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Related literature Cited by Google blog search Other articles by authors   on Google Scholar Stowell NC Seideman J Raymond HA Smalley KA Lamb RJ Egenolf DD Bugelski PJ Murray LA Marsters PA Bunting RA Flavell RA Alexopoulou L San Mateo LR Griswold DE Sarisky RT Mbow ML Das AM   on PubMed Stowell NC Seideman J Raymond HA Smalley KA Lamb RJ Egenolf DD Bugelski PJ Murray LA Marsters PA Bunting RA Flavell RA Alexopoulou L San Mateo LR Griswold DE Sarisky RT Mbow ML Das AM Related articles/pages on Google on Google Scholar on PubMed Tools Download references Download XML Order reprints Post a comment   Download to ... Papers Mendeley Download to ... Papers Mendeley Share this article
Nicole C Stowell 1 * , Jonathan Seideman 1 , Holly A Raymond 1 , Karen A Smalley 1 , Roberta J Lamb 1 , Devon D Egenolf 1 , Peter J Bugelski 1 , Lynne A Murray 1 , Paul A Marsters 1 , Rachel A Bunting 1 , Richard A Flavell 2 , Lena Alexopoulou 3 , Lani R San Mateo 1 , Don E Griswold 1 , Robert T Sarisky 1 , M Lamine Mbow 1 4 and Anuk M Das 1
The electronic version of this article is the complete one and can be found online at: http://respiratory-research.com/content/10/1/43 Received: 3 March 2008 Accepted: 1 June 2009 Published: 1 June 2009
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The immune mechanisms associated with infection-induced disease exacerbations in asthma and COPD are not fully understood. Toll-like receptor (TLR) 3 has an important role in recognition of double-stranded viral RNA, which leads to the production of various inflammatory mediators. Thus, an understanding of TLR3 activation should provide insight into the mechanisms underlying virus-induced exacerbations of pulmonary diseases. Methods
There was a significant increase in total cells, especially neutrophils, in BALF samples from poly(I:C)-treated mice. In addition, IL-6, CXCL10, JE, KC, mGCSF, CCL3, CCL5, and TNFα were up regulated. Histological analyses of the lungs revealed a cellular infiltrate in the interstitium and epithelial cell hypertrophy in small bronchioles. Associated with the pro-inflammatory effects of poly(I:C), chartbase the mice exhibited significant impairment of lung function both at baseline and in response to methacholine challenge as measured by whole body plethysmography and an invasive chartbase measure of airway resistance. chartbase Importantly, TLR3 KO mice were protected from poly(I:C)-induced changes in lung function at baseline, which correlated with milder inflammation in the lung, and significantly reduced epithelial cell hypertrophy. Conclusion
These findings demonstrate that TLR3 activation by poly(I:C) modulates the local inflammatory response in the lung and suggest a critical role of TLR3 activation in driving lung function impairment. Thus, TLR3 activation may be one mechanism chartbase through which viral infections contribute toward exacerbation of respiratory disease. Background
The activation of Toll-Like Receptors (TLRs), a family of innate immune receptors, is believed to be an important step in the initiation of the inflammatory response raised against numerous pathogens. TLR3 is a mammalian pattern recognition receptor that recognizes double-stranded (ds) RNA as well as the synthetic ds RNA analog poly-riboinosinic-ribocytidylic acid (poly(I:C)) [ 1 ]. Activation of TLR3 by poly(I:C) or by endogenous mRNA ligands, such as those released from necrotic cells [ 2 ], induces secretion of pro-inflammatory cytokines and chemokines, a finding that suggests that TLR3 agonists modulate disease outcome during infection-associated inflammation [ 3 ]. Thus, long-term activation of TLR3 in vivo is thought to occur in the context of viral infection [ 4 ] or necrosis associated with inflammation [ 2 ].
In vitro studies have demonstrated that stimulation of lung epithelial cells with poly(I:C) elicited the secretion of multiple cytokines, chemokines, the induction of transcription factors chartbase and increased expression of TLRs [ 3 ]. It has also been demonstrated that poly(I:C) enhanced bradykinin- and [des-Arg 9 ]-bradykinin-induced contractions of tracheal explants in vitro , an effect chartbase mediated by C-jun-amino-terminal kinase chartbase (JNK) and nuclear factor kappa B (NF-kB) signaling pathways [ 5 ]. Taken together, these data suggest that TLR3 activation may have a physiological consequence in the lung. Further, these data demonstrate that ligation of TLR3 initiates chartbase cascades of phosphorylation and transcriptional activation events that result in the production of numerous inflammatory cytokines that are thought to contribute to innate immunity [ 5 ]. Overall, these data suggest that sustained TLR3 activation can be a critical component in the modulation of infection-associated inflammator