{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T12:43:34Z","timestamp":1770381814914,"version":"3.49.0"},"reference-count":50,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2002,6,1]]},"abstract":"<jats:p> Hypertonic stress (HS) suppresses neutrophil (PMN) functions. We studied the underlying mechanism and found that HS rapidly (&lt;1 min) increased intracellular cAMP levels by up to sevenfold. cAMP levels correlated with applied hypertonicity and the degree of neutrophil suppression. HS and cAMP-elevating drugs (forskolin and dibutyryl cAMP-acetoxymethyl ester) similarly suppressed extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase activation and superoxide formation in response to N-formylmethionyl-leucyl-phenylalanine (fMLP) stimulation. Inhibition of cAMP-dependent protein kinase A (PKA) with H-89 abrogated the suppressive effects of HS, restoring fMLP-induced ERK and p38 activation and superoxide formation. Inhibition of phosphodiesterase with 3-isobutyl-1-methylxanthine augmented cAMP accumulation and the suppressive effects of HS, while inhibition of adenylyl cyclase with MDL-12330A abolished these effects. These findings suggest that HS-activated cAMP\/PKA signaling inhibits superoxide formation by intercepting fMLP-induced activation steps upstream of ERK and p38. In contrast to its effects in the presence of moderate hypertonicity levels (40 mM), H-89 was unable to rescue neutrophil functions from suppression by higher hypertonicity levels (100 mM), indicating that more severe HS suppresses neutrophils via secondary PKA-independent mechanisms. <\/jats:p>","DOI":"10.1152\/ajpcell.00479.2001","type":"journal-article","created":{"date-parts":[[2013,5,14]],"date-time":"2013-05-14T00:08:47Z","timestamp":1368490127000},"page":"C1261-C1269","source":"Crossref","is-referenced-by-count":40,"title":["Hypertonicity increases cAMP in PMN and blocks oxidative  burst by PKA-dependent and -independent mechanisms"],"prefix":"10.1152","volume":"282","author":[{"given":"Tatjana","family":"Orlic","sequence":"first","affiliation":[{"name":"Surgical Immunology Research Laboratory, Department of Surgery, Division of Trauma, University of California, San Diego, California 92103-8236"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William 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