PMID- 19542247
OWN - NLM
STAT- MEDLINE
DCOM- 20090902
LR  - 20200930
IS  - 1522-1504 (Electronic)
IS  - 1040-0605 (Linking)
VI  - 297
IP  - 3
DP  - 2009 Sep
TI  - TLR3 activation stimulates cytokine secretion without altering agonist-induced 
      human small airway contraction or relaxation.
PG  - L530-7
LID - 10.1152/ajplung.00133.2009 [doi]
AB  - Respiratory infections exacerbate chronic lung diseases promoting airway 
      inflammation and hyperreactivity. Toll-like receptor 3 (TLR3) recognizes viral 
      double-stranded (ds) RNA such as polyinosinic-polycytidylic acid [poly(I:C)] and 
      stimulates innate immune responses. The objective of this study was to test the 
      hypothesis that dsRNA promotes lung inflammation and alters airway responsiveness 
      to cholinergic and beta-adrenergic receptor agonists in human lung slices. Human 
      airway smooth muscle (ASM) was incubated for 24 h in poly(I:C) +/- TNFalpha and a 
      TLR3 monoclonal antibody. Precision-cut lung slices (PCLS; 250-microm thickness) 
      from healthy human lungs containing a small airway were incubated in 0, 10, or 
      100 microg/ml poly(I:C) for 24 h. Intravital microscopy of lung slices was used 
      to quantify contractile and relaxation responsiveness to carbachol and 
      isoproterenol, respectively. Supernatants of ASM and PCLS were analyzed for 
      cytokine secretion using a 25-multiplex bead assay. In human ASM, poly(I:C) (0.5 
      microg/ml) increased macrophage inflammatory protein-1alpha (MIP-1alpha) and 
      RANTES that was prevented by a TLR3 monoclonal receptor antibody. Incubation of 
      human PCLS with poly(I:C) (10 and 100 microg/ml) had little effect on the log 
      EC(50) or maximum drug effect (E(max)) for contraction and relaxation in response 
      to carbachol and isoproterenol, respectively. The responsiveness of the same 
      human PCLS to poly(I:C) incubation was confirmed by the robust increase in 
      chemokines and cytokines. In separate experiments, incubation of PCLS with IL-13 
      or TNFalpha (100 ng/ml) increased airway sensitivity to carbachol. Poly(I:C) 
      promotes inflammatory mediator release that was not associated with enhanced 
      bronchoconstriction or attenuated bronchodilation in normal healthy human lung 
      slices. Transduction at the TLR3 initiated by dsRNA stimulates downstream innate 
      immune responses.
FAU - Cooper, Philip R
AU  - Cooper PR
AD  - Airways Biology Initiative, Pulmonary, Allergy, and Critical Care Division, Univ. 
      of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Lamb, Roberta
AU  - Lamb R
FAU - Day, Nicole D
AU  - Day ND
FAU - Branigan, Patrick J
AU  - Branigan PJ
FAU - Kajekar, Radhika
AU  - Kajekar R
FAU - San Mateo, Lani
AU  - San Mateo L
FAU - Hornby, Pamela J
AU  - Hornby PJ
FAU - Panettieri, Reynold A Jr
AU  - Panettieri RA Jr
LA  - eng
PT  - Journal Article
DEP - 20090619
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 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-13)
RN  - 0 (TLR3 protein, human)
RN  - 0 (Toll-Like Receptor 3)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Chemokines/metabolism
MH  - Cytokines/*metabolism
MH  - Humans
MH  - In Vitro Techniques
MH  - Interleukin-13/pharmacology
MH  - Muscle Contraction/*drug effects
MH  - Muscle Relaxation/*drug effects
MH  - Myocytes, Smooth Muscle/drug effects/metabolism
MH  - Poly I-C/*pharmacology
MH  - Toll-Like Receptor 3/*metabolism
MH  - Trachea/cytology/*drug effects/*physiology
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 2009/06/23 09:00
MHDA- 2009/09/03 06:00
CRDT- 2009/06/23 09:00
PHST- 2009/06/23 09:00 [entrez]
PHST- 2009/06/23 09:00 [pubmed]
PHST- 2009/09/03 06:00 [medline]
AID - 00133.2009 [pii]
AID - 10.1152/ajplung.00133.2009 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2009 Sep;297(3):L530-7. doi: 
      10.1152/ajplung.00133.2009. Epub 2009 Jun 19.