4-Chloro-DL-phenylalanine protects against monocrotaline-induced pulmonary vascular remodeling and lung inflammation

Abstract

The present study was performed to investigate the effects of 4-chloro-DL-phenylalanine (PCPA), a tryptophan hydroxylase (Tph) inhibitor (TphI), on pulmonary vascular remodeling and lung inflammation in monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Animal models of PAH were established using Sprague-Dawley (SD) rats by a single intraperitoneal injection of MCT (60 mg/kg). PCPA (50 or 100 mg/kg/day) was administered to the rats with PAH. On day 22, hemodynamic measurements and morphological observations of the lung tissues were performed. The levels of Tph-1 and serotonin transporter (SERT) in the lungs were analyzed by immunohistochemistry and western blot analysis. The expression of matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 and inflammatory cytokines were assayed by western blot analysis. The activity of MMP-2 and MMP-9 was evaluated by gelatin zymography (GZ). MCT markedly promoted PAH, increased the right ventricular hypertrophy index, pulmonary vascular remodeling, lung inflammation and mortality, which was associated with the increased expression of Tph-1, SERT, MMP-2/-9, TIMP-1/-2 and inflammatory cytokines. PCPA markedly attenuated MCT-induced pulmonary vascular remodeling and lung inflammation, inhibited the expression of Tph-1 and SERT and suppressed the expression of MMP-2/-9, TIMP-1/-2, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1). These findings suggest that the amelioration of MCT-induced pulmonary vascular remodeling and lung inflammation by PCPA is associated with the downregulation of Tph-1, SERT, MMP/TIMP and inflammatory cytokine expression in rats.

Fluoxetine protects against methamphetamine-induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats

“…SERT-induced rapid activation of MAPK is associated with 5-HT-induced pulmonary inflammation (30). The p38 MAPK signaling pathways are involved in the regulation of the Nrf2-mediated cytoprotective effect (31).…”

The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

“…The data of pulmonary arterial pressure (PAP) and systemic arterial pressure (SAP) were kept as records under the same factors, as previously described (17,18). To measure PAP, a PV-1 catheter was inserted into the right jugular vein via the right atrium and ventricle, and was finally introduced into the pulmonary artery (16,18). A polyethylene catheter (PE-50) was introduced into the right carotid artery for the measurement of SAP (16,18).…”

“…To measure PAP, a PV-1 catheter was inserted into the right jugular vein via the right atrium and ventricle, and was finally introduced into the pulmonary artery (16,18). A polyethylene catheter (PE-50) was introduced into the right carotid artery for the measurement of SAP (16,18). Hemodynamic indexes were surveyed by a pressure pickup and a polygraph system (RM6000; Nihon Kohden, Tokyo, Japan) for recording.…”

“…We performed histopathological observations as previously described (16). We used 4% paraform and sterile physiological saline to exsanguinate the rats.…”

“…One non-reversible inhibitor of TPH-1, 4-chloro-DL-phenylalanine (PCPA), has been shown to reduce monocrotaline (MCT)-induced inflammation and remodeling in rat lungs (16). Nevertheless, the synthesis amongst these transcriptional effector signaling pathways and their role in inflammation and remodeling have not been discussed in PAH to date, at least to the best of our knowledge.…”