1. Severe asthma: Advances in current management and future therapy
Peter J. Barnes, FMedSci, FRS 
Journal of Allergy and Clinical Immunology 
Volume 129, Issue 1, Pages (January 2012)
DOI: /j.jaci
Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2. Fig 1
PGD2 might play a role in severe asthma. It is synthesized mainly in mast cells by PDGD synthase (PGDS) and acts on DP1 receptors on vessels to mediate vasodilatation and on dendritic cells to enhance their activation through DP2 receptors (also known as CRTH2) to attract TH2 lymphocytes and eosinophils and on thromboxane (TP) receptors to cause bronchoconstriction. DP2 (CRTH2) antagonists are now in a clinical trial in patients with severe asthma. Antagonists of DP1 and receptors and inhibitors of PGDS are now in clinical development for asthma therapy.
Adapted from Barnes.5
Journal of Allergy and Clinical Immunology  , 48-59DOI: ( /j.jaci )
Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3. Fig 2
Inhibition of proinflammatory kinase pathways for severe asthma. Several kinases activate the expression of multiple inflammatory genes and might therefore amplify the inflammation in asthmatic patients, leading to more severe disease. Selective inhibitors have been developed for several kinases, including spleen tyrosine kinase (SYK), which activates several signaling pathways, including phospholipase Cγ (PLCγ); inhibitor of NF-κB kinase (IKK2), which activates NF-κB; p38 MAPK, which activates MAPK-activated protein kinase 2 (MAPKAPK2); Jun kinase (JNK), which activates activator protein 1 (AP-1); and PI3K, which activates Akt. Selective inhibitors have now been developed for all of these enzyme targets.
Journal of Allergy and Clinical Immunology  , 48-59DOI: ( /j.jaci )
Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4. Fig 3
Inhibition of mast cells in asthmatic patients. Mast cell activation can be inhibited by blocking IgE binding to FcεRI; by inhibiting c-Kit, which is activated by stem cell factor (SCF); or by inhibiting spleen tyrosine kinase (SYK). Mast cell stabilizers, such as cromones and furosemide, might work through specific ion channels or G protein–coupled receptors for which novel modulators can be developed.
Adapted from Barnes.5
Journal of Allergy and Clinical Immunology  , 48-59DOI: ( /j.jaci )
Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5. Fig 4
Corticosteroid resistance in some patients with severe asthma is due to a reduction in HDAC2 activity and expression as a result of oxidative stress through activation of PI3Kδ. This can be reversed by antioxidants, including Nrf2 activators, theophylline, nortriptyline, and selective PI3Kδ inhibitors. Macrolides also reverse corticosteroid resistance by acting further down the pathway. In the future, selective HDAC2 activators might be developed.
Journal of Allergy and Clinical Immunology  , 48-59DOI: ( /j.jaci )
Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions