI, United 
      States.
FAU - Das, Rupali
AU  - Das R
AD  - Department of Physiology, College of Human Medicine, Michigan State University, 
      East Lansing, MI, United States.
LA  - eng
GR  - K22 CA188149/CA/NCI NIH HHS/United States
GR  - R00 HL121073/HL/NHLBI NIH HHS/United States
GR  - R25 HL108864/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211029
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Glucocorticoids)
RN  - 0 (Nitriles)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - 82S8X8XX8H (ruxolitinib)
RN  - EC 2.7.10.2 (Janus Kinases)
SB  - IM
MH  - Animals
MH  - Asthma/blood/*drug therapy/immunology/pathology
MH  - Disease Models, Animal
MH  - Drug Resistance
MH  - Female
MH  - Glucocorticoids/*pharmacology/therapeutic use
MH  - Humans
MH  - Immunoglobulin E/blood/immunology
MH  - Janus Kinases/*antagonists & inhibitors/metabolism
MH  - Mice
MH  - Nitriles/*pharmacology/therapeutic use
MH  - Pneumonia/blood/*drug therapy/immunology/pathology
MH  - Pyrazoles/*pharmacology/therapeutic use
MH  - Pyrimidines/*pharmacology/therapeutic use
MH  - Pyroglyphidae/immunology
PMC - PMC8586657
OTO - NOTNLM
OT  - T2-low asthma
OT  - airway hyperresponsiveness (AHR)
OT  - corticosteroid resistance
OT  - house dust mite extract (HDME)
OT  - interleukin (IL)-17
OT  - lung inflammation
OT  - ruxolitinib
OT  - severe asthma
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/11/16 06:00
MHDA- 2022/02/15 06:00
PMCR- 2021/01/01
CRDT- 2021/11/15 06:58
PHST- 2021/09/30 00:00 [received]
PHST- 2021/10/18 00:00 [accepted]
PHST- 2021/11/15 06:58 [entrez]
PHST- 2021/11/16 06:00 [pubmed]
PHST- 2022/02/15 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.786238 [doi]
PST - epublish
SO  - Front Immunol. 2021 Oct 29;12:786238. doi: 10.3389/fimmu.2021.786238. eCollection 
      2021.