Inflammation-induced Fibrosis Research Articles

Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk.

Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.

An Assessment of Administration Route on MSC-sEV Therapeutic Efficacy.

Mesenchymal stem/stromal cell-derived small extracellular vesicles (MSC-sEVs) are promising therapeutic agents. In this study, we investigated how the administration route of MSC-sEVs affects their therapeutic efficacy in a mouse model of bleomycin (BLM)-induced skin scleroderma (SSc). We evaluated the impact of topical (TOP), subcutaneous (SC), and intraperitoneal (IP) administration of MSC-sEVs on dermal fibrosis, collagen density, and thickness. All three routes of administration significantly reduced BLM-induced fibrosis in the skin, as determined by Masson's Trichrome staining. However, only TOP administration reduced BLM-induced dermal collagen density, with no effect on dermal thickness observed for all administration routes. Moreover, SC, but not TOP or IP administration, increased anti-inflammatory profibrotic CD163+ M2 macrophages. These findings indicate that the administration route influences the therapeutic efficacy of MSC-sEVs in alleviating dermal fibrosis, with TOP administration being the most effective, and this efficacy is not mediated by M2 macrophages. Since both TOP and SC administration target the skin, the difference in their efficacy likely stems from variations in MSC-sEV delivery in the skin. Fluorescence-labelled TOP, but not SC MSC-sEVs when applied to skin explant cultures, localized in the stratum corneum. Hence, the superior efficacy of TOP over SC MSC-sEVs could be attributed to this localization. A comparison of the proteomes of stratum corneum and MSC-sEVs revealed the presence of >100 common proteins. Most of these proteins, such as filaggrin, were known to be crucial for maintaining skin barrier function against irritants and toxins, thereby mitigating inflammation-induced fibrosis. Therefore, the superior efficacy of TOP MSC-sEVs over SC and IP MSC-sEVs against SSc is mediated by the delivery of proteins to the stratum corneum to reinforce the skin barrier.

Increased Activity of MAPKAPK2 within Mesenchymal Cells as a Target for Inflammation-Associated Fibrosis in Crohn's Disease.

Mesenchymal stromal cells are suggested to play a critical role in Crohn's disease [CD]-associated fibrosis. MAPKAPK2 [MK2] has emerged as a potential therapeutic target to reduce inflammation in CD. However, the cell-specific pattern of phospho-MK2 activation and its role in CD-associated fibrosis are unknown. The objectives of this study were to evaluate cell-specific changes in MK2 activity between predominantly inflammatory CD vs CD with fibrotic complications and define the role of stromal cell-specific MK2 activation in CD-associated fibrosis. CD tissue, CD tissue-derived mesenchymal stromal cells known as myo-/fibroblasts [CD-MFs], and fibroblast-specific MK2 conditional knockout [KO] mice were used. In the inflamed area of predominantly inflammatory CD, high MK2 activity was equally distributed between mesenchymal and haematopoietic cells. By contrast, in CD with fibrotic complications, high MK2 activity was mostly associated with mesenchymal stromal cells. Using ex vivo CD tissue explants and an IL-10KO murine colitis model, we demonstrated that pro-fibrotic responses are significantly reduced by treatment with the MK2 inhibitor PF-3644022. Inhibition of MK2 activity in primary cultures of CD-MFs significantly reduced basal and TGF-β1-induced profibrotic responses. Using fibroblast-specific MK2 knockout mice in chronic dextran saline sulphate colitis, we demonstrated that fibroblast intrinsic MK2 signalling is among the key processes involved in the chronic inflammation-induced profibrotic responses. Our data suggest that activation of MK2 within fibroblasts contributes to the chronic inflammation-induced fibrosis in CD and that targeting MK2 has potential for the development of novel therapeutic approaches for fibrosis in CD.

Increased Collagen I/Collagen III Ratio Is Associated with Hemorrhage in Brain Arteriovenous Malformations in Human and Mouse.

Background: The increase in the collagen I (COL I)/COL III ratio enhances vessel wall stiffness and renders vessels less resistant to blood flow and pressure changes. Activated microglia enhance inflammation-induced fibrosis. Hypotheses: The COL I/COL III ratio in human and mouse brain arteriovenous malformations (bAVMs) is associated with bAVM hemorrhage, and the depletion of microglia decreases the COL I/COL III ratio and hemorrhage. Method: COL I, COL III, and hemorrhages were analyzed in 12 human bAVMs and 6 control brains, and mouse bAVMs induced in three mouse lines with activin receptor-like kinase 1 (n = 7) or endoglin (n = 7) deleted in the endothelial cells or brain focally (n = 5). The controls for the mouse study were no-gene-deleted litter mates. Mouse bAVMs were used to test the relationships between the Col I/Col III ratio and hemorrhage and whether the transient depletion of microglia reduces the Col I/Col III ratio and hemorrhage. Results: The COL I/COL III ratio was higher in the human and mouse bAVMs than in controls. The microhemorrhage in mouse bAVMs was positively correlated with the Col I/Col III ratio. Transient depletion of microglia reduced the Col I/Col III ratio and microhemorrhage. Conclusions: The COL I/COL III ratio in the bAVMs was associated with bAVM hemorrhage. The depletion of microglia reduced the bAVM Col I/Col III ratio and hemorrhage.

Extracellular Matrix Protein-1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction

Irreversible fibrosis is a hallmark of myocardial infarction (MI) and heart failure. Extracellular matrix protein-1 (ECM-1) is up-regulated in these hearts, localized to fibrotic, inflammatory, and perivascular areas. ECM-1 originates predominantly from fibroblasts, macrophages, and pericytes/vascular cells in uninjured human and mouse hearts, and from M1 and M2 macrophages and myofibroblasts after MI. ECM-1 stimulates fibroblast-to-myofibroblast transition, up-regulates key fibrotic and inflammatory pathways, and inhibits cardiac fibroblast migration. ECM-1 binds HuCFb cell surface receptor LRP1, and LRP1 inhibition blocks ECM-1 from stimulating fibroblast-to-myofibroblast transition, confirming a novel ECM-1-LRP1 fibrotic signaling axis. ECM-1 may represent a novel mechanism facilitating inflammation-fibrosis crosstalk.

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

Extracellular Matrix Protein 1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction

Fibrosis is a hallmark of heart disease, particularly following myocardial infarction (MI) and in heart failure. We previously identified a key role for extracellular matrix protein (ECM1) in wound healing post-MI but the cellular origin and mechanism of ECM1 remained elusive. Here, we investigate the spatiotemporal cellular origin of ECM1 in healthy and diseased human and mouse hearts, and ECM1 dependent human cardiac fibroblast (HuCFb) signalling mechanisms.

Baicalin attenuates fibrogenic process in human renal proximal tubular cells (HK−2) exposed to diabetic milieu

AimsBaicalin, a flavonoid glycoside substance extracted from Scutellaria baicalensis Georgi, has been shown to exhibit multiple therapeutic properties owing to its anti-inflammatory effect. Diabetes is characterized by chronic hyperglycemia, inflammation and oxidative stress, which promote renal fibrosis and kidney failure. Although anti-fibrogenic effects of baicalin in lung and liver have been reported previously, no study has investigated its roles in renal fibrosis. Here, we demonstrated protective effects of baicalin against fibrogenic process in human kidney proximal tubular epithelial cells (HK-2) exposed to diabetic milieu. Main methodsTo investigate the effects of baicalin on oxidative stress- and inflammation-induced fibrosis in HK-2 cells, protein and gene expressions of NF-κB- and STAT3-associated inflammatory molecules and TGFβ-associated extracellular matrix proteins were examined by western blotting, immunocytochemistry and qRT-PCR. To determine physiological changes of HK-2 exposed to diabetic milieu in response to baicalin, production of cAMP and cGMP and Ca2+ influx were measured. Key findingsBaicalin attenuated oxidative stress- and inflammation-inudced IκB and JAK2 phosphorylations and, subsequent, NF-κB nuclear translocation and STAT3 phosphorylation. Consequently, it markedly reduced transactivation of NF-κB- and STAT3-associated inflammatory genes such as ICAM1, VCAM1, TGFβ, IL1β and MCP1, and protein expression of TGFβ-associated extracellular matrix proteins, such as fibronectin and collagen IV. These effects are, partially, attributed to its regulatory function of intracellular concentration of Ca2+ via interaction with type A γ-aminobutyric acid receptor. SignificanceThis is the first study which investigated anti-fibrogenic effect of baicalin in human kidney cells, and our results highlight a potential therapeutic application of baicalin for diabetic nephropathy.

Trained immunity modulates inflammation-induced fibrosis

Chronic inflammation and fibrosis can result from inappropriately activated immune responses that are mediated by macrophages. Macrophages can acquire memory-like characteristics in response to antigen exposure. Here, we show the effect of BCG or low-dose LPS stimulation on macrophage phenotype, cytokine production, chromatin and metabolic modifications. Low-dose LPS training alleviates fibrosis and inflammation in a mouse model of systemic sclerosis (SSc), whereas BCG-training exacerbates disease in this model. Adoptive transfer of low-dose LPS-trained or BCG-trained macrophages also has beneficial or harmful effects, respectively. Furthermore, coculture with low-dose LPS trained macrophages reduces the fibro-inflammatory profile of fibroblasts from mice and patients with SSc, indicating that trained immunity might be a phenomenon that can be targeted to treat SSc and other autoimmune and inflammatory fibrotic disorders.

Fibroblastic Reticular Cells Control Conduit Matrix Deposition during Lymph Node Expansion

SummaryLymph nodes (LNs) act as filters, constantly sampling peripheral cues. This is facilitated by the conduit network, a tubular structure of aligned extracellular matrix (ECM) fibrils ensheathed by fibroblastic reticular cells (FRCs). LNs undergo rapid 3- to 5-fold expansion during adaptive immune responses, but these ECM-rich structures are not permanently damaged. Whether conduit flow or filtering function is affected during LN expansion is unknown. Here, we show that conduits are partially disrupted during acute LN expansion, but FRC-FRC contacts remain connected. We reveal that polarized FRCs deposit ECM basolaterally using LL5-β and that ECM production is regulated at transcriptional and secretory levels by the C-type lectin CLEC-2, expressed by dendritic cells. Inflamed LNs maintain conduit size exclusion, and flow is disrupted but persists, indicating the robustness of this structure despite rapid tissue expansion. We show how dynamic communication between peripheral tissues and LNs provides a mechanism to prevent inflammation-induced fibrosis in lymphoid tissue.

Inflammation-induced fibrosis in skeletal muscle of female carriers of Duchenne muscular dystrophy

Female carriers of DMD gene mutations may be symptomatic and show variable skeletal as well as cardiac muscle symptoms. Skeletal muscle can exhibit morphological alterations. However, inflammatory, degenerative and fibrotic changes as seen in Duchenne boys have not been specifically analysed yet, so we addressed the question whether skeletal muscle of female carriers show such alterations. Thirteen carriers with an age range of 3 to 50 years were studied retrospectively. Five out of 13 women had clinically affected relatives. Clinically, most women showed mild muscle weakness, while the CK levels were increased in nine of them. Histomorphological analyses highlighted the typical mosaic pattern of dystrophin-positive and -negative fibres. Regenerating fibres were diffusely scattered and focally pronounced, while endo- and perimysial fibrosis was a variable but constant feature. Infiltration of CD206+TGFß+ macrophages and scattered T cells was noted in the endomysium. TGFb and CCL18, were significantly increased. However, gene expression of markers involved in Th1/Th2 immunity did not reach statistical significance compared to non-diseased controls. In summary, skeletal muscle of clinically manifest female DMD gene mutation carriers shows mild fibrosis and increased regeneration associated with endomysial CD206+TGFβ+ and STAT6+ macrophages, which are most likely involved in fibrotic remodelling.

Conduit Integrity is Compromised During Acute Lymph Node Expansion

Lymph nodes (LNs) act as filters, constantly sampling peripheral cues. This is facilitated by the conduit network, a tubular structure of aligned extracellular matrix (ECM) fibrils ensheathed by fibroblastic reticular cells (FRCs). LNs undergo 3-5-fold expansion during each adaptive immune response but these ECM-rich structures are not permanently damaged. Whether conduit integrity and filtering function is affected during LN expansion is unknown. Here we show that conduits are disrupted during acute LN expansion but FRC-FRC contacts remain connected. We reveal that polarised FRCs deposit ECM basolaterally utilising LL5-β, and that ECM production is regulated at transcriptional and secretory levels by the C-type lectin CLEC-2, expressed by dendritic cells. Inflamed LNs maintain conduit size-exclusion, but flow becomes leaky, allowing soluble molecules increased access to antigen-presenting cells. We show how dynamic communication between peripheral tissues and LNs changes during immune responses, and describe a mechanism enabling LNs to prevent inflammation-induced fibrosis.

Comparison of surgical outcomes of trabeculectomy, Ahmed shunt, and Baerveldt shunt in uveitic glaucoma

BackgroundUveitis is defined as a collection of syndromes involving intraocular inflammation which can lead to pain, tissue damage, and vision loss. Ophthalmic surgery in uveitis patients can be challenging due to inflammation-induced fibrosis and scarring. Trabeculectomy and implantation of glaucoma drainage devices (aqueous shunts) have been used in surgical management of uveitic glaucoma, however there is a paucity of literature examining the comparative results of these entities in this unique setting. The purpose of this retrospective comparative study is to compare clinical outcomes of trabeculectomy with MMC, Ahmed shunt, and Baerveldt shunt surgery specifically in uveitic glaucoma.ResultsMedian IOP, IOP reduction, glaucoma medication use, and visual acuity at 6- and 12-month follow-up were similar across groups. Postoperative hypotony rate was significantly different across trabeculectomy (53%), Baerveldt (24%), and Ahmed (18%) groups (p = 0.027); other complication rates were similar. Baerveldt eyes had a lower failure rate compared to trabeculectomy (p = 0.0054) and Ahmed (p = 0.0008) eyes.ConclusionsWhile there was no difference in IOP reduction between trabeculectomy, Ahmed, and Baerveldt, Baerveldt eyes had the lowest failure rate.

MP45-07 ROLES OF PROSTATE ENLARGEMENT, INFLAMMATION AND FIBROSIS IN BLADDER OUTLET OBSTRUCTION

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology1 Apr 2018MP45-07 ROLES OF PROSTATE ENLARGEMENT, INFLAMMATION AND FIBROSIS IN BLADDER OUTLET OBSTRUCTION Matthew D Grimes, Andrew Schneider, Sijian Wang, and Wade Bushman Matthew D GrimesMatthew D Grimes More articles by this author , Andrew SchneiderAndrew Schneider More articles by this author , Sijian WangSijian Wang More articles by this author , and Wade BushmanWade Bushman More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1446AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate enlargement, inflammation and fibrosis have all been implicated in the genesis of LUTS in aging men. Recent studies in our laboratory demonstrated that prostate inflammation induced an increase in prostate collagen (fibrosis) and this finding suggested that inflammation-induced fibrosis in the human prostate contributes to development of bladder outlet obstruction (BOO). Using surgical specimens from a cohort of patients with BPH/LUTS, we performed quantitative analysis of inflammation and collagen content to test the hypothesis that histologic inflammation is positively correlated with prostate collagen content and to evaluate the role of fibrosis in BOO. METHODS We identified 44 men who underwent either TURP or open simple prostatectomy (OSP) for BPH/LUTS for whom preoperative urodynamic data were available. Prostate volume was calculated from CT or TRUS using the ellipsoid formula. Inflammation was quantitated using a consensus scoring system for prostate inflammation (Nickel, et al., 2001) and the total inflammation score represented the sum of stromal, epithelial and glandular inflammation. Collagen was quantitated using a previously validated quantitative method of picrosirius red staining for collagen and image J analysis (Wong et al., 2014). Bladder outlet obstruction index (BOOI) was calculated from the formula BOOI = PdetQmax - 2Qmax. RESULTS The surgical cohort included 35 men (77%) who underwent TURP and 11 (23%) who underwent OSP. Median age was 63 (IQR 55.8-73.3) and median prostate volume 48cc (IQR 37-82.4). We observed a significant correlation between BOOI and prostate volume (p-value=0.04) and linear regression analysis suggested the contribution of prostate enlargement to BOOI is greater for larger glands (>45g). We observed no significant correlation between inflammation and collagen content and no significant contribution of fibrosis to BOOI. CONCLUSIONS These data affirm a positive correlation of prostate volume with BOOI but do support the hypothesis that inflammation-induced fibrosis contributes to obstruction in most men. The suggestion that prostate volume makes a greater contribution to obstruction in larger glands suggests differing drivers of BOO in patients with smaller prostates. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e599 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Matthew D Grimes More articles by this author Andrew Schneider More articles by this author Sijian Wang More articles by this author Wade Bushman More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Young Investigator: Use of High Resolution Anorectal Manometry in UC Patients in Remission With Persistent Anorectal Symptoms

BACKGROUND: A group of patients with UC continue to present symptomatology despite being in remission. Previous studies with conventional anorectal manometry in patients with active UC or remission, decreased rectal compliance was reported, and sphincter pressures within normal parameters. Because of inflammation-induced fibrosis in activity periods, decreased rectal compliance has been proposed as the cause of persistent symptomatology, in remission. Our aim was evaluated UC patients in remission with persistent anorectal symptoms with HRAM. METHODS: Patients in remission in the Montreal and Mayo activity score for colonoscopy, from July 1, 2015 to June 31, 2016. Inclusion criteria:> 18 years, anorectal symptoms, signing of consent for HRAM. Exclusion criteria: alterations in proctological examination, loss of remission, anorectal surgery. A Manoscan 360 Sierra Scientific device with solid-state catheter, Manoview 2.1 software, was used. The mean volume for the first sensation, sensation and urgency of defecation, mean basal pressure of the sphincter and maximum contraction were reported. We analyzed the association between symptoms and HRAM results with the t test, and the association between symptoms and the extent of disease and evolution with X2. P=<0.5 to two tails was taken as significant. Analyzed with SPSS v22. RESULTS: The inclusion criteria were 17 patients with anorectal symptoms, 9 accepted HRAM. The median age: 59 years, with 14 years of evolution, 66.7% female gender. Patients who accepted HRAM, according to Montreal: E3 44.4%, E1 33.3% and E2 22.2%; 66.7% were Mayo 1 and Mayo 0, 33.3%. 55.6% had tenesmus, fecal incontinence 22.2%, proctalgia 22.2% and constipation 22.2%. Two patients had constipation and tenesmus, one proctalgia and tenesmus. The median anal resting and squeeze of female patients: anal resting 71.25 mmHg (42.5-75.9), squeeze 132 mmHg (86.7-267.5). In male patients: anal resting 84.6 (82.6-92.3) and squeeze 251.4 mmHg (208.9-273.2). Volume for first sensation in female: 40 mL (30-50) and urge to defecate 150 mL (120-160). Volume in male: first sensation 50 mL (20-60) and urge to defecate 140 mL (140-150). Two presented paradoxical contraction. We found correlation of proctalgia with first sensation with P=0.210 and urge to defecate P=0.015. There was no relationship of symptoms with years of evolution or extension of UC. CONCLUSION(S): The persistence of anorectal symptoms in patients with UC in remission is high. In our study, the most frequent symptom is tenesmus (55.6%). Patients had hyposensitivity and decreased rectal capacity. The anorectal symptoms are not related to years of evolution and extent of disease. There is correlation between proctalgia and changes in rectal capacity reported in HRAM.

The effect of Nigella sativa on inflammation-induced myocardial fibrosis in male rats.

Nigella sativa (NS) (Ranunculaceae) used as a protective and therapeutic traditional medicine. This study evaluates the effect of NS on inflammation-induced myocardial fibrosis, serum and tissue inflammatory markers, and oxidative stress status in male rats. Fifty male Wistar rats were divided into five groups: (1) control; (2) lipopolysaccharide (LPS), 1 mg/kg/day; (3) LPS + NS (hydroalcoholic extract), 100 mg/kg/day; (4) LPS + NS, 200 mg/kg/day; (5) LPS + NS, 400 mg/kg/day (n = 10 in each group). The duration of LPS administration was two weeks. At the end of the experiment, blood samples were taken and ventricles were homogenized and stained for histological evaluation. Serum nitrite levels were lower in LPS group than the control group (22.98 ± 1.03 vs 28.5 ± 0.93 μmol/L), in which they were significantly increased by NS treatment (P < 0.05). Higher levels of heart interlukine-6 (IL-6) and tumor necrosis factor-α (TNF-α) were observed in LPS group compared to the controls (IL-6: 6805 ± 656 vs 4733 ± 691 pg/mL; TNF-α: 6504 ± 501 vs 5309 ± 452 pg/mL), in which they were reduced by NS 400 mg/kg compared to LPS groups (P < 0.05). A significant increment of malondialdehyde and reduction in heart total thiol, superoxide dismutase and catalase concentrations were observed in LPS group (p < 0.05) which significantly restored with treatment by three doses of NS. Histopathological studies showed higher inflammatory cell infiltrates, cardiac fibrosis, and collagen deposition in LPS group, which were reduced by the administration of NS. Treatment by NS reduced myocardial fibrosis in inflammation-induced fibrosis, possibly through improving oxidative/anti-oxidative balance.

Green Tea Polyphenols and 1-α-OH-Vitamin D3Attenuate Chronic Inflammation-Induced Myocardial Fibrosis in Female Rats

Studies have suggested that 1-α-OH-vitamin D₃ and green tea polyphenols (GTPs) are promising dietary supplements for mitigating chronic inflammation-induced fibrosis of vessels because of their anti-inflammatory properties. This study evaluated (1) the impact of 1-α-OH-vitamin D₃ on myocardial fibrosis in female rats with chronic inflammation and (2) if 1-α-OH-vitamin D₃ and GTPs have an additive or synergistic effect to attenuate myocardial fibrosis in these female rats. A 3-month study of a 2 (no 1-α-OH-vitamin D₃ vs. 0.05 μg/kg 1-α-OH-vitamin D₃, five times per week) ×2 (no GTPs vs. 0.5% GTPs in drinking water) factorial design in lipopolysaccharide (LPS)-administered female rats was performed. Additionally, a group receiving placebo administration was used to compare with a group receiving LPS administration only to evaluate the effect of LPS. Masson's Trichrome staining evaluated myocardial fibrosis in coronary vessels and surrounding myocardium. Spleen cyclooxygenase-2 mRNA expression was determined by real-time polymerase chain reaction. Total lipid profiles were also determined. Whole blood was used for differential cell counts. Data were analyzed by two-way analysis of variance followed by mean separation procedures. At 3 months LPS administration induced myocardial fibrosis in vessels and surrounding myocardium, spleen cyclooxygenase-2 mRNA expression, and elevated leukocyte counts, whereas both 1-α-OH-vitamin D₃ administration and GTPs supplementation significantly attenuated these pro-inflammatory events. The inhibitory effects of 1-α-OH-vitamin D₃ and GTPs seem to be an individual effect, instead of an additive or synergistic effect. 1-α-OH-vitamin D₃ and GTPs lowered red blood cell counts, hematocrit, and hemoglobin. Neither 1-α-OH-vitamin D₃ nor GTPs affected lipid profiles. In summary, both 1-α-OH-vitamin D₃ administration and GTPs supplementation mitigate myocardial fibrosis through suppression of a chronic inflammation innate immune response.

Themes in fibrosis and gastrointestinal inflammation

Wound healing is an appropriate response to inflammation and tissue injury in the gastrointestinal tract. If wound healing responses are excessive, perpetuated, or prolonged, they lead to fibrosis, distortion of tissue architecture, and loss of function. This introductory editorial and the minireviews or reviews in this themes series highlight the diversity in severity and location of fibrosis in response to gastrointestinal inflammation. The multiplicity of cellular and molecular mediators and new players, including stem cells or extracellular matrix-producing cells derived from nonmesenchymal cell types, is reviewed. Comparisons of inflammation-induced fibrosis across organ systems and the need for integrated and systems-based molecular approaches, new imaging modalities, well-characterized animal models, cell culture models, and improved diagnostic or predictive markers are reviewed. To date, intestinal fibrosis has received much less attention than inflammation in terms of defining mechanisms and underlying causes. This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease.

Green tea polyphenols avert chronic inflammation-induced myocardial fibrosis of female rats

Green tea proposes anti-inflammatory properties which may attenuate chronic inflammation-induced fibrosis of vessels. This study evaluated whether green tea polyphenols (GTP) can avert fibrosis or vascular disruption along with mechanisms in rats with chronic inflammation. Forty 3-month-old female rats were assigned to a 2 (placebo vs. lipopolysaccharide, administration)×2 (no GTP vs. 0.5% GTP in drinking water) factorial design for 12weeks. Masson's trichrome staining evaluated myocardial fibrosis in coronary vessels and surrounding myocardium. Whole blood specimens were counted for differentials. Spleen tumor necrosis factor-α (TNF-α) mRNA expression was determined by real-time RT-PCR. Data were analyzed by two-way analysis of variance (ANOVA) followed by mean separation procedures. After 12weeks, lipopolysaccharide administration induced myocardial fibrosis in vessels and surrounding myocardium, spleen TNF-α mRNA expression, and leukocytes, while GTP supplementation in drinking water significantly averted such observation. GTP attenuates myocardial fibrosis through a suppression of chronic inflammation and innate immune responses.

Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and γδ+ T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a−/− mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ−/−, il10−/−, il10−/−il12p40−/−, and il10−/−il17a−/− mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.