Smooth Muscle Hypertrophy Research Articles

Research Advances in Adenomyosis-Related Signaling Pathways and Promising Targets

Adenomyosis is a benign gynecological condition characterized by the proliferation of the endometrial stroma and glands into the myometrium, uterine volume enlargement, and peripheral smooth muscle hypertrophy. The typical clinical symptoms include chronic pelvic pain, abnormal uterine bleeding, and subfertility, all of which significantly impact quality of life. There are no effective prevention or treatment strategies for adenomyosis, partly due to a limited understanding of the pathological mechanisms underlying the initiation and progression of the disease. Given that signaling pathways play a crucial role in the development of adenomyosis, a better understanding of these signaling pathways is essential for identifying therapeutic targets and advancing drug development. The occurrence and progression of adenomyosis are closely linked to various underlying pathophysiological mechanisms, including proliferation, migration, invasion, fibrosis, angiogenesis, inflammation, oxidative stress, immune response, and epigenetic changes. This review summarizes the signaling pathways and targets associated with the pathogenesis of adenomyosis, including CXCL/CXCR, NLRP3, NF-κB, TGF-β/smad, VEGF, Hippo/YAP, PI3K/Akt/mTOR, JAK/STAT, and other relevant pathways. In addition, it identifies promising future targets for the development of adenomyosis treatment, such as m6A, GSK3β, sphks, etc.

Fingolimod, a sphingosine-1-phosphate receptor modulator, prevents neonatal bronchopulmonary dysplasia and subsequent airway remodeling in a murine model.

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation.NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

Rosuvastatin attenuates airway inflammation and remodeling in a chronic allergic asthma model through modulation of the AMPKα signaling pathway.

The efficacy of rosuvastatin in reducing allergic inflammation has been established. However, its potential to reduce airway remodeling has yet to be explored. This study aimed to evaluate the efficacy of rosuvastatin in reducing airway inflammation and remodeling in a mouse model of chronic allergic asthma induced by sensitization and challenge with OVA. Histology of the lung tissue and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) showed a marked decrease in airway inflammation and remodeling in mice treated with rosuvastatin, as evidenced by a decrease in goblet cell hyperplasia, collagen deposition, and smooth muscle hypertrophy. Furthermore, levels of inflammatory cytokines, angiogenesis-related factors, and OVA-specific IgE in BALF, plasma, and serum were all reduced upon treatment with rosuvastatin. Western blotting was employed to detect AMPK expression, while immunohistochemistry staining was used to observe the expression of remodeling signaling proteins such as α-SMA, TGF-β, MMP-9, and p-AMPKα in the lungs. It was found that the activity of 5'-adenosine monophosphate-activated protein kinase alpha (AMPKα) was significantly lower in the lungs of OVA-induced asthmatic mice compared to Control mice. However, the administration of rosuvastatin increased the ratio of phosphorylated AMPK to total AMPKα, thus inhibiting the formation of new blood vessels, as indicated by CD31-positive staining mainly in the sub-epithelial region. These results indicate that rosuvastatin can effectively reduce airway inflammation and remodeling in mice with chronic allergic asthma caused by OVA, likely due to the reactivation of AMPKα and a decrease in angiogenesis.

The Possible Roles of IL-4/IL-13 in the Development of Eosinophil-Predominant Severe Asthma.

Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play roles in the development of bronchial asthma. Among these cytokines, IL-4 is involved in T-cell differentiation, B-cell activation, B-cell differentiation into plasma cells, and the production of immunoglobulin E. Although IL-13 has similar effects to IL-4, IL-13 mainly affects structural cells, such as epithelial cells, smooth muscle cells, and fibroblasts. IL-13 induces the differentiation of goblet cells that produce mucus and induces the airway remodeling, including smooth muscle hypertrophy. IL-4 and IL-13 do not directly activate the effector functions of eosinophils; however, they can induce eosinophilic airway inflammation by upregulating the expression of vascular cell adhesion molecule-1 (for adhesion) and CC chemokine receptor 3 ligands (for migration). Dupilumab, a human anti-IL-4 receptor α monoclonal antibody that inhibits IL-4 and IL-13 signaling, decreases asthma exacerbations and mucus plugs and increases lung function in moderate to severe asthma. In addition, dupilumab is effective for chronic rhinosinusitis with nasal polyps and for atopic dermatitis, and IL-4/IL-13 blocking is expected to suppress allergen sensitization, including transcutaneous sensitization and atopic march.

A murine model of peanut-allergic asthma.

Peanut allergy is an IgE-mediated food allergy that is associated with asthma in certain patients. With increasing prevalence, its great impact on the quality of life, and a lack of treatment options, the need for new therapy options is a given. Hence, models for research and development are required. This study aimed to establish a murine model of allergic airway inflammation induced by peanut allergens. C3H mice were sensitised by intraperitoneal injections of peanut allergen extract and challenged by an intranasal application of the same extract. The assessment of airway inflammation involved the analysis of immune cells in the bronchoalveolar lavage fluid as measured by flow cytometry. Inflammatory reactions in the lung tissue were also studied by histology and quantitative PCR. Moreover, peanut-specific immune responses were studied after re-stimulation of spleen cells in vitro. Sensitisation led to allergen-specific IgE, IgA, and IgG1 seroconversion. Subsequent nasal exposure led to allergic airway inflammation as manifested by structural changes such as bronchial smooth muscle hypertrophy, mucus cell hyperplasia, infiltration of eosinophil cells and T cells, as well as an upregulation of genes expressing IL-4, IL-5, IL-13, and IFN-γ. Upon re-stimulation of splenocytes with peanut allergen, increased secretion of both T-helper type 2 (Th2) and Th1 cytokines was observed. We successfully established a peanut-associated asthma model that exhibited many features characteristic of airway inflammation in human patients with allergic asthma. The model holds potential as a tool for investigating novel therapeutic approaches aimed at preventing the development of allergic asthma.

Impact of obesity on airway remodeling in asthma: pathophysiological insights and clinical implications.

The prevalence of obesity among asthma patients has surged in recent years, posing a significant risk factor for uncontrolled asthma. Beyond its impact on asthma severity and patients' quality of life, obesity is associated with reduced lung function, increased asthma exacerbations, hospitalizations, heightened airway hyperresponsiveness, and elevated asthma-related mortality. Obesity may lead to metabolic dysfunction and immune dysregulation, fostering chronic inflammation characterized by increased pro-inflammatory mediators and adipocytokines, elevated reactive oxygen species, and reduced antioxidant activity. This chronic inflammation holds the potential to induce airway remodeling in individuals with asthma and obesity. Airway remodeling encompasses structural and pathological changes, involving alterations in the airway's epithelial and subepithelial layers, hyperplasia and hypertrophy of airway smooth muscle, and changes in airway vascularity. In individuals with asthma and obesity, airway remodeling may underlie heightened airway hyperresponsiveness and increased asthma severity, ultimately contributing to the development of persistent airflow limitation, declining lung function, and a potential increase in asthma-related mortality. Despite efforts to address the impact of obesity on asthma outcomes, the intricate mechanisms linking obesity to asthma pathophysiology, particularly concerning airway remodeling, remain incompletely understood. This comprehensive review discusses current research investigating the influence of obesity on airway remodeling, to enhance our understanding of obesity's role in the context of asthma airway remodeling.

Oral administration of Lacticaseibacillus paracasei attenuates combined allergic rhinitis and asthma syndrome (CARAS) in mice model: Relevance of short-chain fatty acids on gut-airway axis

Probiotics have been shown to have a beneficial effect on allergic diseases. Anti-allergic effect of Lacticaseibacillus paracasei was demonstrated in asthma, however, its effect in combined allergic rhinitis and asthma syndrome (CARAS) is still unclear. This study evaluated the Lacticaseibacillus paracasei (LPc-G110) supplementation in CARAS mice model. BALB/c mice were ovalbumin-sensitized and challenged after being supplemented with LPc-G110. Supplemented animals showed reduced allergic rhinitis signs, eosinophilic infiltration, mucus, extracellular matrix deposition into airway tissues, and lung smooth muscle hypertrophy. LPc-G110 supplementation also reduced eosinophilia, serum levels of allergen-specific IgE, IL-4, IL-13, and IL-5, and favored the production of IFN-γ, IL-10, and short-chain fatty acids. Additionally, LPc-G110 supplementation preserved the gut tissue integrity and epithelial barrier by increasing the tight junction protein ZO-1. Therefore, LPc-G110 improves the gut-airway axis in CARAS by ameliorating inflammatory parameters in both compartments and is a promising candidate for preventing allergic airway diseases.

Mechanotransduction-induced interplay between phospholamban and yes-activated protein induces smooth muscle cell hypertrophy

The gastrointestinal system is a hollow organ affected by fibrostenotic diseases that cause volumetric compromise of the lumen via smooth muscle hypertrophy and fibrosis. Many of the driving mechanisms remain unclear. Yes-associated protein-1 (YAP) is a critical mechanosensory transcriptional regulator that mediates cell hypertrophy in response to elevated extracellular rigidity. In the type 2 inflammatory disorder, eosinophilic esophagitis (EoE), phospholamban (PLN) can induce smooth muscle cell hypertrophy. We used EoE as a disease model for understanding a mechanistic pathway in which PLN and YAP interact in response to rigid extracellular substrate to induce smooth muscle cell hypertrophy. PLN induced YAP nuclear sequestration in a feed forward loop that caused increased cell size in response to rigid substrate. This mechanism of rigidity sensing may have previously unappreciated clinical implications for PLN expressing hollow systems such as the esophagus and heart.

Role of mechanoregulation in mast cell-mediated immune inflammation of the smooth muscle in the pathophysiology of esophageal motility disorders.

Major esophageal disorders involve obstructive transport of bolus to the stomach, causing symptoms of dysphagia and impaired clearing of the refluxed gastric contents. These may occur due to mechanical constriction of the esophageal lumen or loss of relaxation associated with deglutitive inhibition, as in achalasia-like disorders. Recently, immune inflammation has been identified as an important cause of esophageal strictures and the loss of inhibitory neurotransmission. These disorders are also associated with smooth muscle hypertrophy and hypercontractility, whose cause is unknown. This review investigated immune inflammation in the causation of smooth muscle changes in obstructive esophageal bolus transport. Findings suggest that smooth muscle hypertrophy occurs above the obstruction and is due to mechanical stress on the smooth muscles. The mechanostressed smooth muscles release cytokines and other molecules that may recruit and microlocalize mast cells to smooth muscle bundles, so that their products may have a close bidirectional effect on each other. Acting in a paracrine fashion, the inflammatory cytokines induce genetic and epigenetic changes in the smooth muscles, leading to smooth muscle hypercontractility, hypertrophy, and impaired relaxation. These changes may worsen difficulty in the esophageal transport. Immune processes differ in the first phase of obstructive bolus transport, and the second phase of muscle hypertrophy and hypercontractility. Moreover, changes in the type of mechanical stress may change immune response and effect on smooth muscles. Understanding immune signaling in causes of obstructive bolus transport, type of mechanical stress, and associated smooth muscle changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.NEW & NOTEWORTHY Esophageal disorders such as esophageal stricture or achalasia, and diffuse esophageal spasm are associated with smooth muscle hypertrophy and hypercontractility, above the obstruction, yet the cause of such changes is unknown. This review suggests that smooth muscle obstructive disorders may cause mechanical stress on smooth muscle, which then secretes chemicals that recruit, microlocalize, and activate mast cells to initiate immune inflammation, producing functional and structural changes in smooth muscles. Understanding the immune signaling in these changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.

OP30 Endothelial cell-mediated smooth muscle hyperplasia in Crohn’s disease intestinal strictures: Caveolin 1 as a potential therapeutic target

Abstract Background Intestinal stricture is a severe and common complication of Crohn’s disease (CD). Current therapies offer limited success and surgery is often needed. Smooth muscle hyperplasia and hypertrophy play a key role in CD stricture development. This study explores the transcriptomic features of fibrostenotic CD, focusing on the endothelial contribution to smooth muscle changes within intestinal strictures. Methods 9 CD patients undergoing surgery for fibrotic strictures were prospectively enrolled. Dissected samples from the stricture and the adjacent proximal and distal non-strictured areas were obtained from fresh specimens collected directly from the operating theatre. RNA was extracted from all samples for bulk-transcriptomic analysis. Differentially expressed genes (adj. p-value <0.05) were identified and pathway enrichment analysis pinpointed relevant pathways. Subsequently, single-cell RNA sequencing (scRNAseq) analysis was performed using the 10x Chromium Controller® platform. A total of 31.195 cells were sequenced and bioinformatic analysis revealed 13 distinct clusters based on the expression of key lineage target genes. To better characterise the nature of clusters expressing stromal like markers and positioned closely in the UMAP plot, a further subclustering was performed. This resulted in 5 groups, including plasma cells, endothelial cells, fibroblasts, epithelial cells and dendritic like cells. Results Bulk-transcriptomic analysis identified 81 genes differentially expressed in strictures compared to both proximal and distal regions. Notably, genes associated with leukocyte and macrophage recruitment and chemotaxis, namely Platelet and Endothelial Cell Adhesion Molecule 1 (PECAM1), C-C motif Chemokine Ligand 2 (CCL2), and Endothelin Receptor Type B (EDNRB), resulted overexpressed in strictures. scRNAseq identified a distinct subset of endothelial cells (CD34+, PECAM1+). Caveolin 1 (CAV1), a gene encoding for a structural protein predominantly expressed in smooth muscle cell plasma membrane invaginations, was exclusively up-regulated in endothelial cells of ileal stricture samples. Previous research linked CAV1 to smooth muscle proliferation and fibrosis in various organs. Conclusion This study highlights the pivotal role of endothelial cells in CD strictures. The transcriptomic analysis shows the involvement of inflammatory targets featured genes involved in transendothelial immune cell migration. Furthermore, the up-regulation of CAV1 in endothelial cells within stricture segments suggests a mechanistic connection between endothelial cells and smooth muscle hyperplasia in intestinal strictures. CAV1 holds promise as a potential therapeutic target in fibrostenotic CD.

Ayurvedic Management of Adenomyosis

Adenomyosis is a gynaecologic condition characterized by ectopic endometrial tissue within the uterine myometrium. Adenomyosis, if not treated can lead to endometriosis, and hence can lead to more complications and hysterectomy might be the option. But by using Ayurvedic formulation with properties like Anulomaka, Vatashamaka, Lekhagana, Rakta prasadaka etc properties patient got significant relief from pain and irregular menses along with improvement in quality of life. Uterine adenomyosis is a benign condition in which endometrium like epithelial and stromal tissues appear in myometrium, surrounded by hypertrophic smooth muscle. Endometrial cells from the lining of endometrial cavity, migrate; most commonly into the posterior side or back wall of uterus, as these cells respond to monthly hormonal change. Severity and symptoms associated with adenomyosis, directly proportional to degree of involvement and penetration of uterine muscle. Adenomyosis can cause heavy menstrual bleeding (cyclic or acyclic) or scanty menstruation (oligomennorhoea or hypomenorrhoea) along with dysmenorrhoea. So in this case study patient having adenomyosis presented symptom of dysmenorrhoea with scanty menses and irregular menses. In this study there is Sanga of Doshas predominantly of Vata- kapha, so Lekhana is accepted and Vatavaigunya is present were Mamsa-rakta dusti is present, so Vatanulomana and Rakta prasadan chikitsa is adapted. So adenomyosis can be compared in Ayurveda with Udavartini yonivyapada among 20 Yonivyapada.

Time-dependent progress of lower urinary tract dysfunction in streptozotocin-induced diabetic rats with or without low-dose insulin treatment.

Objectives: To examine time-dependent functional and structural changes of the lower urinary tract in streptozotocin-induced diabetic rats with or without low-dose insulin treatment and explore the pathophysiological characteristics of insulin therapy on lower urinary tract dysfunction (LUTD) caused by diabetes mellitus (DM). Methods: Female Sprague-Dawley rats were divided into five groups: normal control (NC) group, 4 weeks insulin-treated DM (4-DI) group, 4 weeks DM (4-DM) group, 8 weeks insulin-treated DM (8-DI) group and 8 weeks DM (8-DM) group. DM was initially induced by i.p. injection of streptozotocin (65 mg/kg), and then the DI groups received subcutaneous implantation of insulin pellets under the mid dorsal skin. Voiding behavior was evaluated in metabolic cages. The function of bladder and urethra in vivo were evaluated by simultaneous recordings of the cystometrogram and urethral perfusion pressure (UPP) under urethane anesthesia. The function of bladder and urethra in vitro were tested by organ bath techniques. The morphologic changes of the bladder and urethra were investigated using Hematoxylin-Eosin and Masson's staining. Results: Both 4-and 8-weeks diabetic rats have altered micturition patterns, including increased 12-h urine volume, urinary frequency/12 hours and voided volume. In-vivo urodynamics showed the EUS bursting activity duration is longer in 4-DM group and shorter in 8-DM group compared to NC group. UPP change in 8-DM were significantly lower than NC group. While none of these changes were found between DI and NC groups. Organ bath showed the response to Carbachol and EFS in bladder smooth muscle per tissue weights was decreased significantly in 4- and 8-weeks DM groups compared with insulin-treated DM or NC groups. In contrast, the contraction of urethral muscle and maximum urethral muscle contraction per gram of the tissue to EFS stimulation were significantly increased in 4- and 8-weeks DM groups. The thickness of bladder smooth muscle was time-dependently increased, but the thickness of the urethral muscle had no difference. Conclusions: DM-induced LUTD is characterized by time-dependent functional and structural remodeling in the bladder and urethra, which shows the hypertrophy of the bladder smooth muscle, reduced urethral smooth muscle relaxation and EUS dysfunction. Low-dose insulin can protect against diuresis-induced bladder over-distention, preserve urethral relaxation and protect EUS bursting activity, which would be helpful to study the slow-onset, time-dependent progress of DM-induced LUTD.

MR Imaging Findings of Uterine Adenomatoid Tumors.

Adenomatoid tumor is a rare benign genital tract neoplasm of mesothelial origin. Uterine adenomatoid tumors occur in the outer myometrium and may mimic leiomyomas. Because hormonal treatment is not applicable to adenomatoid tumors and laparoscopic enucleation is not easy as myomectomy, it is important to differentiate adenomatoid tumors from leiomyomas for the adequate treatment. The purpose of this study is to evaluate the MRI findings of adenomatoid tumor for the differentiation from leiomyoma. MRI findings of surgically proven 10 uterine adenomatoid tumors in 9 women were retrospectively evaluated with correlation to histopathological findings. All 10 tumors appeared as solid myometrial masses and showed heterogeneous signal intensity with admixture of partially ill-defined slight high-intensity areas containing abundant tubular tumor cells and well-defined myoma-like low-intensity areas reflecting smooth muscle hypertrophy on T2WI including 4 lesions with peripheral ring-like high intensity. High-intensity areas on T2WI tended to show high intensity on diffusion-weighted imaging (DWI) with relatively high apparent diffusion coefficient (ADC), suggesting T2 shine-through effect due to abundant tubules. Intra-tumoral hemorrhage revealed on MRI was rare. Early intense contrast-enhanced areas on dynamic contrast-enhanced study were observed dominantly within the high-intensity areas but rarely within the low-intensity areas on T2WI. The outer myometrial mass with the admixture of well-defined low- and ill-defined high-intensity areas on T2WI may be suggestive of adenomatoid tumor. Peripheral ring-like high intensity on T2WI and DWI may also be suggestive. Dynamic contrast-enhanced MR study may be helpful for the differentiation from leiomyoma.

New phosphodiesterase-4 inhibitors present airways relaxant activity in a guinea pig acute asthma model.

Asthma is a disease characterized by chronic inflammation and hyper responsiveness of airways. We aimed to assess the relaxant potential of phosphodiesterase-4 (PDE4) inhibitors N-sulfonilhidrazonic derivatives on non-asthmatic and asthmatic guinea pig trachea. Firstly, guinea pigs were sensitized and challenged with ovalbumin, and then morphological, and contractile changes were evaluated resulting from asthma, followed by evaluation of relaxant effect of derivatives on guinea pig trachea and the cAMP levels measurement by ELISA. It has been evidenced hypertrophy of airway smooth muscle, inflammatory infiltrate, and vascular abnormalities. Moreover, only sensitized tracheal rings were responsive to OVA. Contractile response to histamine, but not to carbachol, was greater in sensitized animals, however the relaxant response to aminophylline and isoprenaline were the same in non-asthmatics and asthmatics. N-sulfonilhidrazonic derivatives presented equipotent relaxant action independent of epithelium, with exception of LASSBio-1850 that presented a low efficacy (< 50%) and LASSBio-1847 with a 4-fold higher potency on asthmatics. LASSBio-1847 relaxant curve was impaired in the presence of propranolol and potentiated by isoprenaline in both groups. Furthermore, relaxation was potentiated 54- and 4-fold by forskolin in non-asthmatics and asthmatics, respectively. Likewise, LASSBio-1847 potentiated relaxant curve of aminophylline 147- and 4-fold in both groups. The PKA inhibitor H-89 impaired the relaxant potency of the derivative. Finally, LASSBio-1847 increased tracheal intracellular cAMP levels similarly to rolipram, selective PDE4 inhibitor, in both animals. LASSBio-1847 showed to be promising to relax guinea pig trachea from non-sensitized and sensitized guinea pigs by activation of β2-adrenergic receptors/AC/cAMP pathway.

Bronchial Asthma, Airway Remodeling and Lung Fibrosis as Successive Steps of One Process.

Bronchial asthma is a heterogeneous disease characterized by persistent respiratory system inflammation, airway hyperreactivity, and airflow obstruction. Airway remodeling, defined as changes in airway wall structure such as extensive epithelial damage, airway smooth muscle hypertrophy, collagen deposition, and subepithelial fibrosis, is a key feature of asthma. Lung fibrosis is a common occurrence in the pathogenesis of fatal and long-term asthma, and it is associated with disease severity and resistance to therapy. It can thus be regarded as an irreversible consequence of asthma-induced airway inflammation and remodeling. Asthma heterogeneity presents several diagnostic challenges, particularly in distinguishing between chronic asthma and other pulmonary diseases characterized by disruption of normal lung architecture and functions, such as chronic obstructive pulmonary disease. The search for instruments that can predict the development of irreversible structural changes in the lungs, such as chronic components of airway remodeling and fibrosis, is particularly difficult. To overcome these challenges, significant efforts are being directed toward the discovery and investigation of molecular characteristics and biomarkers capable of distinguishing between different types of asthma as well as between asthma and other pulmonary disorders with similar structural characteristics. The main features of bronchial asthma etiology, pathogenesis, and morphological characteristics as well as asthma-associated airway remodeling and lung fibrosis as successive stages of one process will be discussed in this review. The most common murine models and biomarkers of asthma progression and post-asthmatic fibrosis will also be covered. The molecular mechanisms and key cellular players of the asthmatic process described and systematized in this review are intended to help in the search for new molecular markers and promising therapeutic targets for asthma prediction and therapy.

Attenuated airways inflammation and remodeling in IL-37a and IL-37b transgenic mice with an ovalbumin-induced chronic asthma

BackgroundAsthma is a common chronic respiratory disease characterized by airways inflammation, hyperresponsiveness and remodeling. IL-37, an anti-inflammatory cytokine, consists of five splice isoforms, that is, a-e. Although it has been previously shown that recombinant human IL-37b is able to inhibit airway inflammation and hyperresponsiveness in animal models of asthma, the effects and difference of other IL-37 isoforms, such as IL-37a on features of asthma are unknown. MethodsAnimal models of chronic asthma were established using IL-37a and IL-37b transgenic mice with C57BL/6J background and wild-type (WT) mice sensitized and nasally challenged with ovalbumin (OVA). Airway hyperresponsiveness was measured using FlexiVent apparatus, while histological and immunohistological stainings were employed to measure airways inflammation and remodeling indexes, including goblet cell metaplasia, mucus production, deposition of collagen, hypertrophy of airway smooth muscles and pulmonary angiogenesis. ResultsCompared to WT mice, both IL-37a and IL-37b transgenic mice had significant reduced airway hyperresponsiveness and the declined total numbers of inflammatory cells, predominant eosinophils into airways and lung tissues. Furthermore, all features of airways remodeling, including degrees of mucus expression, collagen deposition, hypertrophy of smooth muscles, thickness of airways and neovascularization markedly decreased in IL-37 transgenic mice compared with OVA-treated WT mice. ConclusionOur data suggest that both IL-37a and IL-37b isoforms are able to not only ameliorate airways inflammation and airways hyperresponsiveness, but also greatly reduce airways structural changes of animal models of chronic asthma.

Hibiscus attenuates renovascular hypertension-induced aortic remodeling dose dependently: the oxidative stress role and Ang II/cyclophilin A/ERK1/2 signaling.

Introduction: The high levels of angiotensin II (Ang II) can modify the vascular tone, enhance vascular smooth muscle cells (VSMCs) proliferation and hypertrophy and increase the inflammatory cellular infiltration into the vessel wall. The old herbal nonpharmacological agent, Hibiscus (HS) sabdariffa L has multiple cardioprotective impacts; thus, we investigated the role of HS extract in amelioration of renovascular hypertension (RVH)-induced aortic remodeling. Materials and methods: Thirty-five rats (7/group) were randomly allocated into 5 groups; group: I: Control-sham group, and RVH groups; II, III, IV, and V. The rats in RVH groups were subjected to the modified Goldblatt two-kidneys, one clip (2K1C) for induction of hypertension. In group: II, the rats were left untreated whereas in group III, IV, and V: RVH-rats were treated for 6weeks with low dose hibiscus (LDH), medium dose hibiscus (MDH), and high dose hibiscus (HDH) respectively. Results: We found that the augmented pro-contractile response of the aortic rings was ameliorated secondary to the in-vivo treatment with HS dose dependently. The cyclophilin A (CyPA) protein levels positively correlated with the vascular adhesion molecule-1 (VCAM-1) and ERK1/2, which, in turn, contribute to the reactive oxygen species (ROS) production. Daily HS intake modified aortic renovation by enhancing the antioxidant capacity, restraining hypertrophy and fibrosis, downregulation of the metastasis associated lung adenocarcinoma transcript (MALAT1), and cyclophilin A (CyPA)/ERK1/2 levels. Discussion: Adding to the multiple beneficial effects, HS aqueous extract was able to inhibit vascular smooth muscle cell proliferation induced by 2K1C model. Thus, adding more privilege for the utilization of the traditional herbal extracts to attenuate RVH-induced aortopathy.

Immunohistochemical basing of the pathogenesis equality of varicose vein transformation in varicocele and varicose veins of the lower extremities

Background. Varicocele as well as varicose veins of the lower extremities are quite widespread. To date, the mechanisms of variceal transformation remain not completely clear.Aim. To study the immunohistochemical profile in order to substantiate the common pathogenesis of varicose veins transformation in varicocele and varicose veins of the lower limbs; to confirm the key role of undifferentiated connective tissue dysplasia syndrome in the development of these diseases.Materials and methods. Vein wall fragments from 24 male patients aged 6–35 years old divided into the corresponding groups: group 1–12 patients with varicocele, group 2–12 patients with varicose veins of the lower limbs. Control group – 5 practically healthy men (age 16–32 years). Immunohistochemical study was performed with monoclonal antibodies to collagen types III, IV, α-SMA, fibronectin, laminin, MMP-2 and MMP-9, TGF-β1.Results and discussion. Histological and immunohistochemical studies of vein wall biopsy specimens in both groups revealed similar morphological changes, different from the control group. When assessing the expression level of α-SMA in both study groups, there was marked expression in the bundles of hypertrophic smooth muscle cells (in the zone of wall thickening where fibrosis was minimal) and weak expression in the bundles of smooth muscle cells “enmeshed” in connective tissue sleeves. Collagen type III showed weak expression in the subintimal zone and between the bundles of superficially located smooth muscle cells in both study groups. Expression of type IV collagen was detected in the areas of wall thickening and hypertrophy of smooth muscle cells. In both groups there was a pronounced expression of fibronectin in the most altered sections of the vein walls, especially in the middle layer, around the bundles of smooth muscle cells. There was marked expression of MMP-2 in all layers of the wall, and overexpression of MMP-9 in the areas of wall thinning (in the subintimal zone and muscular layer). TGF-β1 overexpression was also detected in vein biopsy specimens from both groups, predominantly in areas of thinning and pronounced intermuscular fibrosis.Conclusion. Taking into account the similarity of immunohistochemical manifestations in the vein walls in varicocele and varicose veins of the lower limbs we can speak about the common morphogenetic mechanisms of their remodeling. Thus, we consider it possible to combine various forms of varicosity into a single disease – varicose vein disease.

The impact of conventional smoking versus electronic cigarette on the expression of VEGF, PEMPA1, and PTEN in rat prostate.

The use of electronic cigarettes (e-cigarettes), the alternative to conventional smoking, is increasing considerably worldwide; however, their safety is a matter of debate. Several studies have demonstrated their toxic effects, but no study assessed their effects on the prostate. The current study aimed at evaluating e-cigarettes and conventional smoking prostate toxicity and effects on the expression of vascular endothelial growth factor A (VEGFA), phosphatase and tensin (PTEN), and prostate transmembrane protein androgen induced 1 (PMEPA1). 30 young Wistar rats were categorized into three groups (n=10) as follows: the control group, the conventional smoking group, and the e-cigarette group. The case groups were exposed to cigarettes or e-cigarettes for 40minutes, 3 times a day for four months. Serum parameters, prostate pathology, and gene expression were measured at the end of the intervention. Data were analyzed by Graph Pad prism 9. Histopathological findings presented that both types of cigarette-induced hyperemia and induced inflammatory cell infiltration and hypertrophy of smooth muscle of the vascular wall in the e-cigarette group. Expression of PMEPA1, and VEGFA genes significantly increased in conventional (2.67-fold; P=0.0108, 1.80-fold; P=0.0461 respectively) and e-cigarettes (1.98-fold; P=0.0127, 1.34-fold; P=0.938, respectively) groups compared to the control group. Expression of the PTEN gene non-significantly decreased in the case of groups compared to the control group. We found no significant differences between the two groups in terms of PTEN and PMEPA1 expression, whereas VEGFA was significantly more expressed in a conventional smoking group compared to the e-cigarette group. Therefore, it seems that e-cigarettes could not be taken into account as a better option than conventional smoking, and quitting smoking still is the optimal option.

The role and mechanism of FTO in pulmonary vessels

ABSTRACT Pulmonary vascular remodeling (PVR) is the main factor of pulmonary hypertension (PH). The pathological characteristics of PVR are vascular smooth muscle hyperplasia, hypertrophy, and extensive damage. In vivo experiments, the expression of FTO in PH rat lung tissues of different rat models of hypoxia PH was observed by immunohistochemical method. mRNA microarray analysis was used to analyze the differential expressed genes in rat lung tissues. In vitro experiments, we developed models of overexpression and knockdown of FTO to study the effect of FTO protein expression on cell apoptotic, cell cycle, and the abundance of m6A. The expression of FTO was increased in PH rats. FTO knockdown can inhibit the proliferation of PASMCs, thereby regulating the cell cycle and reducing the expression of Cyclin D1 and the abundance of m6A, while overexpression of FTO leads to increased expression of Cyclin D1 and the abundance of m6A. FTO destroys the stability of Cyclin D1 by regulating the abundance of Cyclin D1 m6A, causing cell cycle arrest and inducing cell proliferation, thus inducing the occurrence and development of PVR in PH.