Current therapeutic approaches to avoid or reverse bronchoconstriction rely primarily on β2 adrenoceptor agonists (β-agonists) that regulate pharmacomechanical coupling/cross bridge cycling in airway smooth muscle (ASM). Targeting actin cytoskeleton polymerization in ASM represents an alternative means to regulate ASM contraction. Herein we report the cooperative effects of targeting these distinct pathways with β-agonists and inhibitors of the mammalian Abelson tyrosine kinase (Abl1 or c-Abl). The cooperative effect of β-agonists (isoproterenol) and c-Abl inhibitors (GNF-5, or imatinib) on contractile agonist (methacholine, or histamine) -induced ASM contraction was assessed in cultured human ASM cells (using Fourier Transfer Traction Microscopy), in murine precision cut lung slices, and in vivo (flexiVent in mice). Regulation of intracellular signaling that regulates contraction (pMLC20, pMYPT1, pHSP20), and actin polymerization state (F:G actin ratio) were assessed in cultured primary human ASM cells. In each (cell, tissue, in vivo) model, c-Abl inhibitors and β-agonist exhibited additive effects in either preventing or reversing ASM contraction. Treatment of contracted ASM cells with c-Abl inhibitors and β-agonist cooperatively increased actin disassembly as evidenced by a significant reduction in the F:G actin ratio. Mechanistic studies indicated that the inhibition of pharmacomechanical coupling by β-agonists is near optimal and is not increased by c-Abl inhibitors, and the cooperative effect on ASM relaxation resides in further relaxation of ASM tension development caused by actin cytoskeleton depolymerization, which is regulated by both β-agonists and c-Abl inhibitors. Thus, targeting actin cytoskeleton polymerization represents an untapped therapeutic reserve for managing airway resistance.
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http://dx.doi.org/10.1096/fj.202100154R | DOI Listing |
Hematology Am Soc Hematol Educ Program
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Adult Leukemia Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Diagn Microbiol Infect Dis
February 2025
Department of Immunology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey. Electronic address:
Brucellosis remains a significant public health issue in some parts of the world. It is clear that new laboratory methods are needed to diagnose brucellosis. Currently, no test method meets the criteria of high specificity, sensitivity, reliability, and low cost for the diagnosis of brucellosis, which could also predict chronicity.
View Article and Find Full Text PDFPLoS Comput Biol
November 2024
Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.
Resistance to therapy is a major clinical obstacle to treatment of cancer and communicable diseases. Drug selection in treatment of patients where the disease is showing resistance to therapy is often guided by IC50 or fold-IC50 values. In this work, through a model of the treatment of chronic myeloid leukaemia (CML), we contest using fold-IC50 values as a guide for treatment selection.
View Article and Find Full Text PDFBMJ Open
October 2024
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
Life (Basel)
September 2024
Department Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA.
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