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2030-01-01
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- IOC - Artigos de Periódicos [12596]
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TWO FOR ONE: CYCLIC AMP MEDIATES THE ANTI-INFLAMMATORY AND ANTI-SPASMODIC PROPERTIES OF THE NON-ANESTHETIC LIDOCAINE ANALOG JMF2-1
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ. Brasil.
Abstract
Inhalation of JMF2-1, an analog of lidocaine with reduced anesthetic activity, prevents airway contraction and
lung inflammation in experimental asthma models. We sought to test if the JMF2-1 effects are a consequence
of increased intracellular cAMP levels in asthma cell targets, such as smooth muscle cells and T cells. Functional
effect of JMF2-1 on carbachol-induced contraction of intact or epithelial-denuded rat trachea was assessed
in conventional organ baths. cAMP was quantified by radioimmunoassay in cultured guinea pig tracheal
smooth muscle cells, as well as lymph node cells from BALB/c mice, exposed to JMF2-1. We found that
JMF2-1 (0.1–1 mM) concentration-dependently inhibited epithelium-intact tracheal ring contraction induced
by carbachol challenge. The antispasmodic effect remained unaltered following epithelium removal or
pretreatment with NG-nitro-L-arginine methyl ester (100 μM), but it was clearly sensitive to 9-(tetrahydro-
2-furyl) adenine (SQ22,536, 100 μM), an adenylate cyclase inhibitor. JMF2-1 (300 and 600 μM) also dosedependently
increased cAMP intracellular levels of both cultured airway smooth muscle cells and T
lymphocytes. This effect was consistently abrogated by SQ22,536 and reproduced by forskolin in both systems.
JMF2-1 induced apoptosis of anti-CD3 activated T cells in a mechanism sensitive to zIETD, indicating that
JMF2-1 mediates caspase-8-dependent apoptosis. Furthermore, forskolin also inhibited anti-CD3 induced T cell
proliferation and survival. Our results suggest that JMF2-1 inhibits respiratory smooth muscle contraction as
well as T cell proliferation and survival through enhancement of intracellular cAMP levels. These findings may
help to explain the anti-inflammatory and antispasmodic effects of JMF2-1 observed in previous studies.
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