Inflammation, kinins, and kinin receptors
Sammanfattning: Evidence is accumulating that the pathogenesis of many diseases is triggered by inappropriate inflammatory responses. These serious complications may occur when the tightly regulated inflammatory network is out of balance and it is now clear that this can eventually cause substantial harm to own cells and tissues. Successful infectious agents have evolved an enormous repertoire of modulatory mechanisms that allow the evasion, re-direction, dampening, over-stimulation, and even the use of inflammatory responses for their own purposes. The contact system, which is studied in the present thesis, is part of this inflammatory network and it has been shown that its systemic activation contributes to an exacerbation in many disease areas.
Bradykinin (BK) belongs to the group of vasoactive peptides, so-called kinins, which are potent inflammatory mediators. BK, once released from the human contact system, elicits a transient inflammatory response via activation of the constitutively expressed B2 receptor, which desensitizes and is internalized upon ligand binding. The kininase I metabolite of BK, desArg9BK, on the other hand mediates chronic deleterious inflammatory responses by interacting with the B1 receptor. Although normally absent, B1 receptor expression can be induced under inflammatory conditions.
The aim of the present thesis was to explore and analyze modifications in the regulation of kinins and their receptors in different settings of inflammation. It is known that BK is generated in the airways of asthmatic subjects and that disease symptoms are exacerbated during respiratory viral infections. In paper I, we report that BK induces an up-regulation of B2 receptors in human airway epithelial cells, which is in sharp contrast to other investigated cells. Further more, rhinovirus induces up-regulation of functional B1 receptors in the same cell type (paper II). Both mechanisms may render the respiratory tract more responsive to generated kinins and can significantly influence the inflammatory response and thereby symptom severity. In paper III and IV we demonstrate that the important human pathogens S. aureus and S. pyogenes can induce profound inflammatory reactions in the human host by secreting toxins that via stimulation of monocytic cells induce up-regulation of B1 receptors. Concurrently, both bacterial species are able to induce release of BK and its subsequent conversion to desArg9BK, which can evoke an over-amplification and prolongation of the inflammatory response.
Taken together, the present thesis demonstrates that kinin receptor regulation and kinin generation is affected during different settings of inflammation and we conclude that this may have a great impact on disease progression.
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