A similar phenomenon was observed in the current investigati

A similar phenomenon was observed in the current investigation. The disparate findings with regard to pretreatment and post-treatment with HJP272 suggest that very early inflammatory events are responsible for programming the lung for subsequent fibrosis. A single treatment with this ERA leads to less inflammation, and decreased fibrosis several weeks later, despite the generally rapid clearance of these agents from the circulation [24]. The relationship between the inflammatory and fibrotic reactions involves a number of different cytokines. Early recruitment of inflammatory 4sc mg results in elevated levels of PDGF, TGF-β, and CXCL12, which promote subsequent fibrosis [25], [26], [27], [28], [29], [30], [31], [32], [33]. Migration of lung fibroblasts to the site of injury is facilitated by expression of PDGF and TGF-β, and is followed by differentiation of these cells into myofibroblasts [25], [26], [27], [28]. Furthermore, PDGF promotes mesenchymal cell synthesis of glycosaminoglycans, while TGF-β is responsible for epithelial-mesenchymal transitions that require dedifferentiation of pulmonary epithelial cells into mesenchymal stem cells [29]. CXCL12, in contrast, attracts extrapulmonary fibrocytes to the lung, which then undergo differentiation into myofibroblasts [30], [31], [32]. This cytokine is a member of the CXC family of mediators that are involved in multiple injury and repair processes, including recruitment of leukocytes, vascular remodeling, and mobilization of mesenchymal progenitor cells such as fibrocytes [33]. The observed reductions in PDGF, TGF-β, and CXCL12 following pretreatment with HJP272 may therefore contribute to the decrease in parenchymal fibrosis and lung collagen deposition. The effect of ET-1 activity on the development of experimental pulmonary fibrosis has also been examined by other investigators. One study found that repeated administration of Bosentan, an ERA used to treat pulmonary arterial hypertension (PAH), significantly decreased bleomycin-induced pulmonary fibrosis [34]. Conversely, transgenic mice overexpressing human ET-1 developed rapidly progressive pulmonary fibrosis [35]. Whether other ERAs would have the same time-related effects on the BLM model as HJP272 may depend on their specific mode of action. HJP272 is a selective ERA, with a primary affinity for the ET-1 subtype A (ET-A) receptor, whereas mixed ERAs also bind to ET-1 subtype B (ET-B) receptors. However, the difference between selective and mixed antagonists is not well-defined pharmacologically [36]. Selective ERAs, when used at relatively high doses, may act on both receptors, while mixed ERAs usually demonstrate a greater affinity for ET-A receptors. Among the ERAs used to treat PAH, Ambrisentan is selective for ET-A receptors, whereas Bosentan and Macitentan are mixed antagonists. Clinical trials using each of these agents to treat pulmonary fibrosis have been largely unsuccessful [11], [12], [13], [14]. Although a subgroup of patients with less severe disease showed a trend toward improved survival with Bosentan, the result could not be confirmed in a subsequent trial [14].