Background: Airway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined. Recently, fibroblast growth factor 2 (FGF2) has been reported to be an inflammatory regulator; however, its role in asthma remains elusive. This study aimed to investigate the immunomodulatory role of FGF2 in asthma. Methods: First, FGF2 expression was characterised in clinical asthma samples and the house dust mite (HDM)-induced mouse chronic asthma model. Second, recombinant mouse FGF2 (rm-FGF2) protein was intranasally delivered to determine the effect of FGF2 on airway inflammatory cell infiltration. Third, human airway epithelium-derived A549 cells were stimulated with either HDM or recombinant human interleukin-1β (IL-1β) protein combined with or without recombinant human FGF2. IL-1β-induced IL-6 or IL-8 release levels were determined using enzyme-linked immunosorbent assay, and the involved signalling transduction was explored via Western blotting. Results: Compared with the control groups, the FGF2 protein levels were significantly upregulated in the bronchial epithelium and alveolar areas of clinical asthma samples (6.70 ± 1.79 vs. 16.32 ± 2.40, P = 0.0184; 11.20 ± 2.11 vs. 21.00 ± 3.00, P = 0.033, respectively) and HDM-induced asthmatic mouse lung lysates (1.00 ± 0.15 vs. 5.14 ± 0.42, P < 0.001). Moreover, FGF2 protein abundance was positively correlated with serum total and anti-HDM IgE levels in the HDM-induced chronic asthma model ( R ² = 0.857 and 0.783, P = 0.0008 and 0.0043, respectively). Elevated FGF2 protein was mainly expressed in asthmatic bronchial epithelium and alveolar areas and partly co-localised with infiltrated inflammatory cell populations in HDM-induced asthmatic mice. More importantly, intranasal instillation of rm-FGF2 aggravated airway inflammatory cell infiltration (2.45 ± 0.09 vs. 2.88 ± 0.14, P = 0.0288) and recruited more subepithelial neutrophils after HDM challenge [(110.20 ± 29.43) cells/mm ² vs. (238.10 ± 42.77) cells/mm ² , P = 0.0392] without affecting serum IgE levels and Th2 cytokine transcription. In A549 cells, FGF2 was upregulated through HDM stimulation and promoted IL-1β-induced IL-6 or IL-8 release levels (up to 1.41 ± 0.12- or 1.44 ± 0.14-fold change vs . IL-1β alone groups, P = 0.001 or 0.0344, respectively). The pro-inflammatory effect of FGF2 is likely mediated through the fibroblast growth factor receptor (FGFR)/mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. Conclusion: Our findings suggest that FGF2 is a potential inflammatory modulator in asthma, which can be induced by HDM and acts through the FGFR/MAPK/NF-κB pathway in the airway epithelial cells.

Delayed neutrophil apoptosis has been proved to be closely associated with acute lung injury. A Bcl-2 inhibitor, venetoclax, can improve the clinical outcome of acute lung injury based on its pro-apoptotic effect. However, pulmonary delivery of free venetoclax is hindered by its water insolubility, which results in limited bioavailability and pharmacological effects. An amphipathic polymer-based nanodelivery system has been extensively used to improve the delivery of this insoluble drug and enhance its bioavailability. In this study, an amphiphilic poly(ethylene glycol) modified poly(α-lipoic acid) nanoparticle with an extended lung tissue-resident time was utilized to deliver venetoclax. Compared to free venetoclax, the nanoformulated venetoclax (Nf-venetoclax) presented better efficacy for acute lung injury through increasing neutrophil apoptosis in vivo. In addition, a stronger pro-apoptotic effect of Nf-venetoclax was also demonstrated in vitro. Our study provides encouraging evidence that Nf-venetoclax exhibits effective therapy for acute lung injury.

Bacteria-induced acute lung injury (ALI) is associated with a high mortality rate due to the lack of an effective treatment. Patients often rely on supportive care such as low tidal volume ventilation to alleviate the symptoms. Nanomedicine has recently received much attention owing to its premium benefits of delivering drugs in a sustainable and controllable manner while minimizing the potential side effects. It can effectively improve the prognosis of bacteria-induced ALI through targeted delivery of drugs, regulation of multiple inflammatory pathways, and combating antibiotic resistance. Hence, in this review, we first discuss the pathogenesis of ALI and its potential therapeutics. In particular, the state-of-the-art nanomedicines for the treatment of bacteria-induced ALI are highlighted, including their administration routes, in vivo distribution, and clearance. Furthermore, the available bacteria-induced ALI animal models are also summarized. In the end, future perspectives of nanomedicine for ALI treatment are proposed.

Background: Biliary atresia (BA) is a severe cholangiopathy of early infancy that destroys cholangiocytes, obstructs ductular pathways and if left untreated, culminates to liver cirrhosis. Mechanisms underlying the etiological heterogeneity remain elusive and few studies have attempted phenotyping BA. We applied machine learning to identify distinct subtypes of BA which correlate with the underlying pathogenesis.Methods: The BA microarray dataset GSE46995 was downloaded from the Gene Expression Omnibus (GEO) database. Unsupervised hierarchical cluster analysis was performed to identify BA subtypes. Then, functional enrichment analysis was applied and hub genes identified to explore molecular mechanisms associated with each subtype. An independent dataset GSE15235 was used for validation process.Results: Based on unsupervised cluster analysis, BA patients can be classified into three distinct subtypes: Autoimmune, Viral and Embryonic subtypes. Functional analysis of Subtype 1 correlated with Fc Gamma Receptor (FCGR) activation and hub gene FCGR2A, suggesting an autoimmune response targeting bile ducts. Subtype 2 was associated with immune receptor activity, cytokine receptor, signaling by interleukins, viral protein interaction, suggesting BA is associated with viral infection. Subtype 3 was associated with signaling and regulation of expression of Robo receptors and hub gene ITGB2, corresponding to embryonic BA. Moreover, Reactome pathway analysis showed Neutrophil degranulation pathway enrichment in all subtypes, suggesting it may result from an early insult that leads to biliary stasis.Conclusions: The classification of BA into different subtypes improves our current understanding of the underlying pathogenesis of BA and provides new insights for future studies.