Histopathologic Findings Associated With Matrix Metalloproteinases Proceeding to Recurrence of Primary Spontaneous Pneumothorax in Adolescents

Background: Primary spontaneous pneumothorax is potentially life-threatening, and its recurrence is always a serious problem. Pathological examination provides molecular insights into the pathophysiology of primary spontaneous pneumothorax.Objectives: To investigate the association of histopathologic features of primary spontaneous pneumothorax with matrix metalloproteinase expression and their relevance to the recurrence.Methods: A total of 217 tissue section slides in 172 adolescent patients with primary spontaneous pneumothorax were retrospectively reviewed from January 2001 to June 2020. All histopathologic features were recorded and pathologic findings related to ipsilateral recurrence and second surgery were analyzed. Serum levels of matrix metalloproteinases were prospectively measured in 25 primary spontaneous pneumothorax patients receiving surgery and 18 healthy controls. Their relevance to the histopathologic features of primary spontaneous pneumothorax related to its recurrence was also examined.Results: The major presenting histopathologic findings of primary spontaneous pneumothorax were bleb/bulla (98%) followed by fibrosis (68%). Low prevalence of the pathologic findings of granulation tissue and macrophage accumulation were significantly associated with recurrent primary spontaneous pneumothorax, whereas fibrosis was significantly higher in patients receiving more than once surgery. Furthermore, the ratios of matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 were significantly higher in theses pathological findings as well as multinucleated giant cells and mesothelial cell hyperplasia in comparison with healthy controls.Conclusions: Low prevalence of macrophage accumulation and granulation tissue related to the overexpression of matrix metalloproteinase-2 and−9 activities may contribute to healing impairment and primary spontaneous pneumothorax recurrence.

Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis

During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β+ cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β+ cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β+ cells transition into myofibroblasts. In contrast to PDGFR-β+ cells, KLF4 reduction in α-smooth muscle actin (SMA)+ cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β+ cells via a Forkhead box M1 to C-C chemokine ligand 2—receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β+ cells and SMA+ cells and highlight the importance of further studies of interactions between distinct mesenchymal cell types.

713 Culprit plaque morphology and healing capacity in patients with and without preinfarction angina: an optical coherence tomography imaging study

Aims The relationship between culprit plaque morphology, healed culprit plaques prevalence and clinical presentation of acute myocardial infarction (AMI) remains largely unexplored. We hypothesized that angina preceding the occurrence of AMI (pre-infarction angina, PIA) may reflect a distinct morphologic phenotype of culprit plaques and potentially different healing capacity. Methods and results We conducted a retrospective observational study in patients with AMI who underwent intracoronary optical coherence tomography (OCT) imaging of the culprit lesion before PCI at the Fondazione Policlinico A. Gemelli–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome. Based on the clinical history, patients were classified into two groups: (i) PIA group, defined as either intermittent chest pain within 6 h preceding the final episode of chest pain, or unstable angina (or both) in the week preceding AMI or (ii) no-PIA group, defined as a single episode of chest pain without prodromal symptoms in the preceding week. Culprit plaques were classified as plaque rupture (PR) or intact fibrous cap (IFC), and presence of layered appearance (healed plaque, HP) was assessed. Thrombus burden (TB) was estimated, and prevalence of diffuse calcification, neovascularization, and OCT-defined macrophage accumulation were evaluated. A total of 102 patients with AMI were included (50 PIA, 52 no-PIA). Patients with PIA showed a higher prevalence of IFC than PR (58% vs. 42%, P = 0.030). PR in patients with PIA were more frequently associated with macrophage accumulation (71.4% vs. 28.6% P = 0.001), and TB tended to be lower [22.0 (15.8–30.3) vs. 38.5 (12.8–67.5), P = 0.145]. Diffuse calcifications were significantly less frequent in patients with PIA (22.0% vs. 40.4%, P = 0.045), while neovascularization tended to be more frequent (58.0% vs. 42.3%, P = 0.113). HPs prevalence was significantly higher in the PIA than in the no-PIA group (66.0% vs. 25.0%, P < 0.001). Conclusions Patients with PIA have a distinct culprit plaque phenotype, more frequently characterized by IFC and a relatively lower TB, with a significantly higher prevalence of plaque healing.

Prevalence of Healed Plaque and Factors Influencing Its Characteristics Under Optical Coherence Tomography in Patients With Coronary Artery Disease: A Systematic Review, Meta-Analysis, and Meta-Regression

Aim: The purpose of this study was to determine the prevalence of healed plaque and its characteristics under optical coherence tomography (OCT) through a formal systematic review, meta-analysis, and meta-regression.Methods and Results: Thirteen studies were selected from MEDLINE, EMBASE, Cochrane, and online databases. The overall incidence of healed plaques was 40% (95% CI: 39–42), with 37% (95% CI: 35–39) in patients with acute coronary syndrome (ACS) and with 46% (95% CI: 43–49) in patients with stable angina pectoris (SAP). The incidence of healed plaque among culprit plaques (48%, 95% CI: 46–50) was nearly two times higher than that among non-culprit plaques (24%, 95% CI: 21–27). The incidence of thin cap fibroatheroma (TCFA), plaque rupture, microvessel, macrophage accumulation, and calcification was significantly higher in the healed plaque group. Meta-regression revealed an association between smoking (P = 0.033) and healed plaque rupture. Gender (P = 0.047) was independently associated with macrophage accumulation, and mean low-density lipoprotein cholesterol (LDL-C) was independently associated with microvessel.Conclusions: In summary, with a total incidence of 40%, the incidence of healed plaques under OCT was higher in SAP than in ACS, and higher in culprit plaques than in non-culprit plaques. Higher incidence of TCFA, plaque rupture, microvessel, macrophage accumulation, and calcification was found in the healed-plaque group. Smoking, gender, and mean LDL-C level were associated with healed-plaque characteristics.

Anti-inflammatory and -apoptotic effects of a long-term herbal extract treatment on DSS-induced colitis in mice fed with high AGEs-fat diet

Background Obesity is associated with many comorbidities including inflammatory bowel disease (IBD). We investigated prophylactic effects of an herbal extract (HE) on the DSS-induced colitis mice challenged with high AGEs-fat diet 60% (HFD). Methods Six-week-old C57BL/6 male mice were fed with either HFD (8 groups, 6 mice in each group), or normal diet (ND) (8 groups, 6 mice in each group). After 6 weeks, animals received HE (combination of turmeric, ginger, boswellia and cat’s claw extract) for 7 weeks in three doses (high dose (0.6 mg/g); low dose (0.15 mg/g) and mid dose (0.3 mg/g)). Next, mice were subjected to 2.5% DSS in drinking water. Control mice received ND and instead of HE and DSS they received distilled water. Obesity index markers were determined, H&E staining and TUNEL assay evaluated apoptosis. Colonic expressions of IL-6, RAGE, AGER1, Sirt1, Bax, Bcl2, ZO-1 and P53 were determined. Results HE ameliorated colitis in HFD mice by reducing colonic myeloperoxidase activity (by 2.3-fold), macrophage accumulation (by 2.6-fold) and mRNA expression of IL-6 (by 2.3-fold) in HFD mice. Moreover, HE restored ZO-1 (by 2.7-fold), prevented apoptosis and maintained immune homeostasis. HE reduced activation of NF-κB protein (by 1.3-fold) through decreasing RAGE (by 1.93-fold) and up-regulation of Sirt1 (by 7.71-fold) and prevented down-regulation of DDOST (by 6.6-fold) in HFD mice. Conclusions HE ameliorated colitis in prophylactic in HFD mice and it was, at least partly, due to the restoration of the gut integrity, suppression of inflammation and apoptosis via modulation of colonic Sirt1, RAGE and DDOST signaling. Graphic abstract

The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism

The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from Ldlr–/– rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid disorder in the rat model, which has not been reported in mouse studies. Examination of aortas revealed exacerbated atherosclerotic plaques in G2A deficient rats, together with increased oxidative stress and macrophage accumulation. In addition, consistently promoted migration and apoptosis were noticed in G2A deficient macrophages, even in macrophages from G2A single knockout rats. Further analysis found significantly declined phosphorylation of PI3 kinase (PI3K) and AKT, together with reduced downstream genes Bcl2 and Bcl-xl, suggesting possible involvement of PI3K/AKT pathway in G2A regulation to macrophage apoptosis. These data indicate that G2A modulates atherosclerosis by regulating lipid metabolism and macrophage migration and apoptosis. Our study provides a new understanding of the role of G2A in atherosclerosis, supporting it as a potential therapeutic target.

Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

In heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.