Induction of Tachykinin Production in Airway Epithelia in Response to Viral Infection

The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to lung challenge has been previously demonstrated but has been focused predominantly on the release of the tachykinins from nerves innervating the lung. We have previously demonstrated the most dramatic phenotype described for the substance P encoding gene preprotachykinin-A (PPT-A) to date in controlling the host immune response to the murine gammaherpesvirus 68, in the lung.In this study we have utilised transgenic mice engineered to co-ordinately express the beta-galactosidase marker gene along with PPT-A to facilitate the tracking of PPT-A expression. Using a combination of these mice and conventional immunohistology we now demonstrate that PPT-A gene expression and substance P peptide are induced in cells of the respiratory tract including tracheal, bronchiolar and alveolar epithelial cells and macrophages after viral infection. This induction was observed 24h post infection, prior to observable inflammation and the expression of pro-inflammatory chemokines in this model. Induced expression of the PPT-A gene and peptide persisted in the lower respiratory tract through day 7 post infection.Non-neuronal PPT-A expression early after infection may have important clinical implications for the progression or management of lung disease or infection aside from the well characterised later involvement of the tachykinins during the inflammatory response

Characterization of the neurogenic plasma extravasation in the airways

Release of neuropeptides from sensory nerves causes an increase in vascular permeability, plasma extravasation and edema. The sensory nerves in the airways can be activated by electrical stimulation of the vagus nerve or by application of chemical and mechanical irritants, such as capsaicin, hypertonic saline, isocapnic hyperpnea and cigarette smoke. In rodent airways, the neurogenic plasma extravasation is mediated by tachykinins released from the capsaicin-afferent nerve fibres, and involves activation of neurokinin-l tachykinin receptors. In peripheral guinea-pig airways, neurokinin-2 tachykinin receptors have also been implicated in the neurogenic plasma exudation. The tachykinins can increase vascular permeability by both a direct effect on venular endothelium, and indirect mechanisms involving mast cell activation and serotonin release. Tachykinins and their receptors are present in the human airways. Release of tachykinins, following antigen. challenge, has been demonstrated in the nose and lower airways. In humans, tachykinins have been shown to increase plasma exudation in the nasal mucosa, but whether neurogenic inflammation also occurs in the lower airways still remains to be proven

IL-1β induces murine airway 5-HT_2Areceptor hyperresponsiveness via a non-transcriptional MAPK-dependent mechanism

<p>Abstract</p> <p>Background</p> <p>Interleukin 1 beta (IL-1β) is found in bronchoalveolar lavage fluids from asthmatic patients and plays an important role in normal immunoregulatory processes but also in pathophysiological inflammatory responses. The present study was designed to investigate if IL-1β could be involved in the development of airway hyperresponsiveness and if transcriptional mechanisms, epithelium contractile factors and mitogen-activated protein kinase (MAPK) pathways are involved in IL-1β effect.</p> <p>Methods</p> <p>The effect of IL-1β on 5-hydroxytryptamine (5-HT) induced bronchoconstriction was evaluated in an <it>in-vitro </it>model for assessment of long-term effects of inflammatory mediators on the airway smooth muscle. Murine tracheal segments were cultured up to 8 days in the absence or presence of IL-1β with subsequent evaluation in a myograph system, along with mRNA quantification, focusing on the role of the epithelium, acetylcholine release, transcriptional mechanisms and MAPK activity.</p> <p>Results</p> <p>During control conditions, 5-HT induced a relatively weak contraction. Presence of IL-1β increased this response in a time- and concentration-dependent way. The increased concentration-effect curves could be shifted rightwards in a parallel manner by ketanserin, a selective 5-HT_2Areceptor antagonist, indicating that the responses are mediated by 5-HT_2Areceptors. The mRNA levels of 5-HT_2Areceptors were not changed as a consequence of the IL-1β treatment and actinomycin D, a general transcriptional inhibitor, failed to affect the contractile response, suggesting a non-transcriptional mechanism behind this phenomenon. Neither the removal of the epithelium nor the addition of atropine affected the IL-1β induced enhancement of 5-HT_2Areceptor-mediated contractile response. Application of inhibitors for c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase 1 and 2 (ERK1/2) showed that the signaling pathways for JNK and ERK1/2 dominated only in cultured segments (control) whereas JNK and p38 dominated in segments treated with IL-1β.</p> <p>Conclusion</p> <p>IL-1β induces murine airway hyperresponsiveness, via a non-transcriptional up-regulation of 5-HT_2Areceptor-mediated contractile response. The increase of 5-HT contraction is unrelated to epithelial and cholinergic factors, but is dependent on IL-1β-induced changes of MAPK pathways. The fact that IL-1β can alter airway responses to contractile agents such as 5-HT, via alteration of the intracellular MAPK signal transduction pathways, might provide a new concept for future treatment of asthma.</p