RESUMO
Hypertrophic scar and keloid are two types of fibroproliferative conditions that result from excessive extracellular matrix production. The underlying pathological mechanism is not entirely clear. Activation of the renin-angiotensin system (RAS) is associated with fibrosis in various organs. RAS components including angiotensin II (Ang II), angiotensin AT1 and AT2 receptors, and angiotensin-converting enzyme (ACE) are expressed in the skin and act independently from the plasma RAS. AT1 receptors, which are usually the dominating receptor subtype, promote fibrosis and scar formation, while AT2 receptors inhibit the aforementioned AT1 receptor-coupled effects. Elevated angiotensin II (Ang II) levels acting on the AT1 receptor contribute to skin scar formation through increased expression of inflammatory factors such as interleukin-6 (IL-6), angiogenic factors such as vascular endothelial growth factor (VEGF) and fibrinogenic factors such as transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF), while at the same time suppressing the anti-fibrotic tissue inhibitors of matrix metalloproteinase (TIMPs). First, small clinical trials have provided evidence that inhibition of the ACE/Ang II/ AT1 receptor axis may be effective in the treatment of hypertrophic scars/keloids. This review provides a detailed overview of the current literature on the RAS in skin, wound healing and scar formation and discusses the translational potential of targeting this hormonal system for treatment and prevention of hypertrophic scars and keloids.
Assuntos
Cicatriz Hipertrófica/etiologia , Queloide/etiologia , Sistema Renina-Angiotensina , Pele/metabolismo , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Cicatriz Hipertrófica/tratamento farmacológico , Fibrose , Humanos , Queloide/tratamento farmacológico , Pele/patologia , CicatrizaçãoRESUMO
BACKGROUND: Metformin ameliorates non-histamine-mediated itch. We have recently reported that the nitric oxide (NO) pathway is involved in chloroquine (CQ)-induced scratching behavior. Here we investigated the involvement of the NO pathway in the antipruritic effect of metformin on CQ-induced itch. METHODS: Metformin (5-200 mg/kg, given intraperitoneally [i.p.]) was injected 4 h before CQ (400 µg/site, given intradermally [i.d.]) or compound 48/80 (100 µg/site, i.d.). A nonspecific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 and 10 mg/kg, i.p.), or an NO precursor, L-arginine (10 and 100 mg/kg, i.p.) was administered 30 min before injection of CQ. A neural NOS (nNOS) inhibitor, 7-nitroindazole (7-NI; 1 and 10 nmol/site, i.d.) was concurrently administered with CQ. The scratching behavior was recorded for 30 min following the injection of CQ. We studied the changes in skin and spinal nitrite levels after treatments. RESULTS: Our results showed that metformin (100 and 200 mg/kg) significantly reduced the CQ-induced scratching behavior but not the compound 48/80-induced scratching behavior. L-Arginine inhibited the antipruritic effect of metformin, while L-NAME and 7-NI significantly potentiated the inhibitory effects of a subeffective dose of metformin on the CQ-induced scratching behavior. The skin but not the spinal nitrite level was significantly increased after CQ administration. The elevated cutaneous nitrite level was reversed by effective doses of either metformin or 7-NI, but not by the subeffective doses of metformin + 7-NI. CONCLUSION: Acute injection of metformin significantly inhibits CQ-induced scratching behavior. This effect is mediated through inhibition of the NO pathway, especially by inhibiting the dermal nNOS enzyme.
Assuntos
Antipruriginosos/uso terapêutico , Cloroquina/efeitos adversos , Metformina/uso terapêutico , Óxido Nítrico/biossíntese , Prurido/tratamento farmacológico , Pele/efeitos dos fármacos , Animais , Antipruriginosos/metabolismo , Antipruriginosos/farmacologia , Cloroquina/farmacologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Injeções , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Prurido/induzido quimicamente , Prurido/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/inervação , Pele/metabolismoRESUMO
Flavonoids comprise a group of natural polyphenols consisting of more than 5,000 subtypes mostly existing in fruits and vegetables. Flavonoids consumption could potentially attenuate the incidence and recurrence risk of colorectal cancers through their antiperoxidative, antioxidant, and anti-inflammatory effects. In addition, these compounds regulate the mitochondrial function, balance the bacterial flora and promote the apoptosis process in cancerous cells. However, some previous data failed to show the effectiveness of flavonoids in reducing the risk of colorectal cancer. In this study, we have reviewed the efficacy of different flavonoids subtypes on the risk of colon cancer and molecular mechanisms involved in this process in both clinical and animal studies. In addition, we tried to elucidate the potential synergy between these compounds and current colorectal cancer treatments.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/prevenção & controle , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Frutas/química , Humanos , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Verduras/químicaRESUMO
Cannabinoid receptor (CBR) agonist could act as a protective agent against seizure susceptibility in animal models of epilepsy. Studies have shown that potassium channels could play a key role in ameliorating neuronal excitability. In this study, we attempted to evaluate how CBRs and Adenosine Tri-Phosphate (ATP)-sensitive potassium channels collaborate to affect seizure susceptibility by changing the clonic seizure threshold (CST). We used male Naval Medical Research Institute (NMRI) mice and treated them with the following drugs: cromakalim (a potassium channel opener, 10⯵g/kg), glibenclamide (a potassium channel blocker, 0.03 and 1â¯mg/kg), 0.5â¯mg/kg of AM-251 (a selective CB1 antagonist), AM-630 (a selective CB2 antagonist), and 0.5, 3, and 10â¯mg/kg of WIN 55,212-2 (a nonselective agonist of CBRs); and CST was appraised after each type of administration. Also, we evaluated the ATP level of the hippocampus in each treatment to clarify the interaction between the cannabinoid system and potassium channel. Our results showed that administration of WIN 55,212-2 at 10â¯mg/kg significantly increased CST (Pâ¯<â¯0.001). This change could be reversed by using AM-251(Pâ¯<â¯0.001) but not AM-630. Also, either cromakalim (10⯵g/kg) or glibenclamide (0.03 and 1â¯mg/kg) could not significantly affect the CST. In addition, glibenclamide (1â¯mg/kg) could reverse the anticonvulsant effect of WIN 55,212-2 (10â¯mg/kg) on CST (Pâ¯<â¯0.001). However, the anticonvulsant effect was observed when cromakalim (10⯵g/kg) was added to WIN 55,212-2 at its subeffective dose (3â¯mg/kg) in comparison to single-treated animals. Interestingly, we observed that CB1 agonist could significantly decrease ATP level. In conclusion, CB1 agonist accomplishes at least a part of its anticonvulsant actions through ATP-sensitive potassium channels, probably by decreasing the mitochondrial ATP level to open the potassium channel to induce its anticonvulsant effect.
Assuntos
Trifosfato de Adenosina/metabolismo , Anticonvulsivantes/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Hipocampo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismo , Canais de Potássio/metabolismo , Distribuição Aleatória , Convulsões/metabolismo , Resultado do TratamentoRESUMO
Aim: The purpose of this study is to examine the protective effects of Dapsone on inflammation of intestinal tissue through inhibition of NF-kB pathway in acetic acid-induced colitis in rats.Methods: Acute colitis was produced by intra-rectal instillation of 2 mL of 4% acetic acid diluted in normal saline. Then, two hours after induction of colitis, DMSO as vehicle, dexamethasone (2 mg/kg) and dapsone (12.5 mg/kg) were given to the animals intraperitoneally (i.p.) and continued for five following days. Evaluation of macroscopic and microscopic damages were done. Myeloid peroxidase enzyme (MPO) activity was measured by a biochemical technique. Moreover, tumor necrosis factor-α (TNF-α) activity was identified by ELISA, and the expression level of pNF-kB protein was evaluated by immunohistochemistry (IHC).Results: Dexamethasone (2 mg/kg) and dapsone (12.5 mg/kg) decreased the macroscopic and microscopic damages compared with acetic acid group (p Ë .001). Additionally, these agents decreased the activity of MPO (p Ë .001), TNF-α (p Ë .001) and the expression level of p-NF-kB (p Ë .001) in rat colon tissue compared with the acetic acid group.Conclusion: It is proposed that the anti-inflammatory activity of dapsone on acetic acid-induced colitis in rats may involve the inhibition of NF-kB pathway.
Assuntos
Ácido Acético/toxicidade , Colite , Colo/imunologia , Dapsona/farmacologia , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/imunologia , Colite/patologia , Colo/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: Recent reports have identified angiogenic, anti-inflammatory, and antioxidant properties of acute treatment with nicotine via activation of nicotinic acetylcholine receptors (nAChRs). In addition, the nitric oxide (NO) pathway is involved in ischemic reperfusion injuries. OBJECTIVES: We investigated the effects of acute pretreatment with nicotine in a rat model of random-pattern skin flap and the potential role of the NO pathway. METHODS: The Sprague-Dawley rats received increasing doses of (-)-nicotine (0.5, 1, 1.5, 2, and 3 mg/kg) before the procedure. Dorsal skin flaps with caudal pedicles were elevated at the midline, and flap survival was evaluated 7 days after surgery. In addition, animals received an α7-nAChR antagonist, methyllycaconitine, with nicotine. Quantitative reverse transcription polymerase chain reaction was also applied to measure the dermal expression of α7-nAChR. Next, a nonselective NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride; a selective inducible NO synthase inhibitor, aminoguanidine; and an NO precursor, L-arginine, were administered with nicotine. RESULTS: Nicotine at doses of 1, 1.5, and 2 mg/kg significantly increased flap survival, whereas the protective effects of nicotine disappeared at higher doses. Methyllycaconitine completely reversed the protective effects of nicotine and the elevated cutaneous expression of α7-nAChR in nicotine-pretreated rats. In addition, systemic administration of N-nitro-L-arginine methyl ester hydrochloride or aminoguanidine with an effective dose of nicotine caused a significant decrease in flap survival. Conversely, coinjection of a subeffective dose of L-arginine with the subeffective dose of nicotine significantly boosted its protective effects. CONCLUSIONS: Acute pretreatment with nicotine by stimulating the expression and activation of cutaneous α7-nAChR improves skin flap survival, which is partially mediated through modulation of the NO pathway.
Assuntos
Sobrevivência de Enxerto , Nicotina/farmacologia , Transplante de Pele , Retalhos Cirúrgicos , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Arginina/farmacologia , Guanidinas/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
STUDY DESIGN: This is an animal study. OBJECTIVES: Metformin is a safe drug for controlling blood sugar in diabetes. It has been shown that metformin improves locomotor recovery after spinal cord injury (SCI). Neuropathic pain is also a disturbing component of SCI. It is indicated that metformin has neuroprotective and anti-inflammatory effects, which attenuate neuropathic pain and hyperalgesia in injured nerves. Thus, we evaluated metformin's therapeutic effects on SCI neuroinflammation and its sensory and locomotor complications. Meanwhile, results were compared to minocycline, an anti-neuroinflammation therapy in SCI. SETTING: Experimental Medicine Research Center, Tehran University of Medical Sciences, Iran METHODS: In an animal model of SCI, 48 male rats were subjected to T9 vertebra laminectomy. Animals were divided into a SHAM-operated group and five treatment groups. The treatments included normal saline as a vehicle control group, minocycline 90 mg/kg and metformin at the doses of 10, 50 and 100 mg/kg. Locomotor scaling, behavioral tests for neuropathic pain and weight changes were evaluated and compared through a 28-days period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes. RESULTS: Metformin 50 mg/kg improved the locomotors ability (p < 0.001) and decreased sensitivity to mechanical and thermal allodynia (p < 0.01). These results were compatible with minocycline effect on SCI (p > 0.05). While metformin led to weight loss, both metformin and minocycline significantly decreased neuroinflammation in the assessment of cord tissue histopathology, and levels of TNF-α and interleukin-1ß (p < 0.001). CONCLUSIONS: Metformin could be considered as an alternative therapeutic agent for SCI, as it potentially attenuates neuroinflammation, sensory and locomotor complications of cord injury.
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Locomoção/efeitos dos fármacos , Metformina/farmacologia , Neuralgia/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Neuralgia/metabolismo , Neuralgia/patologia , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologiaRESUMO
Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ. In contrast, combined pre-treatment with sub-effective doses of an NMDAR antagonist, MK-801, and the NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), decreases CQ-induced scrat-ching behavior. While intradermal administration of CQ significantly increases the concentration of intradermal nitrite, the end product of NO metabolism, effective doses of intraperitoneal and intradermal MK-801 significantly decrease intradermal nitrite levels. Likewise, administration of an effective dose of L-NAME significantly decreases CQ-induced nitrite production. We conclude that the NMDA/NO pathway in the skin modulates CQ-induced scratching behavior.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cloroquina , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/metabolismo , Prurido/prevenção & controle , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Masculino , Camundongos , Óxido Nítrico Sintase/metabolismo , Nitritos/metabolismo , Prurido/induzido quimicamente , Prurido/metabolismo , Prurido/psicologia , Receptores de N-Metil-D-Aspartato/metabolismo , Pele/metabolismoRESUMO
Cholestatic itch can be severe and significantly impair the quality of life of patients. The serotonin system is implicated in cholestatic itch; however, the pruritogenic properties of serotonin have not been evaluated in cholestatic mice. Here, we investigated the serotonin-induced itch in cholestatic mice which was induced by bile duct ligation (BDL). Serotonin, sertraline or saline were administered intradermally to the rostral back area in BDL and sham operated (SHAM) mice, and the scratching behaviour was videotaped for 1 hour. Bile duct ligated mice had significantly increased scratching responses to saline injection on the seventh day after surgery. Additionally, serotonin or sertraline significantly induced scratching behaviour in BDL mice compared to saline at day 7 after surgery, while it did not induce itch at day 5. The scratching behaviour induced by serotonin or sertraline was significantly less in BDL mice compared to SHAM mice. Likewise, the locomotor activity of BDL or SHAM mice was not significantly different from unoperated (UNOP) mice on the fifth and seventh day, suggesting that the scratching behaviour was not affected by motor dysfunctions. Our data suggest that despite the potentiation of evoked itch, a resistance to serotonin-induced itch is developed in cholestatic mice.
Assuntos
Ductos Biliares/cirurgia , Prurido/induzido quimicamente , Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Colestase/complicações , Relação Dose-Resposta a Droga , Ligadura/efeitos adversos , Masculino , Camundongos , Prurido/complicações , Prurido/fisiopatologiaAssuntos
Dermatologia/legislação & jurisprudência , Equidade em Saúde/legislação & jurisprudência , Política de Saúde/legislação & jurisprudência , Cobertura do Seguro/legislação & jurisprudência , Telemedicina/legislação & jurisprudência , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/transmissão , Dermatologia/economia , Dermatologia/métodos , Dermatologia/tendências , Equidade em Saúde/economia , Equidade em Saúde/tendências , Política de Saúde/economia , Política de Saúde/tendências , Humanos , Cobertura do Seguro/economia , Cobertura do Seguro/tendências , Distanciamento Físico , Racismo/economia , Racismo/prevenção & controle , Telemedicina/economia , Telemedicina/tendências , Populações Vulneráveis/legislação & jurisprudênciaRESUMO
The phenomenon of contagious itch, observed in both humans and rodents, remains a topic of ongoing debate concerning its modulators and underlying pathways. This study delves into the relationship between contagious itch and familiar olfactory cues, a non-visual factor contributing to this intriguing behavior. Our findings showed that contagious itch in observer mice occurs during physical interaction with the cagemate itch-demonstrator but not with a stranger demonstrator or in a non-physical encounter condition. Notably, itch-experienced observer mice displayed an increased contagious itch behavior, highlighting the relevance of itch-associated memory in this phenomenon. Furthermore, anosmic observer mice, whether itch-naïve or itch-experienced, displayed no contagious itch behavior. These results demonstrate that the familiar olfactory cues, specifically cagemate body odors, are required for contagious itch behaviors in mice. In line with these behavioral findings, our study reveals increased activity in brain regions associated with olfaction, emotion, and memory during contagious itch, including the olfactory bulb, the amygdala, the hypothalamus, and the hippocampus, with this activity diminished in anosmic mice. In conclusion, our study unveils the critical role of familiar olfactory cues in driving contagious itch in mice, shedding light on the interplay between social factors, sensory perception, and memory in this phenomenon.
Assuntos
Sinais (Psicologia) , Prurido , Olfato , Animais , Prurido/fisiopatologia , Camundongos , Olfato/fisiologia , Masculino , Comportamento Animal , Relações Interpessoais , Camundongos Endogâmicos C57BL , Odorantes , Bulbo Olfatório/fisiopatologia , Encéfalo/fisiopatologiaRESUMO
Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using Olink targeted proteomics. Flow and Olink data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Spatial and Olink data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. Our Olink data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3.
RESUMO
BACKGROUND: Cholestatic pruritus is a distressful sensation that can cause a massive desire of scratching skin. Despite maximum medication therapy, some patients still experience pruritus. In this study, we evaluated the effect of infliximab on cholestatic pruritus induced in mice by bile duct ligation. METHODS: Twenty-four balb/c mice were randomly assigned to three groups; sham, control, and treatment. The bile duct ligation procedure was performed on mice in the control and treatment groups. After six days, mice in the treatment group received subcutaneous administration of infliximab, and the next day all mice were subjected to the scratching behavior test. Skin, dorsal root ganglia (DRG), and blood samples of mice were collected and evaluated by histopathological, molecular, and biochemical tests. RESULTS: The scratching behavior has significantly decreased in mice with cholestasis after the administration of infliximab. The levels of TNFα, TNFR1, TNFR2, NF-κB, and IL-31were higher in control mice compared to sham. In addition, expression levels of TNFR1, NF-κB, and IL-31 were decreased in the treatment group compared to the controls in skin and DRG, while TNFR2 levels were decreased only in DRG. CONCLUSION: Infliximab can block TNFα interaction with receptors and inhibit further inflammatory response. Also, our results suggested that infliximab can suppress IL-31 expression indirectly, which is a well-known cytokine in pruritus pathophysiology Infliximab can be a potential therapeutic approach in resistant pruritus in cholestatic disorders.
Assuntos
Colestase , Fator de Necrose Tumoral alfa , Humanos , Animais , Camundongos , Infliximab/uso terapêutico , Receptores Tipo I de Fatores de Necrose Tumoral , Receptores Tipo II do Fator de Necrose Tumoral , NF-kappa B , Ductos Biliares/cirurgia , Colestase/complicações , Colestase/tratamento farmacológico , Prurido/tratamento farmacológico , Prurido/etiologia , Modelos Animais de DoençasRESUMO
Renin-angiotensin system (RAS) components such as angiotensin II, angiotensin receptors (AT1R and AT2R), and angiotensin-converting enzyme (ACE) are expressed in different cell types of the skin. Through AT1R, angiotensin II increases proinflammatory cytokines contributing to fibrosis, angiogenesis, proliferation, and migration of immune cells to the skin. In contrast, AT2R suppresses the effects mentioned above. Many studies show that angiotensin receptor blockers (ARBs) and angiotensin-converting enzymes (ACEi) reduce the proinflammatory cytokines and fibrogenic factors including transforming growth factor ß (TGF-ß), Connective tissue growth factor (CTGF), and IL-6. This review article provides a detailed research study on the implications of ARBs in wound healing, hypertrophic scar, and keloids. We further discuss the therapeutic potentials of ARBs in autoimmune and autoinflammatory skin diseases and cancer, given their anti-fibrotic and anti-inflammatory effects.
RESUMO
Morphea is characterized by initial inflammation followed by fibrosis of the skin and soft tissue. Despite its substantial morbidity, the pathogenesis of morphea is poorly studied. Previous work showed that CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in the sera and lesional skin of patients with morphea. We found that an early inflammatory subcutaneous bleomycin mouse model of dermal fibrosis mirrors the clinical, histological, and immune dysregulation observed in human morphea. We used this model to examine the role of the CXCR3 chemokine axis in the pathogenesis of cutaneous fibrosis. Using the REX3 (Reporting the Expression of CXCR3 ligands) mice, we characterized which cells produce CXCR3 ligands over time. We found that fibroblasts contribute the bulk of CXCL9-RFP and CXCL10-BFP by percentage, whereas macrophages produce high amounts on a per-cell basis. To determine whether these chemokines are mechanistically involved in pathogenesis, we treated Cxcl9-, Cxcl10-, or Cxcr3-deficient mice with bleomycin and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9 but not CXCL10 to cultured mouse fibroblasts induced Col1a1 mRNA expression, indicating that the chemokine itself contributes to fibrosis. Taken together, our studies provide evidence that CXCL9 and its receptor CXCR3 are functionally required for inflammatory fibrosis.
Assuntos
Dermatite , Esclerodermia Localizada , Humanos , Animais , Camundongos , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Regulação para Cima , Ligantes , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Fibrose , Inflamação , Fibroblastos/metabolismo , Bleomicina/toxicidade , Receptores CXCR3/genética , Receptores CXCR3/metabolismoRESUMO
Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.
Assuntos
Inibidores de Janus Quinases , Vitiligo , Camundongos , Animais , Humanos , RNA Interferente Pequeno/genética , Linfócitos T CD8-Positivos/metabolismo , Autoimunidade/genética , Vitiligo/tratamento farmacológico , Vitiligo/genética , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , RNA de Cadeia DuplaRESUMO
BACKGROUND: Allergic rhinitis is a systemic disease with high prevalence, which some of its neuropsychological problems have been reported. The primary pathophysiology and mechanism of the neuropsychological dysfunction of AR patients have not been described yet, so here we subjected an animal model of AR to identify any behavioral or seizure threshold changes and to assess the pathophysiology of the disease. METHODS: Eighty male BALB/C mice were randomly divided into the allergic rhinitis group and controls. Allergic rhinitis was induced in the first group by administering OVA and aluminum hydroxide intraperitoneally and then nasal injection of OVA for 14 consecutive days. Both groups were subjected to different tests for assessing depressive-like behavior, anxiety, spatial and contextual memory, and learning and seizure threshold. Hippocampus and plasma samples of mice were subjected for analyzing cytokines and immune modulators and for pathology and immunohistochemistry evaluation. RESULTS: The depressive and anxiety-like behavior were increased in AR, and the spatial learning and memory were disturbed in the AR group. Also, AR mice had lower seizure thresholds compared to controls. Lab data suggested that TLR4, NF-κB, IL-1ß, and TNFα expressions were increased in the AR hippocampus as well as their plasma proinflammatory cytokines. Likewise, demyelination, cell death, and M1 macrophage aggregation were increased in the AR hippocampus. CONCLUSION: Behavioral and cognitive problems should be taken seriously in patients with AR or other atopic diseases, and more investigating is required to clear the pathophysiology behind it and its treatment.
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NF-kappa B , Rinite Alérgica , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Imunoglobulina E , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Mucosa Nasal , Doenças Neuroinflamatórias , Ovalbumina , Convulsões/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismoRESUMO
Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression. Nevertheless, Th2 effector subsets have also been implicated in CLE. We have now assessed the role of specific T cell subsets in the initiation and persistence of skin disease using a T cell-inducible murine model of CLE, dependent on KJ1-26 T cell recognition of an ovalbumin fusion protein. We found that only Th2-skewed cells, and not Th1-skewed cells, induced the development of skin lesions. However, we provide strong evidence that the Th2 disease-initiating cells convert to a more Th1-like functional phenotype in vivo by the time the skin lesions are apparent. This phenotype is maintained and potentiates over time, as T cells isolated from the skin, following a second induction of self-antigen, expressed more IFN-γ than T cells isolated at the time of the initial response. Transcriptional analysis identified additional changes in the KJ1-26 T cells at four weeks post injection, with higher expression levels of interferon stimulated genes (ISGs) including CXCL9, IRF5, IFIH1, and MX1. Further, injection of IFN-γ-/- T cells faied to induce skin disease in mice. We concluded that Th2 cells trigger skin lesion formation in CLE, and these cells switch to a Th1-like phenotype in the context of a TLR7-driven immune environment that is stable within the T cell memory compartment.