To the Editor: Asthma is an abnormal chronic inflammatory disease characterized by the involvement of a complex network of cells. Barrier epithelial cells (ECs) represent the first line of defense and express pattern recognition receptors to recognize type-2 cell-mediated immune insults. An exaggerated abnormal barrier function or inadequate immune response may contribute to the pathophysiology of asthma.[1,2]
The alarmin high mobility group box 1 (HMGB1) is secreted into the extracellular environment by lung ECs during inflammation. HMGB1, an inflammatory mediator, promotes an immediate immune response to tissue damage in inflammatory pulmonary disease. Therefore, we aimed to determine whether HMGB1 levels are associated with asthma.
This study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered at Prospective Register of Systematic Review (PROSPERO, CRD42022329371). The Embase and PubMed databases were searched until April 28, 2022. The inclusion criteria were as follows: (1) case-control studies with more than three cases; (2) patients diagnosed with asthma; and (3) sufficient HMGB1 data. Literature screening and data extraction were performed independently by two investigators. Any disagreement was resolved through discussion with a third reviewer. The methodological quality of each risk-of-bias item for each eligible study was assessed using the Newcastle–Ottawa Scale (NOS). Review Manager software 5.2 (The Cochrane Collaboration, 2014) was used for data synthesis and analysis.
After screening, 13 studies were included for qualitative and quantitative analyses in our meta-analysis [Supplementary Figure 1, https://links.lww.com/CM9/B340]. The characteristics of the eligible studies, which included 977 participants (359 healthy subjects in the control group and 618 patients with asthma in the case group), are presented in Supplementary Table 1, https://links.lww.com/CM9/B340. The percentage of females in the control group was 50.14% (180/359) and 49.84% (308/618) in the case group. The mean age range in the healthy subjects and patients with asthma was 11.07 to 54.23 years and 10.56 to 57.44 years, respectively. HMGB1 expression was detected by the enzyme-linked immunosorbent assay. The specimen sources were bronchial brushings, biopsies, serum, plasma, sputum, and bronchoalveolar lavage fluid.
Four articles compared serum/plasma HMGB1 levels between patients with asthma and healthy subjects; the levels were significantly higher in patients with asthma (mean difference [MD] = 27.25, 95% confidence intervals [CI] = 17.73–36.77). However, heterogeneity (I2 = 95%, P < 0.001) was detected across studies; thus, a random-effects model was used [Figure 1A]. Furthermore, eight articles focused on sputum HMGB1 levels. HMGB1 levels were significantly elevated in patients with asthma (MD = 190.99, 95% CI = 127.08–254.91) compared to those in healthy subjects, and the results were highly heterogeneous (I2 = 100%, P < 0.001) [Figure 1B].
We also revealed a relationship between HMGB1 levels and disease severity. Eligible articles were pooled, and patients with asthma were classified as having mild-to-moderate asthma or severe asthma in accordance with the Global Initiative for Asthma. Serum/plasma HMGB1 levels were significantly elevated in patients with mild-to-moderate asthma (MD = 10.90, 95% CI = 2.16–19.65, I2=54%, P = 0.14) and significantly higher in patients with severe asthma (MD = 27.63, 95% CI = 7.92–47.33, I2 = 66%, P = 0.08) than in the control group. Furthermore, patients with severe asthma had significantly higher serum/plasma HMGB1 levels than those with mild-to-moderate asthma (MD = 13.31, 95% CI = 6.92–19.71, I2 = 0%, P = 0.38) [Figure 1C]. Similar results were observed for sputum HMGB1 levels. HMGB1 expression was significantly higher in patients with mild-to-moderate and severe asthma than in healthy subjects (mild-to-moderate asthma, MD = 176.80, 95% CI = 122.19–231.41, I2 = 97%, P < 0.001; severe asthma, MD = 265.80, 95% CI = 220.73–310.87, I2 = 95%, P < 0.001). Additionally, patients with severe asthma had significantly higher sputum HMGB1 levels than those with mild-to-moderate asthma (MD = 102.31, 95% CI = 78.04–126.57, I2 = 73%, P = 0.01) [Figure 1D].
Subgroup analyses based on country, sex, age, body mass index (BMI), and percent of forced expiratory volume in one second (FEV1%) predicted were performed to explore the source of heterogeneity. No significant heterogeneity was observed in the group with BMI < 18.5 kg/m2 (P = 1.000, I2 = 0%) and 18.5 ≤ BMI < 24.0 kg/m2 (P = 0.200, I2=39%); however, there was considerable heterogeneity in the BMI ≥ 24.0 kg/m2 groups (P = 0.002, I2 = 100%). No other variables were sources of heterogeneity [Supplementary Table 2, https://links.lww.com/CM9/B340]. The NOS scores are summarized in Supplementary Table 1, https://links.lww.com/CM9/B340, and each numbered item of all qualified studies is shown in the percentage chart [Supplementary Figure 2, https://links.lww.com/CM9/B340]. All included articles were high-quality studies (scores >7.0).
New non-invasive biomarkers for airway inflammation are essential. Sputum HMGB1 levels were significantly higher in patients with severe asthma than in those with mild-to-moderate asthma, and HMGB1 levels increased with the degree of airflow limitation. Therefore, HMGB1 could be an independent risk factor affecting the predicted value of FEV1%. Our results reveal a significant difference in HMGB1 levels in serum/plasma/sputum specimens between patients with asthma and healthy controls. Additionally, HMGB1 overexpression was more pronounced in patients with moderate-to-severe and severe asthma than in healthy subjects, suggesting that high HMGB1 levels correlated positively with disease severity. Therefore, elevated HMGB1 levels may be a potential biomarker of asthma severity.
HMGB1, a damage-associated molecular pattern molecule, participates in the inflammatory response and releases inflammatory mediators by binding to specific receptors, including advanced glycation end product receptors (RAGEs) and Toll-like receptors (TLRs). Airway ECs are direct participants and specific target cells in the development of asthmatic inflammation. The surface of these cells is enriched with TLRs and RAGEs, and this is one of the cell types that is the most responsive to HMGB1.
Although the mechanism of HMGB1 in human asthma remains unclear, previous studies have demonstrated that HMGB1 is involved in the pathogenesis of airway inflammation, hyper-responsiveness, and remodeling in a mouse model of asthma, which was prevented or reversed by blocking HMGB1 activity. A recent study identified the G protein-coupled receptor P2Y13 as a novel gatekeeper of HMGB1, and targeting this receptor via genetic deletion or a small-molecule antagonist may inhibit the occurrence and development of experimental asthma. However, long-term clinical trials are needed to ascertain whether the specific blockage of the receptor for HMGB1 can be achieved in an effective and safe manner in human asthma patients.
In conclusion, our results suggest that HMGB1 could be a potential biomarker of asthma severity. Early detection of HMGB1 and blocking its specific receptors may be valuable therapeutic strategies for asthma. Given the limitations of this study, further investigations are warranted to confirm these findings and allow for efficient clinical translation.
This work was supported by grants from the National Key Research and Development Program of China (Nos. 2022YFF0710800 and 2018YFC1313600), Major International (Regional) Joint Research Project of China (No. 81820108001), National Natural Science Foundation of China (Nos. 81670029 and 82000038), Jiangsu Key Principal Investigator of Medicine (No. ZDRCA2016018), and Project 333 for Cultivation of High-Level Talents (Leading Talents of the Young and Middle-Aged) (No. BRA2019078), and the Nanjing Key Project of Science and Technology (No. 2019060002).
Conflicts of interest
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