PMID- 18055842
OWN - NLM
STAT- MEDLINE
DCOM- 20080319
LR  - 20200930
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 294
IP  - 2
DP  - 2008 Feb
TI  - Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in 
      mice.
PG  - L300-8
AB  - Toll-like receptors (TLRs) mediate inflammation in sepsis, but their role in 
      sepsis-induced respiratory failure is unknown. Hypoxic pulmonary vasoconstriction 
      (HPV) is a unique vasoconstrictor response that diverts blood flow away from 
      poorly ventilated lung regions. HPV is impaired in sepsis and after challenge 
      with the TLR4 agonist lipopolysaccharide (LPS). Unlike TLR4 agonists, which are 
      present only in Gram-negative bacteria, TLR2 agonists are ubiquitously expressed 
      in all of the major classes of microorganisms that cause sepsis, including both 
      Gram-positive and Gram-negative bacteria and fungi. We tested the hypothesis that 
      (S)-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys(4)-OH, 
      trihydrochloride (Pam3Cys), a TLR2 agonist, impairs HPV and compared selected 
      pulmonary and systemic effects of Pam3Cys vs. LPS. HPV was assessed 22 h after 
      challenge with saline, Pam3Cys, or LPS by measuring the increase in the pulmonary 
      vascular resistance of the left lung before and during left lung alveolar hypoxia 
      produced by left mainstem bronchus occlusion (LMBO). Additional endpoints 
      included arterial blood gases during LMBO, hemodynamic parameters, weight loss, 
      temperature, physical appearance, and several markers of lung inflammation. 
      Compared with saline, challenge with Pam3Cys caused profound impairment of HPV, 
      reduced systemic arterial oxygenation during LMBO, weight loss, leukopenia, and 
      lung inflammation. In addition to these effects, LPS-challenged mice had lower 
      rectal temperatures, metabolic acidosis, and were more ill appearing than 
      Pam3Cys-challenged mice. These data indicate that TLR2 activation impairs HPV and 
      induces deleterious systemic effects in mice and suggest that TLR2 pathways may 
      be important in sepsis-induced respiratory failure.
FAU - Petersen, Bodil
AU  - Petersen B
AD  - Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 
      Fruit Street, Boston, MA 02114, USA.
FAU - Bloch, Kenneth D
AU  - Bloch KD
FAU - Ichinose, Fumito
AU  - Ichinose F
FAU - Shin, Hae-Sook
AU  - Shin HS
FAU - Shigematsu, Misako
AU  - Shigematsu M
FAU - Bagchi, Aranya
AU  - Bagchi A
FAU - Zapol, Warren M
AU  - Zapol WM
FAU - Hellman, Judith
AU  - Hellman J
LA  - eng
GR  - AI 058106/AI/NIAID NIH HHS/United States
GR  - HL 42397/HL/NHLBI NIH HHS/United States
GR  - HL 71987/HL/NHLBI NIH HHS/United States
GR  - HL 74352/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20071130
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Dipeptides)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Lipoproteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 98598-79-9 (2,3-bis-(palmitoyloxy)-2-propyl-N-palmitoyl-cysteinylserine)
RN  - EC 1.11.1.7 (Peroxidase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Blood Gas Analysis
MH  - Dipeptides/pharmacology
MH  - Hemodynamics/drug effects
MH  - Hypoxia/*physiopathology
MH  - Leukocytes/cytology
MH  - Lipopolysaccharides/pharmacology
MH  - Lipoproteins/pharmacology
MH  - Lung/drug effects/enzymology/metabolism/physiopathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neutrophil Infiltration/drug effects
MH  - Nitric Oxide Synthase Type II/genetics/metabolism
MH  - Organ Size/drug effects
MH  - Oxygen/metabolism
MH  - Peroxidase/metabolism
MH  - Pulmonary Artery/drug effects/metabolism
MH  - Pulmonary Circulation/*physiology
MH  - RNA, Messenger/genetics/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Toll-Like Receptor 2/*metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/metabolism
MH  - Up-Regulation/drug effects
MH  - Vasoconstriction/*physiology
MH  - Weight Loss/drug effects
EDAT- 2007/12/07 09:00
MHDA- 2008/03/20 09:00
CRDT- 2007/12/07 09:00
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/03/20 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
AID - 00243.2007 [pii]
AID - 10.1152/ajplung.00243.2007 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L300-8. doi: 
      10.1152/ajplung.00243.2007. Epub 2007 Nov 30.