The concept that inflammation is important in the pathogenesis of pulmonary hypertension (PH) is gaining credence. Studies have suggested that Interleukin-6 (IL-6) and -1 are involved in the development of PH and that IL-6 can stimulate smooth muscle cell proliferation. The adventitial fibroblast has been suggested as a potential source of mitogens and inflammatory mediators which contribute to the development of PH.
Methods Rat pulmonary artery fibroblasts (RPAF) were isolated from normal Sprague–Dawley rats, rats exposed to 2 weeks of hypobaric hypoxia. Cells were cultured by explant technique. Normal RPAF were quiesced for 24 h in serum free media (SFM) and then exposed to periods of prolonged acute hypoxia or maintained in normoxia. The conditioned media was collected and stored at −70oC. RPAF from the chronic hypoxic and monocrotaline models were exposed to 1% serum or maintained in SFM and conditioned media collected. The effect of p38 MAPK blockade using SB203580 (an alpha-isoform specific inhibitor) was examined. The conditioned media was analysed using cytokine array technology and ELISA.
Results In normoxic conditions after 48 h, conditioned media from normal fibroblasts showed release of TIMP-1 and low levels of VEGF-A. The expression profile changed with 48 h exposure to hypoxia showing increased levels of VEGF-A and immunomodulators such as IL-6 (see Abstract P28 Figure 1), MIP-3α (CXCL20), LIX, CINC-1, sICAM-1. The secretion of these mediators were blocked by the addition of SB203580 suggesting an important role for p38MAPK in the control of these proteins. TNF-α was not released from these cells under the conditions studied. With the chronic hypoxic RPAF after 48 h of 1% serum stimulation in normoxia, the cytokine profile mirrored that of normal RPAF in acute hypoxia. Again this was blocked using SB203580.
Conclusion Pulmonary artery fibroblasts release mediators in response to hypoxia, which have been implicated in both recruitment of inflammatory cells and the proliferation of pulmonary artery smooth muscle cells. We have demonstrated that inhibition of the p38MAPK-alpha isoform can block the secretion of these mediators. This may have therapeutic implications for the treatment of hypoxia related pulmonary hypertension.
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