BACKGROUND: Pulmonary hypertension (PH) is a lethal disease characterized in part by progressive pulmonary arteriole (PA) remodeling. Excessive PA fibrosis and macrophage infiltration are often present in PH, but the potential associations are obscure. We investigated the link between interstitial macrophage (iMΦ) infiltration and PA fibrosis in PH and idiopathic pulmonary arterial hypertension. METHODS: Lung tissue samples from patients with idiopathic pulmonary arterial hypertension and experimental PH animals were obtained to analyze the extent of fibrosis and iMΦ infiltration in the different layers of PAs and their correlation with disease severity. Single-cell RNA sequencing, lineage tracing, histological analyses, iMΦ and PA smooth muscle cell coculture, and transgenic animal experiments were used to investigate the cell heterogeneity and origins and molecular mechanisms by which iMΦs promote PA fibrosis. RESULTS: We found that increased collagen deposition and fibrosis in the PA media were most strongly related to the severity of PH, and medial iMΦ infiltration may be involved in these pathological processes. Single-cell transcriptomics revealed that major histocompatibility complex class II (high) lymphatic vessel endothelial hyaluronan receptor 1 (low) C-C motif chemokine receptor 2 (high) (MHCII ^hi LYVE1 ^lo CCR2 ^hi ) iMΦs were the major type of iMΦ that expanded upon Sugen-5416 and hypoxia plus normoxia stimulation and were responsible for PA medial fibrosis. Lineage tracing experiments suggested that these medial iMΦs were largely from recruited monocytes. Mechanistically, MHCII ^hi LYVE1 ^lo CCR2 ^hi iMΦs promoted the transition of PA smooth muscle cells to a fibroblast-like phenotype through the WNT11 (wingless member 11)/planar cell polarity (PCP) pathway. Wnt11 deletion in iMΦs from PH rats normalized the fibrotic PA smooth muscle cell phenotype and decreased PA medial fibrosis, thereby improving vascular compliance and protecting against PH. Moreover, myeloid-specific Ccr2 deficiency in PH-PAs inhibited the medial infiltration of MHCII ^hi LYVE1 ^lo CCR2 ^hi iMΦs, which also relieved PH. CONCLUSIONS: This study demonstrates that the recruitment of MHCII ^hi LYVE1 ^lo CCR2 ^hi iMΦs leads to medial fibrosis in PH-PAs associated with PH severity and that inhibition of their pathogenicity or recruitment reverses PA medial fibrosis and PH.

Skeletal muscle ischemia-reperfusion (IR) injury is a prevalent type of muscle injury caused by events, such as trauma, arterial embolism, and primary thrombosis. The development of an IR injury is associated with oxidative stress and an excessive inflammatory response. Nanozymes, which have exceptional free radical scavenging activities, have gained significant attention for treating oxidative stress. This study demonstrates that carbon dot (C-dot) nanozymes possess superoxide dismutase (SOD)-like activity and can act as free radical scavengers. The carbon dot nanozymes are presented to mitigate inflammation by downregulating the iNOS/COX-2 pathway and scavenging reactive oxygen-nitrogen species to reduce oxidative stress, thereby suppressing inflammation. In the IR injury of skeletal muscle mice, we demonstrate that C-dots can effectively reduce inflammatory cytokines and tissue edema in skeletal muscle following IR injury in the limb. These findings suggest that C-dots have potential as a therapeutic approach for IR injury of skeletal muscle with negligible systemic toxicity. This offers a promising strategy for clinical intervention.

Pulmonary hypertension (PH) is a disease characterized by advanced pulmonary vasculature remodeling that is thought to be curable only through lung transplantation. The application of angiogenic hepatocyte growth factor (HGF) is reported to be protective in PH through its anti–vascular remodeling effect, but excessive HGF-mediated immature neovascularization is not conducive to the restoration of pulmonary perfusion because of apparent vascular leakage. As a canonical antiangiogenic molecule, pigment epithelium–derived factor (PEDF) inhibits angiogenesis and reduces vascular permeability in a variety of diseases. However, the effect of PEDF on HGF-based PH treatment remains to be determined. In this study, monocrotaline-induced PH rats and endothelial cells isolated from rat and human PH lung tissues were used. We assessed PH progression, right cardiac function, and pulmonary perfusion in HGF- and/or PEDF-treated rats with PH. Additionally, the receptor and mechanism responsible for the role of PEDF in HGF-based PH therapy were investigated. In this study, we found that HGF and PEDF jointly prevent PH development and improve right cardiac function in rats with PH. Moreover, PEDF delivery increases the pulmonary perfusion in PH lungs and inhibits immature angiogenesis and vascular endothelial (VE)-cadherin junction disintegration induced by HGF without affecting the therapeutic inhibition of pulmonary vascular remodeling by HGF. Mechanistically, PEDF targets VE growth factor receptor 2 and suppresses its phosphorylation at Y951 and Y1175 but not Y1214. Finally, VE growth factor receptor 2/VE protein tyrosine phosphatase/VE-cadherin complex formation and Akt and Erk1/2 inactivation were observed in rat and human PH lung endothelial cells. Collectively, our data indicate that PEDF additively enhances the efficacy of HGF against PH, which may provide new insights into treatment strategies for clinical PH.

The efficacy of dexamethasone palmitate in extending durations of local anesthetic blocks is uncertain. In a randomized, double-blind study of patients undergoing video-assisted thoracoscopic surgery, we tested whether intravenous or perineural dexamethasone palmitate caused prolonged analgesia after intercostal nerve block. A total of 90 patients subjected to video-assisted thoracoscopic surgery between May and December 2022 were randomly assigned to one of three intercostal nerve blocks study arms (n = 30 each), requiring the addition of 0.5% ropivacaine (23 ml) as follows: controls (C group), 2 ml saline; IV-DXP group, 2 ml saline + 2 ml (8 mg) intravenous dexamethasone palmitate; and PN-DXP group, 2 ml (8 mg) perineural dexamethasone palmitate. Time to first postoperative remedial analgesia served as primary outcome measure. Secondary endpoints included postoperative opioid consumption, pain scores by Visual Analog Scale, analgesia satisfaction, and related adverse effects. Compared with controls or the IV-DXP group, time to first postoperative remedial analgesia was longer and postoperative opioid consumption for rescue analgesia was lower in the PN-DXP group (p < 0.01). Similarly, the Visual Analog Scale scores in patients at 8, 12, 18, and 24 h postoperatively were lower in the PN-DXP group than in controls and the IV-DXP group (p < 0.01). Patient satisfaction was statistically lower in the PN-DXP group, compared with either the control or IV-DXP group (p < 0.05). Clinically, the three groups did not differ significantly in occurrences of adverse effects during the 48-h postoperative monitoring period (p > 0.05). Perineural dexamethasone palmitate is a promising adjunct to ropivacaine intercostal nerve block by prolonging analgesia with almost no related adverse effects.

Background: This study aimed to compare the analgesic efficacy of transthoracic intercostal nerve block (TINB) and percutaneous intercostal nerve block (PINB) for video-assisted thoracic surgery (VATS) using a retrospective analysis. Methods: A total of 336 patients who underwent VATS between January 2021 and June 2022 were reviewed retrospectively. Of the participants, 194 received TINB and were assigned to the T group, while 142 patients received PINB and were assigned to the P group. Both groups received 25 ml of ropivacaine via TINB or PINB at the end of the surgery. The study measured opioid consumption, pain scores, analgesic satisfaction, and safety. Propensity score matching (PSM) analysis was performed to minimize selection bias due to nonrandom assignment. Results: After propensity score matching, 86 patients from each group were selected for analysis. The P group had significantly lower cumulative opioid consumption than the T group (p < 0.01). The Visual Analogue Scale (VAS) scores were lower for the P group than the T group at 6 and 12 h post-surgery (p < 0.01); however, there was no significant difference in the scores between the two groups at 3, 24, and 48 h (p > 0.05). The analgesic satisfaction in the P group was higher than in the T group (p < 0.05). The incidence of back pain, nausea or vomiting, pruritus, dizziness, and skin numbness between the two groups was statistically insignificant (p > 0.05). Conclusion: The study suggests that PINB provides superior analgesia for patients undergoing thoracic surgery compared to TINB without any extra adverse effects.

Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated. For PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved. PEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6. Our findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/β-catenin pathway.