Sulforaphane alleviates psoriasis by enhancing antioxidant defense through KEAP1-NRF2 Pathway activation and attenuating inflammatory signaling.

Psoriasis is a chronic inflammatory skin disease that affects millions of people worldwide. Sulforaphane (SFN) has been shown to have anti-inflammatory and antioxidant properties. In this study, we investigated the effects of SFN on a mouse model of psoriasis induced by imiquimod (IMQ) and its underlying molecular mechanism. Mice treated with SFN showed significant improvement in psoriatic symptoms, including reduced erythema, scales, and cutaneous thickness. Histopathological analysis and immunohistochemical staining revealed decreased expression of K16, K17, and Ki67 in SFN-treated mice, indicating reduced abnormal differentiation of keratinocytes and cutaneous inflammation. SFN treatment also reduced the activation of STAT3 and NF-κB pathways and downregulated pro-inflammatory cytokines IL-1ß, IL-6, and CCL2. In vitro experiments using HaCaT cells demonstrated that SFN inhibited IL-22 and TNF-α-induced activation of inflammatory pathways and keratinocyte proliferation. Network pharmacology analysis suggested that the KEAP1-NRF2 pathway might be involved in the protective effects of SFN on psoriasis. We observed reduced NRF2 expression in human psoriatic lesions, and subsequent experiments showed that SFN activated KEAP1-NRF2 pathway in vivo and in vitro. Importantly, NRF2-deficient mice exhibited aggravated psoriasis-like symptoms and reduced response to SFN treatment. Our findings indicate that SFN ameliorates psoriasis symptoms and inflammation through the KEAP1-NRF2 pathway, suggesting a potential therapeutic role for SFN in the treatment of psoriasis.

Vitamin D attenuates DNCB-induced atopic dermatitis-like skin lesions by inhibiting immune response and restoring skin barrier function.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease causing erythema and itching. The etiology of AD is complex and not yet clear. Vitamin D is a fat-soluble vitamin that promotes skin cell growth and differentiation and regulates immune function. This study aimed to explore the therapeutic effect of calcifediol, the active metabolite of vitamin D, on experimental AD and the possible mechanism of action. We found that the levels of vitamin D binding protein (VDBP) and vitamin D receptor (VDR) in biopsy skin samples from AD patients decreased compared with controls. We used 2,4-dinitrochlorobenzene (DNCB) to induce an AD mouse model on the ear and back of BALB/c mice. A total of five groups were used: the control group, the AD group, the AD + calcifediol group, the AD + dexamethasone group, and the calcifediol alone group. Under calcifediol treatment, mice exhibited reduced spinous layer thickening, reduced inflammatory cell infiltration, downregulated aquaporin 3 (AQP3) expression, and restored the barrier function of the skin. Simultaneous calcifediol treatment decreased STAT3 phosphorylation, inhibited inflammation and chemokine release, decreased AKT1 and mTOR phosphorylation, and suppressed epidermal cell proliferation and abnormal differentiation. In conclusion, our study demonstrated that calcifediol significantly protected mice against DNCB-induced AD. In a mouse model of AD, calcifediol may reduce inflammatory cell infiltration and chemokines by inhibiting the phosphorylation of STAT3 and may restore skin barrier function through the downregulation of AQP3 protein expression and inhibition of cell proliferation.

Therapeutic effects and mechanism of human amnion-derived mesenchymal stem cells on hypercoagulability in a uremic calciphylaxis patient.

Calciphylaxis is a rare cutaneous vascular disease that manifests with intolerable pains, non-healing skin wounds, histologically characterized by calcification, fibrointimal hyperplasia, and microvessel thrombosis. Currently, there are no standardized guidelines for this disease. Recent studies have recognized a high prevalence of thrombophilias and hypercoagulable conditions in calciphylaxis patients. Here, we report a case of uremic calciphylaxis patient whom was refractory to conventional treatments and then received a salvage strategy with intravenous and local hAMSC application. In order to investigate the therapeutic mechanism of hAMSCs from the novel perspective of hypercoagulability, coagulation-related indicators, wound status, quality of life and skin biopsy were followed up. Polymerase chain reaction (PCR) was performed to determine the distribution of hAMSCs in multiple tissues including lung, kidney and muscle after infusion of hAMSCs for 24 h, 1 week and 1 month in mice aiming to investigate whether hAMSCs retain locally active roles after intravenous administration. Improvement of hypercoagulable condition involving correction of platelet, D-dimer and plasminogen levels, skin regeneration and pain alleviation were revealed after hAMSC administration over one-year period. Skin biopsy pathology suggested regenerative tissues after 1 month hAMSC application and full epidermal regeneration after 20 months hAMSC treatment. PCR analysis indicated that hAMSCs were homing in lung, kidney and muscle tissues of mice even until tail vein injection of hAMSCs for 1 month. We propose that hypercoagulability is a promising therapeutic target of calciphylaxis patients, which can be effectively improved by hAMSC treatment.

A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome.

Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant skin disorder. To date, four mutations in the GJB6 gene, G11R, V37E, A88V, and D50N, have been confirmed to cause this condition. In previous studies, the focus has been mainly on gene sequencing, and there has been a lack of research on clinical manifestations and pathogenesis. To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease, we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree. Detailed clinical examination included histopathology, hair microscopy, and scanning electron microscopy. We found a novel heterozygous missense variant (c.134G>C:p.G45A) for Clouston syndrome. We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients' hair under scanning electron microscopy. Our data reveal that a novel variant (c.134G>C:p.G45A) plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.

Curcumin treatment suppresses cachexia-associated adipose wasting in mice by blocking the cAMP/PKA/CREB signaling pathway.

BACKGROUND: Cachexia is a multifactorial debilitating syndrome that is responsible for 22% of mortality among cancer patients, and there are no effective therapeutic agents available. Curcumin, a polyphenolic compound derived from the plant turmeric, has been shown to have anti-inflammatory, antioxidant, anti-autophagic, and antitumor activities. However, its function in cancer cachexia remains largely unexplored. PURPOSE: This study aimed to elucidate the mechanisms by which curcumin improves adipose atrophy in cancer cachexia. METHODS: C26 tumor-bearing BALB/c mice and ß3-adrenoceptor agonist CL316243 stimulated BALB/c mice were used to observe the therapeutic effects of curcumin on the lipid degradation of cancer cachexia in vivo. The effects of curcumin in vitro were examined using mature 3T3-L1 adipocytes treated with a conditioned medium of C26 tumor cells or CL316243. RESULTS: Mice with C26 tumors and cachexia were protected from weight loss and adipose atrophy by curcumin (50 mg/kg, i.g.). Curcumin significantly reduced serum levels of free fatty acids and increased triglyceride levels. In addition, curcumin significantly inhibited PKA and CREB activation in the adipose tissue of cancer cachectic mice. Curcumin also ameliorated CL316243-induced adipose atrophy and inhibited hormone-mediated PKA and CREB activation in mice. Moreover, the lipid droplet degradation induced by C26 tumor cell conditioned medium in mature 3T3-L1 adipocytes was ameliorated by curcumin (20 µM) treatment. Curcumin also improved the lipid droplet degradation of mature 3T3-L1 adipocytes induced by CL316243. CONCLUSION: Curcumin might be expected to be a therapeutic supplement for cancer cachexia patients, primarily through inhibiting adipose tissue loss via the cAMP/PKA/CREB signaling pathway.

2-Deoxy-D-glucose Alleviates Cancer Cachexia-Induced Muscle Wasting by Enhancing Ketone Metabolism and Inhibiting the Cori Cycle.

Cachexia is characterized by progressive weight loss accompanied by the loss of specific skeletal muscle and adipose tissue. Increased lactate production, either due to the Warburg effect from tumors or accelerated glycolysis effects from cachectic muscle, is the most dangerous factor for cancer cachexia. This study aimed to explore the efficiency of 2-deoxy-D-glucose (2-DG) in blocking Cori cycle activity and its therapeutic effect on cachexia-associated muscle wasting. A C26 adenocarcinoma xenograft model was used to study cancer cachectic metabolic derangements. Tumor-free lean mass, hindlimb muscle morphology, and fiber-type composition were measured after in vivo 2-DG administration. Activation of the ubiquitin-dependent proteasome pathway (UPS) and autophagic-lysosomal pathway (ALP) was further assessed. The cachectic skeletal muscles of tumor-bearing mice exhibited altered glucose and lipid metabolism, decreased carbohydrate utilization, and increased lipid ß-oxidation. Significantly increased gluconeogenesis and decreased ketogenesis were observed in cachectic mouse livers. 2-DG significantly ameliorated cancer cachexia-associated muscle wasting and decreased cachectic-associated lean mass levels and fiber cross-sectional areas. 2-DG inhibited protein degradation-associated UPS and ALP, increased ketogenesis in the liver, and promoted ketone metabolism in skeletal muscle, thus enhancing mitochondrial bioenergetic capacity. 2-DG effectively prevents muscle wasting by increasing ATP synthesis efficiency via the ketone metabolic pathway and blocking the abnormal Cori cycle.

Long-term exposure to PM2.5 aggravates pulmonary fibrosis and acute lung injury by disrupting Nrf2-mediated antioxidant function.

Epidemiological studies have indicated that exposure to ambient air-borne fine particulate matter (PM2.5) is associated with many cardiopulmonary diseases; however, the underlying pathological mechanisms of PM2.5-induced lung injury remain unknown. In this study, we aimed to assess the impact of acute or prolonged exposure to water-insoluble fractions of PM2.5 (PM2.5 particulate) on lung injury and its molecular mechanisms. Balb/c mice were randomly exposed to PM2.5 once (acute exposure) or once every three days for a total of 6 times (prolonged exposure). Lung, BALF and blood samples were collected, and pulmonary pathophysiological alterations were analyzed. Nrf2 knockout mice were adapted to assess the involvement of Nrf2 in lung injury, and transcriptomic analysis was performed to delineate the mechanisms. Through transcriptomic analysis and validation of Nrf2 knockout mice, we found that acute exposure to PM2.5 insoluble particulates induced neutrophil infiltration-mediated airway inflammation, whereas prolonged exposure to PM2.5 insoluble particulate triggered lung fibrosis by decreasing the transcriptional activity of Nrf2, which resulted in the downregulated expression of antioxidant-related genes. In response to secondary LPS exposure, prolonged PM2.5 exposure induced more severe lung injury, indicating that prolonged PM2.5 exposure induced Nrf2 inhibition weakened its antioxidative defense capacity against oxidative stress injury, leading to the formation of pulmonary fibrosis and increasing its susceptibility to secondary bacterial infection.

Alpha-7 nicotinic acetylcholine receptor agonist alleviates psoriasis-like inflammation through inhibition of the STAT3 and NF-κB signaling pathway.

Psoriasis is a chronic inflammatory cutaneous disease; it has been discovered that stimulation of the nervous system increases susceptibility to psoriasis. Although the cholinergic anti-inflammatory pathway, which is mediated by the alpha-7 nicotinic acetylcholine receptor (α7nAChR), is critical for controlling multiple types of inflammation, its expression pattern and pathogenesis function in psoriatic lesioned skin tissue are unknown. We hereby analyzed the expression of α7nAchR in human and mouse psoriatic skin tissue. In vivo, PNU-282987 or Methyllycaconitine, a specific agonist or antagonist of α7nAchR, were administered to imiquimod (IMQ)-induced psoriatic mouse models. The macroscopic appearance and histopathological features of the psoriatic mice skin were evaluated. In addition, cell proliferation and differentiation markers were investigated. The level of pro-inflammatory cytokines released from the lesioned skin, as well as the activation of the relevant signaling pathways, were measured. Our findings indicated that psoriatic lesional skin expressed an increased level of α7nAChR, with its tissue distribution being primarily in skin keratinocytes and macrophages. In an IMQ-induced murine psoriasis model, α7nAChR agonist PNU-282987 treatment alleviated psoriasis-like inflammation by down-regulating the expression of multiple types of pro-inflammatory mediators and normalized keratinocyte proliferation and differentiation, whereas α7nAChR antagonist treatment exacerbated its effect. Mechanically, we observed that activation of the α7nAChR inhibited the activation of the STAT3 and NF-κB signaling pathways in in vitro cultured HaCaT cells induced by Th17-related cytokine IL-6/IL-22 or Th1-related cytokine TNF-α. Taken together, these findings demonstrate that attenuation of psoriatic inflammation via the cholinergic anti-inflammatory pathway is dependent on α7nAChR activation.

A novel long-term intravenous combined with local treatment with human amnion-derived mesenchymal stem cells for a multidisciplinary rescued uremic calciphylaxis patient and the underlying mechanism.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity.

Respiratory exposure to PM2.5 soluble extract induced chronic lung injury by disturbing the phagocytosis function of macrophage.

Exposure to airborne urban particles is a contributing factor for the development of multiple types of respiratory diseases; its pathological role as a cause of lung injury is still unclear. In this study, PM2.5 soluble extract was collected, and its toxicological effect on lung pathological changes was examined. To assess its pathological mechanism, Human Monocyte-Like Cell Line, THP-1, and mouse macrophage, RAW264.7, were used to determine the effects of PM2.5 soluble extract on cell toxicity, phagocytosis, and transcriptome. We found that PM2.5 soluble extract exposure activated NF-κB and MAPK signaling pathways, then induces the production of pro-inflammatory cytokines. RNA-seq results showed that the transcription profiles, including 1213 genes, have been changed in responses to PM2.5 exposure. Additionally, PM2.5 led to phagocytic dysfunction, which may exacerbate the cause of lung injury. Exposure to PM2.5 soluble extract triggers the death of respiratory macrophages, impairs its phagocytosis capacity, thus delaying the inflammatory cell clearance in the lung, which results in chronic lung injury.

Comparative transcriptomic analysis of THP-1-derived macrophages infected with Mycobacterium tuberculosis H37Rv, H37Ra and BCG.

Tuberculosis (TB) remains a worldwide healthcare concern, and the exploration of the host-pathogen interaction is essential to develop therapeutic modalities and strategies to control Mycobacterium tuberculosis (M.tb). In this study, RNA sequencing (transcriptome sequencing) was employed to investigate the global transcriptome changes in the macrophages during the different strains of M.tb infection. THP-1 cells derived from macrophages were exposed to the virulent M.tb strain H37Rv (Rv) or the avirulent M.tb strain H37Ra (Ra), and the M.tb BCG vaccine strain was used as a control. The cDNA libraries were prepared from M.tb-infected macrophages and then sequenced. To assess the transcriptional differences between the expressed genes, the bioinformatics analysis was performed using a standard pipeline of quality control, reference mapping, differential expression analysis, protein-protein interaction (PPI) networks, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Q-PCR and Western blot assays were also performed to validate the data. Our findings indicated that, when compared to BCG or M.tb H37Ra infection, the transcriptome analysis identified 66 differentially expressed genes in the M.tb H37Rv-infected macrophages, out of which 36 genes were up-regulated, and 30 genes were down-regulated. The up-regulated genes were associated with immune response regulation, chemokine secretion, and leucocyte chemotaxis. In contrast, the down-regulated genes were associated with amino acid biosynthetic and energy metabolism, connective tissue development and extracellular matrix organization. The Q-PCR and Western blot assays confirmed increased expression of pro-inflammatory factors, altered energy metabolic processes, enhanced activation of pro-inflammatory signalling pathways and increased pyroptosis in H37Rv-infected macrophage. Overall, our RNA sequencing-based transcriptome study successfully identified a comprehensive, in-depth gene expression/regulation profile in M.tb-infected macrophages. The results demonstrated that virulent M.tb strain H37Rv infection triggers a more severe inflammatory immune response associated with increased tissue damage, which helps in understanding the host-pathogen interaction dynamics and pathogenesis features in different strains of M.tb infection.

Inhibition of heat shock protein (HSP) 90 reverses signal transducer and activator of transcription (STAT) 3-mediated muscle wasting in cancer cachexia mice.

BACKGROUND AND PURPOSE: Cancer cachexia is a common cause of death among cancer patients with no currently effective treatment available. In animal models, aberrant activation of STAT3 in skeletal muscle contributes to muscle wasting. However, clinically the factors regulating STAT3 activation and the molecular mechanisms involved remain incompletely understood. EXPERIMENTAL APPROACH: The expression of HSP90 and the activation of STAT3 were detected in muscle from the patients with cancer cachexia or the tumour-bearing cachectic mice. HSP90 inhibitors, including 17DMAG (alvespimycin) and PU-H71, were administered to cachexic mice and cachexia parameters, weight loss, food intake, survival rate, body composition, serum metabolites, muscle wasting pathology and catabolic activation were analysed. The co-culture of C2C12 myotube cells with C26 conditioned media was performed to investigate the pathological mechanism involved in catabolic muscle wasting. The roles of HSP90, STAT3 and FOXO1 in myotube atrophy were explored via overexpression or knockdown. RESULTS: An enhanced interaction between activated STAT3 and HSP90 in the skeletal muscle of cancer cachexia patients, is a crucial for the development of cachectic muscle wasting. HSP90 inhibitors 17DMAG and PU-H71 alleviated the muscle wasting in C26 and models or the myotube atrophy of C2C12 cells induced by C26 conditional medium. Prolonged STAT3 activation transactivated FOXO1 by binding directly to its promoter and triggered the muscle wasting in a FOXO1-dependent manner in muscle cells. CONCLUSION AND IMPLICATIONS: The HSP90/STAT3/FOXO1 axis plays a critical role in cachectic muscle wasting, which might be a potential therapeutic target for the treatment of cancer cachexia.

An integrative transcriptome study reveals Ddit4/Redd1 as a key regulator of cancer cachexia in rodent models.

Cancer cachexia is a multifactorial metabolic syndrome that causes up to 20% of cancer-related deaths. Muscle atrophy, the hallmark of cancer cachexia, strongly impairs the quality of life of cancer patients; however, the underlying pathological process is still poorly understood. Investigation of the disease pathogenesis largely relies on cachectic mouse models. In our study, the transcriptome of the cachectic gastrocnemius muscle in the C26 xenograft model was integrated and compared with that of 5 more different datasets. The bioinformatic analysis revealed pivotal gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the disease, and the key genes were validated. Construction of the protein-protein interaction network and the comparison of pathways enriched in cancer cachexia with 5 other muscle atrophy models revealed Ddit4 (DNA damage-inducible transcript 4), as a key protein in cancer cachexia. The higher expression of Ddit4 in cachectic muscle was further validated in animal models and cachectic cancer patients. Further study revealed that p38 induced the expression of Ddit4, which in turn inhibited the mTOR pathway in atrophic cells.

Soluble IL-6R-mediated IL-6 trans-signaling activation contributes to the pathological development of psoriasis.

IL-6 has been suggested to function as an autocrine mitogen in the psoriatic epidermis. The biological activity of IL-6 relies on interactions with its receptors, including the membrane-bound IL-6 receptor (mIL-6R) and soluble IL-6 receptor (sIL-6R). Our study presents data showing that the levels of plasma IL-6 and sIL-6R were elevated in psoriatic patients. Genotyping of two single-nucleotide polymorphisms (SNPs) in IL-6R (rs4845617 and rs2228145) demonstrated that the SNP IL-6R (rs4845617) rather than IL-6R (rs2228145) shows a significant association with psoriasis (P = 0.006). To verify the functions of sIL-6R, cultured keratinocytes and imiquimod (IMQ)-induced psoriatic model mice were treated with sIL-6R. We found that the presence of sIL-6R in the HaCaT cell culture medium enhanced the IL-6-induced Stat3 activation, which resulted in abnormal keratinocyte proliferation and aberrant differentiation. Furthermore, the application of sIL-6R in vivo accelerated the pathological development of the disease. Our results demonstrate for the first time that genetic polymorphisms in the IL-6R gene are associated with psoriasis disease phenotypes in a Chinese psoriatic patient population; sIL-6R-mediated trans-signaling pathway plays a pivotal role in keratinocyte proliferation and differentiation, suggesting potential therapeutics for psoriasis. KEY MESSAGES: Patients with psoriasis displayed higher levels of IL-6 and sIL-6R compared with healthy controls. Analysis of genotypes revealed that IL-6R rs4845617 GG genotype associated with the risk of psoriasis. Supplement of sIL-6R further enhanced IL-6-induced Stat3 activation in keratinocytes. In vivo administration of sIL-6R accelerated, whereas sgp130FC alleviated, the pathological development of psoriasis.

Targeting HSP90 Inhibits Proliferation and Induces Apoptosis Through AKT1/ERK Pathway in Lung Cancer.

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer.

Photodynamic therapy with acitretin for treatment of penile verrucous carcinoma.

Penile verrucous carcinoma exhibits a high potential for recurrence. Traditional treatment for penile verrucous carcinoma is radical surgery. Extensive resection generally leads to the loss of the patient's sexual function and limits the tolerance for additional additional surgical resection. Herein, we present a case of penile verrucous carcinoma, who achieved complete remission after 3 sessions of PDT and 6 months Acitretin. There was no recurrence at 12 months of follow-up. This case suggests that photodynamic therapy combined with acitretin is a treatment option for penile verrucous carcinoma.

Respiratory exposure to PM2.5 soluble extract disrupts mucosal barrier function and promotes the development of experimental asthma.

BACKGROUND: Air pollutants are important factors that contribute to the development and exacerbation of asthma, but experimental evidence still needs to be collected and the mechanisms still need to be addressed. In this study, we aimed to assess the association between PM2.5 exposure and asthma development. The effects of PM2.5 exposure on the barrier functions of airway epithelial cells were also determined. METHODS: PM2.5 was collected from Nanjing, China, and its soluble extract was prepared. Human lung epithelial cells (BEAS-2B) were treated with different concentrations of soluble PM2.5 extract, and cell viability was detected by FACS using Annexin V-FITC staining. PM2.5-induced oxidative stress and inflammatory events were assessed by DCF-DA staining and qPCR. PM2.5-induced dysfunction of the airway epithelial barrier was assessed by measuring the expression of tight junction molecules. In vivo, BALB/c mice were treated with OVA in the presence or absence of PM2.5 solution, followed by exposure to OVA aerosols. Allergy-induced airway inflammation and lung injury were assessed by histopathological analyses. RESULTS: Soluble PM2.5 extract exposure in vitro decreased the viability and increased apoptosis of airway epithelial cells. Soluble PM2.5 extract induced oxidative stress and enhanced pro-inflammatory factor expression by activating the NF-κB and MAPK signalling pathways, which were accompanied by reduced airway barrier function. The in vivo data demonstrated that PM2.5 exposure increased the effects of allergy sensitization after respiratory exposure to allergens, which led to the development of asthma. CONCLUSION: This study suggests that exposure to soluble PM2.5 extract contributes to airway barrier dysfunction. The soluble mediators generated by airway epithelial cells in response to PM2.5 exposure orchestrate the breaking of inhalational tolerance and sensitization to allergic antigens, leading to the exacerbated development of asthma.