It is clear that the tissue microenvironment plays a critical role in regulating inflammation and tissue destruction. Chronic inflammation and tissue fibrosis lead not only to increased tumover of the extracellular matrix but also to an increase in inflammatory cells and mediators. We have shown that fragments of the extracellular matrix component hyaluronan, produced at sites of tissue inflammation, playa central role in the activation of the innate immune system via TLR-2. We propose that the extracellular matrix is not only the target of inflammation, but in its low molecular weight form, plays a central role as an endogenous ligand inducing inflammation. The importance of low molecular weight hyaluronan (LMW HA) in lung injury is evident in CD44 receptor null mice thai die of overwhelming inflammation upon exposure to low dose bleomycin in the setting of massive accumulation of LMW HA. We have supportive data that LMW HA induces its Inflammatory signals via TLR-2 and TLR-2 null mice are protected from bleomycin injury. Furthermore, the absence of TLR- 2 reverses the increased mortality of bleomycin injured CD44 null mice. However, MyD88 null and TLR-4 null mice have increased bleomycin lung injury indicating the specificity of the LMW HA-TLR-2 pathway in bleomycin-induced lung injury. Thus, as LMW HA fragments appears to be important in inflammation, regulation of LMW HA Induced inflammatory responses may be important in effectively and specifically treating inflammatory disorders.. . We hypothesize that within the tissue microenvironment a critical mechanism for mediating inflammation is the LMW HA-TLR-2 activation of the innate immune system. To this end, we propose the following alms for the 2-year ARRA funding:
Specific Aim I will deflne the role of LMW HA-TLR-2 signaling in the bleomycin model of lung injury and Specific Aim II will define the role of bone marrow derived cells vs: resident lung cells in bleomycin lung injury using bone marrow transplantations in receptor deficient mice. By deflning and understanding the inflammatory properties of extracellular matrix components, we will better be able to identify specific pharmacologic targets as potential therapies. We believe that these studies will provide the pre-clinical basis for the use of specific agents in the treatment of inflammatory lung dis13ases such as idiopathic pulmonary fibrosis, chronic bronchitis and emphysema.
An understanding of the pathways involved in the ability of extracellular matrix to promote inflammation may lead to potential targets for pharmacologic intervention. We believe that our studies will provide important preclinical data supporting the development of specific treatments for lung inflammation. In addition, given the ubiquitous nature of the extracellular matrix component hyaluronan, our studies should be generalizable to many inflammatory diseases such as arthritis, hepatitis, myocarditis and atherosclerosis.
|Black, Katharine E; Collins, Samuel L; Hagan, Robert S et al. (2013) Hyaluronan fragments induce IFN? via a novel TLR4-TRIF-TBK1-IRF3-dependent pathway. J Inflamm (Lond) 10:23|
|Powell, Jonathan D; Pollizzi, Kristen N; Heikamp, Emily B et al. (2012) Regulation of immune responses by mTOR. Annu Rev Immunol 30:39-68|
|Collins, Samuel L; Black, Katharine E; Chan-Li, Yee et al. (2011) Hyaluronan fragments promote inflammation by down-regulating the anti-inflammatory A2a receptor. Am J Respir Cell Mol Biol 45:675-83|
|Scheibner, Kara A; Boodoo, Sada; Collins, Samuel et al. (2009) The adenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion. Am J Respir Cell Mol Biol 40:251-9|