PMID- 9374723
OWN - NLM
STAT- MEDLINE
DCOM- 19971217
LR  - 20190528
IS  - 0002-9513 (Print)
IS  - 0002-9513 (Linking)
VI  - 273
IP  - 5
DP  - 1997 Nov
TI  - cAMP and purinergic P2y receptors upregulate and enhance inducible NO synthase 
      mRNA and protein in vivo.
PG  - L967-79
LID - 10.1152/ajplung.1997.273.5.L967 [doi]
AB  - Adenosine 3',5'-cyclic monophosphate (cAMP) and purinergic P2y receptor agonists 
      upregulate inducible nitric oxide (NO) synthase (iNOS) but inhibit Escherichia 
      coli endotoxin lipopolysaccharide (LPS)- and cytokine-mediated upregulation of 
      iNOS in cultured cells. We examined the effects of cAMP and P2y receptor agonists 
      on the iNOS system in vivo. Intratracheal administration of dibutyryl-cAMP 
      (DBcAMP, 0.1 and 1 mg/kg), a P2y receptor agonist [2-methylthioadenosine 
      5'-triphosphate (MeS-ATP), 5 mg/kg], or LPS (0.6 mg/kg) to rats 2 h before 
      bronchoalveolar lavage (BAL) increased iNOS mRNA (competitor-equalized reverse 
      transcription-polymerase chain reaction) and iNOS protein (Western blot) in rat 
      alveolar macrophages compared with the effects of sterile phosphate-buffered 
      saline (0.5 ml it). At equal levels of upregulation of iNOS mRNA, 1) LPS, but not 
      DBcAMP or MeS-ATP, upregulated nuclear transcription factor-kappa B (NF-kappa B) 
      and 2) iNOS protein and formation of NO were greater in alveolar macrophages from 
      LPS- and MeS-ATP-treated rats than from DBcAMP-treated rats. Administration of 
      DBcAMP or MeS-AMP 15 min before LPS did not inhibit LPS-induced alveolar 
      macrophage-derived iNOS mRNA, iNOS protein, and NO. Diethyldithiocarbamate (DETC, 
      5 mg/kg it) inhibited LPS-induced iNOS mRNA but did not affect upregulation of 
      iNOS mRNA produced by the other agonists. We conclude that an LPS-dependent and 
      -independent pathway of iNOS mRNA induction exists in vivo. The former is 
      activated by IPS and most cytokines, is associated with upregulation of NF-kappa 
      B and inhibited by DETC, and elicits an inflammatory response. The latter, 
      activated by DBcAMP and MeS-ATP, is not associated with upregulation of NF-kappa 
      B, inhibition by DETC, or activation of inflammation. The two systems are 
      additive in vivo rather than antagonistic. Speculatively, if the LPS-independent 
      iNOS pathway exists in humans, the iNOS in tissues from patients taking drugs 
      affecting cAMP or P2y receptors may be iatrogenic rather than pathogenetic in 
      origin.
FAU - Greenberg, S S
AU  - Greenberg SS
AD  - Department of Medicine, Louisiana State University Medical Center, New Orleans 
      70112, USA.
FAU - Zhao, X
AU  - Zhao X
FAU - Wang, J F
AU  - Wang JF
FAU - Hua, L
AU  - Hua L
FAU - Ouyang, J
AU  - Ouyang J
LA  - eng
GR  - AA-09816/AA/NIAAA NIH HHS/United States
GR  - P05-AA-09803/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Physiol
JT  - The American journal of physiology
JID - 0370511
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Purinergic P2 Receptor Agonists)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Purinergic P2)
RN  - 0 (Thionucleotides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 63X7MBT2LQ (Bucladesine)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 99Z2744345 (Ditiocarb)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - L628TT009W (Isoproterenol)
RN  - QF8SVZ843E (Albuterol)
RN  - Y37441OBL1 (2-methylthio-ATP)
SB  - IM
MH  - Adenosine Triphosphate/*analogs & derivatives/pharmacology
MH  - Albuterol/pharmacology
MH  - Animals
MH  - Bronchoalveolar Lavage Fluid/chemistry
MH  - Bucladesine/*pharmacology
MH  - Chemotaxis, Leukocyte/drug effects
MH  - Cyclic AMP/*metabolism
MH  - Ditiocarb/pharmacology
MH  - Enzyme Induction
MH  - Isoproterenol/pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - Lung/drug effects/*physiology
MH  - Macrophages, Alveolar/drug effects/*enzymology/immunology
MH  - Male
MH  - NF-kappa B/biosynthesis
MH  - Nitric Oxide Synthase/*biosynthesis
MH  - Polymerase Chain Reaction
MH  - Purinergic P2 Receptor Agonists
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Purinergic P2/*physiology
MH  - Thionucleotides/*pharmacology
MH  - Transcription, Genetic/drug effects/*physiology
MH  - Tumor Necrosis Factor-alpha/biosynthesis
EDAT- 1997/12/31 00:00
MHDA- 1997/12/31 00:01
CRDT- 1997/12/31 00:00
PHST- 1997/12/31 00:00 [pubmed]
PHST- 1997/12/31 00:01 [medline]
PHST- 1997/12/31 00:00 [entrez]
AID - 10.1152/ajplung.1997.273.5.L967 [doi]
PST - ppublish
SO  - Am J Physiol. 1997 Nov;273(5):L967-79. doi: 10.1152/ajplung.1997.273.5.L967.