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Idiopathic pulmonary fibrosis (IPF) is characterised by lung scarring and stiffening, for which there is no effective cure. Based on the immunomodulatory and anti-fibrotic effects of induced pluripotent stem cell (iPSC) and mesenchymoangioblast-derived mesenchymal stem cells (iPSCs-MSCs), this study evaluated the therapeutic effects of iPSCs-MSCs in a bleomycin (BLM)-induced model of pulmonary fibrosis. Adult male C57BL/6 mice received a double administration of BLM (0.15 mg/day) 7-days apart and were then maintained for a further 28-days (until day-35), whilst control mice were administered saline 7-days apart and maintained for the same time-period. Sub-groups of BLM-injured mice were intravenously-injected with 1×106 iPSC-MSCs on day-21 alone or on day-21 and day-28 and left until day-35 post-injury. Measures of lung inflammation, fibrosis and compliance were then evaluated. BLM-injured mice presented with lung inflammation characterised by increased immune cell infiltration and increased pro-inflammatory cytokine expression, epithelial damage, lung transforming growth factor (TGF)-ß1 activity, myofibroblast differentiation, interstitial collagen fibre deposition and topology (fibrosis), in conjunction with reduced matrix metalloproteinase (MMP)-to-tissue inhibitor of metalloproteinase (TIMP) ratios and dynamic lung compliance. All these measures were ameliorated by a single or once-weekly intravenous-administration of iPSC-MSCs, with the latter reducing dendritic cell infiltration and lung epithelial damage, whilst promoting anti-inflammatory interleukin (IL)-10 levels to a greater extent. Proteomic profiling of the conditioned media of cultured iPSC-MSCs that were stimulated with TNF-α and IFN-γ, revealed that these stem cells secreted protein levels of immunosuppressive factors that contributed to the anti-fibrotic and therapeutic potential of iPSCs-MSCs as a novel treatment option for IPF.

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Metalloproteins play a crucial role in regulating different aspects of the immune system in humans. They have various functions in immunity, including recognizing and presenting antigens, aiding in the movement and effectiveness of immune cells, and facilitating interactions between the host and pathogens. Understanding how these proteins work can help us develop new methods to control the immune response in different diseases. Metalloproteins contain metal ions in their structure, which allows them to perform these diverse functions. They encompass a wide range of enzymes, signaling molecules, and structural proteins that utilize metal ions as cofactors for their activities. Examples of metalloproteins include superoxide dismutase, catalase, and metalloproteases, which regulate oxidative stress, inflammation, and tissue remodelling processes associated with immune activation. By studying their functions and the effects of their dysfunction, researchers can develop strategies to improve immune function and combat various diseases. This review explores the diverse functions of metalloproteins in immune processes, highlighting their significance in both health and disease.

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AIM: To determine the effects of implant timing and type of soft-tissue grafting on histological and histomorphometric outcomes in a preclinical model. MATERIALS AND METHODS: Four implant placement protocols were randomly applied at the mesial root sites of the third and fourth mandibular premolars in 10 mongrel dogs: immediate placement (group IP), early placement (group EP), delayed placement with/without alveolar ridge preservation (groups ARP and DP, respectively). A connective-tissue graft (CTG) or porcine-derived volume-stable collagen matrix (VCMX) was applied to enhance the ridge profile (simultaneously with implant placement in group IP and staged for others), resulting in five sites for each combination. All dogs were sacrificed 3 months after soft-tissue grafting. Histological and histomorphometric analyses were performed, and the data were analysed descriptively. RESULTS: CTG and VCMX were difficult to differentiate from the augmented area. The median total tissue thickness on the buccal aspect of the implant was largest in group IP/CTG (between 2.78 and 3.87 mm). The soft-tissue thickness was generally favourable with CTG at all implant placement timings. Within the DP groups, CTG yielded statistically significantly larger total and soft-tissue thickness than VCMX (p < .05). Among the groups with VCMX, group EP/VCMX showed the largest soft-tissue thickness at apical levels to the implant shoulder. CONCLUSIONS: CTG generally led to greater tissue thickness than VCMX.

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BACKGROUND: The inactive dephosphorylated and uncarboxylated form of the matrix Gla protein (dp-ucMGP) has been shown to be increased in plasma of inflammatory bowel disease (IBD) patients. Our aim was to assess if the plasmatic level of dp-ucMGP could reflect disease endoscopic activity, presence of strictures and cumulative structural bowel damage in Crohn's disease (CD) patients. METHODS: The plasmatic level of dp-ucMGP was measured in a monocentric cohort of prospectively recruited patients. The analysis was done by chemiluminescent immunoassay on blood samples collected the day of a planned ileocolonoscopy. In addition to classical clinical data (gender, age, body mass index (BMI), disease duration, current treatment), endoscopic data (disease location, Crohn's Disease Endoscopic Index of Severity (CDEIS), mucosal healing (MH), presence of 9 CD lesion types) and biological markers (faecal calprotectin and C-reactive protein (CRP)) were collected. The association between dp-ucMGP level and Lémann index was also investigated. Univariate linear regression was used to investigate the relationship between dp-ucMGP level and different parameters collected. RESULTS: A total of 82 ileocolonoscopies and dp-ucMGP assays were performed in 75 CD patients (45 females; 37 ileocolonic, 19 ileal and 19 colonic diseases) between October 2012 and November 2019. A total of 24 patients (29.3%) showed MH. The dp-ucMGP levels were not associated with MH, CDEIS, faecal calprotectin or CRP levels. Plasmatic dp-ucMGP levels increased significantly with age (p = 0.0032), disease duration (p = 0.0033), corticosteroids use (p = 0.019) and tended to increase in patients with intestinal strictures (p = 0.086) but not with the Lémann index. CONCLUSION: The significant increase of plasmatic dp-ucMGP levels with age, disease duration and the trend observed in patients with non-ulcerated strictures may suggest that this extracellular matrix protein could be a marker of tissue remodelling and physiological ageing of the gut.

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BACKGROUND & AIMS: Ectopic liver regeneration in the spleen is a promising alternative to organ transplantation for treating liver failure. To accommodate transplanted liver cells, the splenic tissue must undergo structural changes to increase extracellular matrix content, demanding a safe and efficient approach for tissue remodelling. METHODS: We synthesised sulphated hyaluronic acid (sHA) with an affinity for the latent complex of transforming growth factor-ß (TGF-ß) and cross-linked it into a gel network (sHA-X) via click chemistry. We injected this glycan into the spleens of mice to induce splenic tissue remodelling via supraphysiological activation of endogenous TGF-ß. RESULTS: sHA-X efficiently bound to the abundant latent TGF-ß in the spleen. It provided the molecular force to liberate the active TGF-ß dimers from their latent complex, mimicking the 'bind-and-pull' mechanism required for physiological activation of TGF-ß and reshaping the splenic tissue to support liver cell growth. Hepatocytes transplanted into the remodelled spleen developed into liver tissue with sufficient volume to rescue animals with a metabolic liver disorder (Fah-/- transgenic model) or following 90% hepatectomy, with no adverse effects observed and no additional drugs required. CONCLUSION: Our findings highlight the efficacy and translational potential of using sHA-X to remodel a specific organ by mechanically activating one single cytokine, representing a novel strategy for the design of biomaterials-based therapies for organ regeneration. IMPACT AND IMPLICATIONS: Cell transplantation may provide a lifeline to millions of patients with end-stage liver diseases, but their severely damaged livers being unable to accommodate the transplanted cells is a crucial hurdle. Herein, we report an approach to restore liver functions in another organ - the spleen - by activating one single growth factor in situ. This approach, based on a chemically designed polysaccharide that can mechanically liberate the active transforming growth factor-ß to an unusually high level, promotes the function of abundant allogenic liver cells in the spleen, rescuing animals from lethal models of liver diseases and showing a high potential for clinical translation.

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Cardiac cachexia is a deadly consequence of advanced heart failure that is characterised by the dysregulation of adipose tissue homeostasis. Once cachexia occurs with heart failure, it prevents the normal treatment of heart failure and increases the risk of death. Targeting adipose tissue is an important approach to treating cardiac cachexia, but the pathogenic mechanisms are still unknown, and there are no effective therapies available. Transcriptomics, metabolomics, and lipidomics were used to examine the underlying mechanisms of cardiac cachexia. Transcriptomics investigation of cardiac cachexia adipose tissue revealed that genes involved in fibrosis and monocyte/macrophage migration were increased and strongly interacted. The ECM-receptor interaction pathway was primarily enriched, as shown by KEGG enrichment analysis. In addition, gene set enrichment analysis revealed that monocyte chemotaxis/macrophage migration and fibrosis gene sets were upregulated in cardiac cachexia. Metabolomics enrichment analysis demonstrated that the sphingolipid signalling pathway is important for adipose tissue remodelling in cardiac cachexia. Lipidomics analysis showed that the adipose tissue of rats with cardiac cachexia had higher levels of sphingolipids, including Cer and S1P. Moreover, combined multiomics analysis suggested that the sphingolipid metabolic pathway was associated with inflammatory-fibrotic changes in adipose tissue. Finally, the key indicators were validated by experiments. In conclusion, this study described a mechanism by which the sphingolipid signalling pathway was involved in adipose tissue remodelling by inducing inflammation and fat fibrosis in cardiac cachexia.

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Uterine rupture during a trial of labor after caesarean delivery (CD) is a serious complication for mother and fetus. The lack of knowledge on histological features and molecular pathways of uterine wound healing has hindered research in this area from evolving over time. We analysed collagen content and turnover in uterine scars on a histological, molecular and ultrastructural level. Therefore, tissue samples from the lower uterine segment were obtained during CD from 16 pregnant women with at least one previous CD, from 16 pregnant women without previous CD, and from 16 non-pregnant premenopausal women after hysterectomy for a benign disease. Histomorphometrical collagen quantification showed, that the collagen content of the scar area in uterine wall specimens after previous CD was significantly higher than in the unscarred myometrium of the same women and the control groups. Quantitative real-time PCR of uterine scar tissue from FFPE samples delineated by laser microdissection yielded a significantly higher COL3A1 expression and a significantly lower COL1A2/COL3A1 ratio in scarred uteri than in samples from unscarred uteri. Histological collagen content and the expression of COL1A2 and COL3A1 were positively correlated, while COL1A2/COL3A1 ratio was negatively correlated with the histological collagen content. Transmission electron microscopy revealed a destroyed myometrial ultrastructure in uterine scars with increased collagen density. We conclude that the high collagen content in uterine scars results from an ongoing overexpression of collagen I and III. This is a proof of concept to enable further analyses of specific factors that mediate uterine wound healing.

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BACKGROUND: End-stage kidney disease and acquired cystic kidney disease are the final stages of chronic kidney disease, leading to loss of kidney function and frequent development of tumours. It has been suggested that an inflammatory microenvironment may be responsible for the progressive kidney remodelling and cancer development. METHODS: Our aim was to analyse gene expression suggested to be involved in the remodelling of kidneys in end-stage kidney disease, and in the development of preneoplastic lesions and tumours. Immunohistochemistry was employed to assess the cellular localisation of different genes involved in these pathways on representative tissue sections. RESULTS: Cellular (αSMA positive naïve activated fibroblasts, endothelial cells, macrophages) and non-cellular components (cytokines IL6, TGFß, IL1ß, CSF2, fibronectin, laminin, and matrix modifier proteases MMP9 and MMP12) of the inflammatory microenvironment were expressed in the kidneys of patients with end-stage kidney disease. IL6 and FN1 expressing naïve activated fibroblasts and recruited inflammatory cells were the most abundant cellular components of the inflammatory microenvironment. CONCLUSION: The progressive inflammatory and fibrotic processes in end-stage kidney disease have features recalling those of  a never healing wound and may explain the frequent development of kidney cancer.

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Aim: The relationship between ligaments and bone is a complex and heterogeneous junction involving bone, mineralized fibro cartilage, non-mineralized fibro cartilage and ligaments. Mesenchymal stem cells (MSC) can be used in vivo to control inflammation and aid in tissue repair, according to studies. This review focused on using exosomes as an alternative to MSC, as a cell-free therapy for modulating the remodelling process. Methods: To conduct a systematic review of the literature, the phrases "exosome" and "ligament" or "tendon" and "extracellular vesicle" and "stem cells" were used as the search keywords in PubMed (MEDLINE), OVID, the Cochrane Library, and Science Direct. From the literature, 73 studies in all were found. Six studies were included in this systematic review after full-text evaluation. Results: Six included studies covered a range of MSC types, isolation techniques, animal models, and interventions. Biomechanical results consistently indicated the beneficial impact of conditioned media, vesicles, and exosomes on treating tendons and ligaments. Noteworthy findings were the reduction of inflammation by iMSC-IEVs, chondrocyte protection by iPSC-EVs (extracellular vesicles generated by inflammation-primed adipose-derived stem cells), osteolysis treatment using DPSC-sEVs (small extracellular vesicles derived from dental pulp stem cells), and the contribution of exosome-educated macrophages to ligament injury wound healing. Conclusion: Exosomes may serve as a cell-free therapeutic substitute for modulating the remodelling process, particularly in ligament healing.

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While the aetiology of asthma is unclear, the onset and/or exacerbation of asthma may be associated with respiratory infections. Virus-induced asthma is also known as virus-associated/triggered asthma, and the reported main causative agent is rhinovirus (RV). Understanding the relationship between viral infections and asthma may overcome the gaps in deferential immunity between viral infections and allergies. Moreover, understanding the complicated cytokine networks involved in RV infection may be necessary. Therefore, the complexity of RV-induced asthma is not only owing to the response of airway and immune cells against viral infection, but also to allergic immune responses caused by the wide variety of cytokines produced by these cells. To better understand RV-induced asthma, it is necessary to elucidate the nature RV infections and the corresponding host defence mechanisms. In this review, we attempt to organise the complexity of RV-induced asthma to make it easily understandable for readers.

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Background: Obesity is associated with enhanced lipid accumulation and the expansion of adipose tissue accompanied by hypoxia and inflammatory signalling. Investigation in human subcutaneous white adipose tissue (scWAT) in people living with obesity in which metabolic complications such as insulin resistance are yet to manifest is limited, and the mechanisms by which these processes are dysregulated are not well elucidated. Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have been shown to modulate the expression of genes associated with lipid accumulation and collagen deposition and reduce the number of inflammatory macrophages in adipose tissue from individuals with insulin resistance. Therefore, these lipids may have positive actions on obesity associated scWAT hypertrophy and inflammation. Methods: To evaluate obesity-associated tissue remodelling and responses to LC n-3 PUFAs, abdominal scWAT biopsies were collected from normal weight individuals and those living with obesity prior to and following 12-week intervention with marine LC n-3 PUFAs (1.1 g EPA + 0.8 g DHA daily). RNA sequencing, qRT-PCR, and histochemical staining were used to assess remodelling- and inflammatory-associated gene expression, tissue morphology and macrophage infiltration. Results: Obesity was associated with scWAT hypertrophy (P < 0.001), hypoxia, remodelling, and inflammatory macrophage infiltration (P = 0.023). Furthermore, we highlight the novel dysregulation of Wnt signalling in scWAT in non-insulin resistant obesity. LC n-3 PUFAs beneficially modulated the scWAT environment through downregulating the expression of genes associated with inflammatory and remodelling pathways (P <0.001), but there were altered outcomes in individuals living with obesity in comparison to normal weight individuals. Conclusion: Our data identify dysregulation of Wnt signalling, hypoxia, and hypertrophy, and enhanced macrophage infiltration in scWAT in non-insulin resistant obesity. LC n-3 PUFAs modulate some of these processes, especially in normal weight individuals which may be preventative and limit the development of restrictive and inflammatory scWAT in the development of obesity. We conclude that a higher dose or longer duration of LC n-3 PUFA intervention may be needed to reduce obesity-associated scWAT inflammation and promote tissue homeostasis. Clinical Trial Registration: www.isrctn.com, identifier ISRCTN96712688.

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Gastro-intestinal nematode (GIN) parasites are a major cause of production losses in grazing cattle, primarily through reduced growth rates in young animals. Control of these parasites relies heavily on anthelmintic drugs; however, with growing reports of resistance to currently available anthelmintics, alternative methods of control are required. A major hurdle in this work has been the lack of physiologically relevant in vitro infection models that has made studying precise interactions between the host and the GINs difficult. Such mechanistic insights into the infection process will be valuable for the development of novel targets for drugs, vaccines, or other interventions. Here we created bovine gastric epithelial organoids from abomasal gastric tissue and studied their application as in vitro models for understanding host invasion by GIN parasites. Transcriptomic analysis of gastric organoids across multiple passages and the corresponding abomasal tissue showed conserved expression of tissue-specific genes across samples, demonstrating that the organoids are representative of bovine gastric tissue from which they were derived. We also show that self-renewing and self-organising three-dimensional organoids can also be serially passaged, cryopreserved, and resuscitated. Using Ostertagia ostertagi, the most pathogenic gastric parasite in cattle in temperate regions, we show that cattle gastric organoids are biologically relevant models for studying GIN invasion in the bovine abomasum. Within 24 h of exposure, exsheathed larvae rapidly and repeatedly infiltrated the lumen of the organoids. Prior to invasion by the parasites, the abomasal organoids rapidly expanded, developing a 'ballooning' phenotype. Ballooning of the organoids could also be induced in response to exposure to parasite excretory/secretory products. In summary, we demonstrate the power of using abomasal organoids as a physiologically relevant in vitro model system to study interactions of O. ostertagi and other GIN with bovine gastrointestinal epithelium.

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Cold and nutrient-activated brown adipose tissue (BAT) is capable of increasing systemic energy expenditure via the uncoupled respiration and secretion of endocrine factors, thereby protecting mice against diet-induced obesity and improving insulin response and glucose tolerance in men. Long non-coding RNAs (lncRNAs) have recently been identified as fine-tuning regulators of cellular function. While certain lncRNAs have been functionally characterised in adipose tissue, their overall contribution in the activation of BAT remains elusive. We identified lncRNAs correlating to interscapular brown adipose tissue (iBAT) function in a high fat diet (HFD) and cold stressed mice. We focused on Gm15551, which has an adipose tissue specific expression profile, is highly upregulated during adipogenesis, and downregulated by ß-adrenergic activation in mature adipocytes. Although we performed comprehensive transcriptional and adipocyte physiology profiling in vitro and in vivo, we could not detect an effect of gain or loss of function of Gm15551.

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BACKGROUND: Metabolic diseases, including type 2 diabetes, have long been considered incurable, chronic conditions resulting from a variety of pathological conditions in obese patients. Growing evidence suggests the Wnt/ß-catenin pathway is a major pathway in adipose tissue remodelling, pancreatic ß-cell regeneration and energy expenditure through regulation of key metabolic target genes in various tissues. CXXC5-type zinc finger protein 5 (CXXC5) is identified negative feedback regulator of the Wnt/ß-catenin pathway that functions via Dishevelled (Dvl) binding. METHODS: Expression level of CXXC5 was characterised in clinical samples and diabetes-induced mice model. Diabetes-induced mice model was established by using high-fat diet (HFD). HFD-fed mice treated with KY19334, a small molecule inhibiting CXXC5-Dvl protein-protein interaction (PPI), was used to assess the role of CXXC5 in metabolic diseases. RESULTS: Here, we show that CXXC5 is overexpressed with suppression of Wnt/ß-catenin signalling in visceral adipose tissues of patients with obesity-related diabetes. Meanwhile, Cxxc5-/- mice fed an HFD exhibited resistance to metabolic dysregulation. KY19334 restores the lowered Wnt/ß-catenin signalling and reverses metabolic abnormalities as observed in HFD-fed Cxxc5-/- mice. Administration of KY19334 on HFD-fed mice had a long-lasting glucose-controlling effect through remodelling of adipocytes and regeneration of pancreatic ß-cells. CONCLUSION: Overall, the inhibition of CXXC5 function by small molecule-mediated interference of Dvl binding is a potential therapeutic strategy for the treatment of obesity-related diabetes.

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AIM: To determine the effect of (1) implant placement timing and (2) the type of soft tissue graft in terms of ridge profile changes. MATERIALS AND METHODS: Four implant treatment modalities were applied in the mesial root areas of the third and fourth mandibular premolars of 10 mongrel dogs alongside connective-tissue graft (CTG) and volume-stable cross-linked collagen matrix (VCMX): immediate, early, and delayed placement (DP), and DP following alveolar ridge preservation (ARP). All dogs were sacrificed 3 months after soft tissue augmentation. Standard Tessellation Language files from designated time points were analysed. RESULTS: Compared with the pre-extraction situation, the median width of the ridge demontstrated a linear increase only in group ARP/CTG (0.07 mm at the 2-mm level), whereas all other groups showed a reduction (between -1.87 and -0.09 mm, p > .05). Groups ARP/CTG (0.17 mm) and DP/CTG (0.05 mm) exhibited a profilometric tissue gain in a set region of interest (p > .05). The net effect of CTG and VCMX ranged from 0.14 to 0.79 mm. CONCLUSIONS: Dimensional ridge changes varied between treatment protocols. ARP with CTG led to the smallest difference in ridge profile between the pre-extraction and the study end time point. Both CTG and VCMX enhanced the ridge contour.

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BACKGROUND Angiogenesis has been implicated in tissue injury in several noninfectious diseases, but its role in Chagas disease (CD) physiopathology is unclear. OBJECTIVES The present study aimed to investigate the effect of Trypanosoma cruzi infection on cardiac angiogenesis during the acute phase of experimental CD. METHODS The signalling pathway involved in blood vessel formation and cardiac remodelling was evaluated in Swiss Webster mice infected with the Y strain of T. cruzi. The levels of molecules involved in the regulation of angiogenesis, such as vascular endothelial growth factor-A (VEGF-A), Flk-1, phosphorylated extracellular-signal-regulated protein kinase (pERK), hypoxia-inducible factor-1α (HIF-1α), CD31, α-smooth muscle actin (α-SMA) and also the blood vessel growth were analysed during T. cruzi infection. Hearts were analysed using conventional histopathology, immunohistochemistry and western blotting. FINDINGS In this study, our data demonstrate that T. cruzi acute infection in mice induces exacerbated angiogenesis in the heart and parallels cardiac remodelling. In comparison with noninfected controls, the cardiac tissue of T. cruzi-infected mice presented higher levels of (i) HIF-1α, VEGF-A, Flk-1 and pERK; (ii) angiogenesis; (iii) α-SMA+ cells in the tissue; and (iv) collagen -1 deposition around blood vessels and infiltrating throughout the myocardium. MAIN CONCLUSIONS We observed cardiac angiogenesis during acute experimental T. cruzi infection parallels cardiac inflammation and remodelling.

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Cellular senescence is a highly complex and programmed cellular state with diverse and, at times, conflicting physiological and pathological roles across the lifespan of an organism. Initially considered a cell culture artifact, senescence evolved from an age-related circumstance to an intricate cellular defense mechanism in response to stress, implicated in a wide spectrum of biological processes like tissue remodelling, injury and cancer. The development of new tools to study senescence in vivo paved the way to uncover its functional roles in various frameworks, which are sometimes hard to reconcile. Here, we review the functional impact of senescent cells on different organismal contexts. We provide updated insights on the role of senescent cells in tissue repair and regeneration, in which they essentially modulate the levels of fibrosis and inflammation, discussing how "time" seems to be the key maestro of their effects. Finally, we overview the current clinical research landscape to target senescent cells and contemplate its repercussions on this fast-evolving field.

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Rationale: The accumulation of macrophages in the airways and the pulmonary interstitium is a hallmark of cigarette smoke-associated inflammation. Notably, pulmonary macrophages are not a homogenous population but consist of several subpopulations. To date, the manner in which cigarette smoke exposure affects the relative composition and functional capacity of macrophage subpopulations has not been elucidated. Methods: Using a whole-body cigarette smoke exposure system, we investigated the impact of cigarette smoke on macrophage subpopulations in C57BL/6 mice using flow cytometry-based approaches. Moreover, we used bromodeoxyuridine labelling plus Il1a-/- and Il1r1-/- mice to assess the relative contribution of local proliferation and monocyte recruitment to macrophage accumulation. To assess the functional consequences of altered macrophage subpopulations, we used a model of concurrent bleomycin-induced lung injury and cigarette smoke exposure to examine tissue remodelling processes. Main Results: Cigarette smoke exposure altered the composition of pulmonary macrophages increasing CD11b+ subpopulations including monocyte-derived alveolar macrophages (Mo-AM) as well as interstitial macrophages (IM)1, -2 and -3. The increase in CD11b+ subpopulations was observed at multiple cigarette smoke exposure timepoints. Bromodeoxyuridine labelling and studies in Il1a-/- mice demonstrated that increased Mo-AM and IM3 turnover in the lungs of cigarette smoke-exposed mice was IL-1α dependent. Compositional changes in macrophage subpopulations were associated with impaired induction of fibrogenesis including decreased α-smooth muscle actin positive cells following intratracheal bleomycin treatment. Mechanistically, in vivo and ex vivo assays demonstrated predominant macrophage M1 polarisation and reduced matrix metallopeptidase 9 activity in cigarette smoke-exposed mice. Conclusion: Cigarette smoke exposure modified the composition of pulmonary macrophage by expanding CD11b+ subpopulations. These compositional changes were associated with attenuated fibrogenesis, as well as predominant M1 polarisation and decreased fibrotic activity. Overall, these data suggest that cigarette smoke exposure altered the composition of pulmonary macrophage subpopulations contributing to impaired tissue remodelling.

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Orthodontic tooth movement is based on the remodeling of tooth-surrounding tissues in response to mechanical stimuli. During this process, human periodontal ligament cells (hPDLCs) play a central role in mechanosensing and mechanotransduction. Various in vitro models have been introduced to investigate the effect of tension on hPDLCs. They provide a valuable body of knowledge on how tension influences relevant genes, proteins, and metabolites. However, no systematic review summarizing these findings has been conducted so far. Aim of this systematic review was to identify all related in vitro studies reporting tension application on hPDLCs and summarize their findings regarding force parameters, including magnitude, frequency and duration. Expression data of genes, proteins, and metabolites was extracted and summarized. Studies' risk of bias was assessed using tailored risk of bias tools. Signaling pathways were identified by protein-protein interaction (PPI) networks using STRING and GeneAnalytics. According to our results, Flexcell Strain Unit® and other silicone-plate or elastic membrane-based apparatuses were mainly adopted. Frequencies of 0.1 and 0.5 Hz were predominantly applied for dynamic equibiaxial and uniaxial tension, respectively. Magnitudes of 10 and 12% were mostly employed for dynamic tension and 2.5% for static tension. The 10 most commonly investigated genes, proteins and metabolites identified, were mainly involved in osteogenesis, osteoclastogenesis or inflammation. Gene-set enrichment analysis and PPI networks gave deeper insight into the involved signaling pathways. This review represents a brief summary of the massive body of knowledge in this field, and will also provide suggestions for future researches on this topic.