To examine whether SP was being produced in situ in the lung as opposed to being released from nerve terminals, animals from a previously established transgenic mouse line expressing human PPT-A co-ordinately with the LacZ marker gene were used for the viral infections. In this transgenic line, a YAC containing the human PPT-A locus had been isolated from a human cDNA library and an internal ribosomal entry site -LacZ marker gene cassette had been cloned into the non-coding exon 7 through homologous recombination. LacZ expression is therefore a surrogate marker for PPT-A gene transcription and positive cells can be easily identified through X-gal staining for LacZ protein. The timing of the htPPT-A and SP induction in airway epithelia is clearly earlier than this and more akin to that of IFN-a, which is rapidly induced in the lung during the first few days after infection. The timing of SP induction is extremely significant and indicates that locally-produced SP is likely to be involved in the UNC2881 initiation of the host inflammatory and immune response in the lung, rather than being downstream of the induction of other inflammatory mediators. The effects of locally-produced SP are likely to involve paracrine and autocrine loops as human Levatin bronchial epithelial cell lines also respond to SP with a rise in synthesis and release of inflammatory cytokines in a receptor mediated fashion. This is especially important for respiratory infection as the epithelial cells lining the lumen are the first to encounter and respond to invasion by pathogens. An important role for tachykinins released from the non neuronal cells to infection has not only been demonstrated in our previous work but also for respiratory syncitial virus. Consistent with this RSV, a respiratory viral infection similar to MHV-68, initiates a lower inflammatory response if the pulmonary neuronal SP release is inhibited analogous in part to the response we had previously observed with MHV-68.The 8-OHdG immunohistochemical experiments indicate that despite a significant anti-oxidant defense system, the RPE developed oxidative DNA damage in mice exposed to cigarette smoke.