The role of toll-like receptors in human lung tissue

Abstract

Viral exacerbations of COPD playa major role in disease pathogenesis. The specific mechanisms through which viruses invoke exacerbations, however, remain unclear. To date, there is little information on the inflammatory response induced by many different viruses and likewise the kinetics and dose dependency of this response. To better understand the innate immune response of human lung tissue to viral infections, this study investigated the role of TLR3 in response to the TLR3 agonist Poly I:C and killed influenza virus. These agonist responses were compared to that of a known inflammatory stimulus, LPS, a well recognized TLR4 activator. Using a tissue explant model system, it has been shown that ligands for TLR3 and TLR4 can initiate responses in human lung tissue of mild to moderate COPD patients. It is apparent however, that the responses between the ligands for these receptor subtypes differ markedly based upon the cytokines produced and their kinetic profiles. It has been demonstrated that different classes of the chemokine family may contribute significantly to the inflammatory response for Poly I:C, killed virus and LPS. Interestingly, however, there appears to be marked inter-patient variability for chemokine production with Poly I:C. It has also been shown that Th2 cytokines do not appear to be significantly elevated by Poly I:.C or killed virus, suggesting the mechanisms of viral exacerbation are likely to be a Thl response. Interestingly, it was also observed that pro-inflammatory cytokines, TNFa, IL-l~ and IL-6 were not significantly elevated by Poly I:C or killed virus, which was in complete contrast to the response seen with LPS. Overall, this work provides an insight into the contribution of cytokines in the acute inflammatory response to viral and bacterial infection.

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