Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma.

BACKGROUND: Non-neuronal cholinergic system (NNCS) contributes to various inflammatory airway diseases. However, the role of NNCS in severe asthma (SA) remains largely unexplored. OBJECTIVE: To explore airway NNCS in SA. METHODS: In this prospective cohort study based on the Australasian Severe Asthma Network in a real-world setting, patients with SA (n = 52) and non-SA (n = 104) underwent clinical assessment and sputum induction. The messenger RNA (mRNA) levels of NNCS components and proinflammatory cytokines in the sputum were detected using real-time quantitative polymerase chain reaction, and the concentrations of acetylcholine (Ach)-related metabolites were evaluated using liquid chromatography coupled with tandem mass spectrometry. Asthma exacerbations were prospectively investigated during the next 12 months. The association between NNCS and future asthma exacerbations was also analyzed. RESULTS: Patients with SA were less controlled and had worse airway obstruction, a lower bronchodilator response, higher doses of inhaled corticosteroids, and more add-on treatments. The sputum mRNA levels of NNCS components, such as muscarinic receptors M1R-M5R, OCT3, VACHT, and ACHE; proinflammatory cytokines; and Ach concentration in the SA group were significantly higher than those in the non-SA group. Furthermore, most NNCS components positively correlated with non-type (T) 2 inflammatory profiles, such as sputum neutrophils, IL8, and IL1B. In addition, the mRNA levels of sputum M2R, M3R, M4R, M5R, and VACHT were independently associated with an increased risk of moderate-to-severe asthma exacerbations. CONCLUSION: This study indicated that the NNCS was significantly activated in SA, leading to elevated Ach and was associated with clinical features, non-T2 inflammation, and future exacerbations of asthma, highlighting the potential role of the NNCS in the pathogenesis of SA. CLINICAL TRIAL REGISTRATION: ChiCTR-OOC-16009529 (http://www.chictr.org.cn).

Airway Stents from Now to the Future: A Narrative Review.

Airway stent insertion is important for patients with airway stenosis. Currently, the most widely used airway stents in clinical procedures are silicone and metallic stents, which offer patients effective treatment. However, these stents composed of permanent materials need to be removed, subjecting patients to invasive manipulation once more. As a result, there is a growing demand for biodegradable airway stents. Biodegradable materials for airway stents are now available in two types: biodegradable polymers and biodegradable alloys. Polymers that include poly (l-lactic acid), poly (D, l-lactide-co-glycolide), polycaprolactone, and polydioxanone are the ultimate metabolites which are generally carbon dioxide and water. Magnesium alloys are the most often utilized metal biodegradable materials for airway stents. The stent's mechanical properties and rate of degradation vary as a result of the different materials, cutting techniques, and structural configurations. We summarized the information above from recent studies on biodegradable airway stents conducted in both animals and humans. There is great potential for clinical applications for biodegradable airway stents. They avoid damage to the trachea during removal and reduce complications to some extent. However, several significant technical difficulties slow down the development of biodegradable airway stents. The efficacy and safety of different biodegradable airway stents still need to be investigated and proved.

Reticulation Is a Risk Factor of Progressive Subpleural Nonfibrotic Interstitial Lung Abnormalities.

Rationale: Interstitial lung abnormalities (ILAs) are being increasingly identified in clinical practice. In particular, for subpleural nonfibrotic ILAs, the risk of progression over time and the risk factors for progressive behavior are still largely unknown. Objectives: To determine the age band prevalence of ILAs and the risk of radiological progression of subpleural nonfibrotic ILAs over time in a large health checkup population and to identify how reticulation contributes to the risk of radiological progression. Methods: On the basis of the ILAs definition by the Fleischner Society, low-dose chest computed tomography images from the community-dwelling population who have undergone health checkups were evaluated for ILAs. Multivariable logistic regression was used to assess the risk of radiological progression. Measurements and Main Results: Among 155,539 individuals, 3,300 (2.1%) were confirmed to have ILAs: the vast majority (81.7%) were defined as subpleural nonfibrotic ILAs. The prevalence of ILAs increased linearly with age (P for trend < 0.0001). Of 454 individuals with subpleural nonfibrotic ILAs, 198 (43.6%) had radiological progression over 4 years. The presence of reticulation on initial imaging was an independent predictor of radiological progression (odds ratio, 1.9; 95% confidence interval, 1.2-3.0; P = 0.0040). No difference in radiological progression was identified between subpleural nonfibrotic ILAs with extensive reticulation and subpleural fibrotic ILAs (73.0% vs. 68.8%; P = 0.7626). Conclusions: The prevalence of ILAs increases linearly with age. Nearly half of subpleural nonfibrotic ILAs progress radiologically over 4 years. The presence of reticulation is a risk factor for radiological progression. Subpleural nonfibrotic ILAs with extensive reticulation are likely to be a feature of subpleural fibrotic ILAs.

Clinical characteristics and predictors of pulmonary hypertension in chronic obstructive pulmonary disease at different altitudes.

BACKGROUND: Pulmonary hypertension (PH) is a common complication in patients with chronic obstructive pulmonary disease (COPD) and is closely associated with poor prognosis. However, studies on the predictors of PH in COPD patients are limited, especially in populations living at high altitude (HA). OBJECTIVES: To investigate the differences in the clinical characteristics and predictors of patients with COPD/COPD and PH (COPD-PH) from low altitude (LA, 600 m) and HA (2200 m). METHODS: We performed a cross-sectional survey of 228 COPD patients of Han nationality admitted to the respiratory department of Qinghai People's Hospital (N = 113) and West China Hospital of Sichuan University (N = 115) between March 2019 and June 2021. PH was defined as a pulmonary arterial systolic pressure (PASP) > 36 mmHg measured using transthoracic echocardiography (TTE). RESULTS: The proportion of PH in COPD patients living at HA was higher than that in patients living at LA (60.2% vs. 31.3%). COPD-PH patients from HA showed significantly different in baseline characteristics, laboratory tests and pulmonary function test. Multivariate logistic regression analysis indicated that the predictors of PH in COPD patients were different between the HA and LA groups. CONCLUSIONS: The COPD patients living at HA had a higher proportion of PH than those living at LA. At LA, increased B-type natriuretic peptide (BNP) and direct bilirubin (DB) were predictors for PH in COPD patients. However, at HA, increased DB was a predictor of PH in COPD patients.

Monitoring small airway dysfunction in connective tissue disease-related interstitial lung disease: a retrospective and prospective study.

BACKGROUND: Small airway dysfunction (SAD), a hallmark of early lung function abnormality, is a major component of several chronic respiratory disorders. The role of SAD in patients with connective tissue disease-related interstitial lung disease (CTD-ILD) has not been explored. METHODS: We conducted a two-parts (retrospective and prospective) study to collect pulmonary function tests from CTD-ILD patients. SAD was defined as at least two of the three measures (MMEF, FEF 50%, and FEF 75%) must be 65% of predicted values. Spearman correlation coefficient was used to evaluate association between SAD and other pulmonary function parameters. Mixed effects regression modeling analysis was used to assess response to treatment. RESULTS: CTD-ILD patients with SAD and without SAD were compared in this study. In the retrospective study, pulmonary function tests (PFTs) from 491 CTD-ILD patients were evaluated, SAD were identified in 233 (47.5%). CTD-ILD patients with SAD were less smokers (17.6% vs. 27.9%, p = 0.007) and more females (74.3% vs. 64.0%, p = 0.015) than those without SAD. CTD-ILD patients with SAD had lower vital capacity (% predicted FVC, 70.4 ± 18.3 vs. 80.0 ± 20.9, p < 0.001) and lower diffusion capacity (% predicted DLCO, 58.8 ± 19.7 vs. 63.8 ± 22.1, p = 0.011) than those without SAD. Among 87 CTD-ILD patients prospectively enrolled, significant improvement in % predicted FVC was observed at 12-months follow-up (6.37 ± 1.53, p < 0.001 in patients with SAD; 5.13 ± 1.53, p = 0.002 in patients without SAD), but not in diffusion capacity and SAD parameters. CONCLUSION: In our cohort, about half of CTD-ILD patients have SAD, which is less frequent in smokers and more common in female patients. CTD-ILD patients with SAD have worse pulmonary function compared to those without SAD. Improvement of FVC but no improvement of SAD was observed in CTD-ILD patients after treatment.

Quantitative evaluation of disease severity in connective tissue disease-associated interstitial lung disease by dual-energy computed tomography.

BACKGROUND: High-resolution computed tomography (HRCT) is recommended diagnosing and monitoring connective tissue disease-associated interstitial lung disease (CTD-ILD). Quantitative computed tomography has the potential to precisely assess the radiological severity of CTD-ILD, but has still been under study. OBJECTIVE: To investigate whether dual-energy computed tomography (DECT), a novel quantitative technique, can be used for quantitative severity assessment in CTD-ILD. METHODS: This cross sectional study recruited adult CTD-ILD patients who underwent DECT scans from the ICE study between October 2019 and November 2021. DECT parameters, including effective atomic number (Zeff), lung (lobe) volume, and monochromatic CT number (MCTN) of each lung lobe, were evaluated. CTD-ILD was classified into extensive CTD-ILD and limited CTD-ILD by staging algorithm using combined forced vital capacity (FVC)%predicted and total extent of ILD (TEI) on CT. Dyspnea, cough, and life quality were scored by Borg dyspnea score, Leicester cough questionnaire (LCQ), and short-form 36 health survey questionnaire (SF-36), respectively. RESULTS: There was a total of 147 patients with DECT scans enrolled. Higher Zeff value (3.104 vs 2.256, p < 0.001), higher MCTN (- 722.87 HU vs - 802.20 HU, p < 0.001), and lower lung volume (2309.51cm3 vs 3475.21cm3, p < 0.001) were found in extensive CTD-ILD compared with limited CTD-ILD. DECT parameters had significant moderate correlations with FVC%predicted (|r|= 0.542-0.667, p < 0.01), DLCO%predicted (|r|= 0.371-0.427, p < 0.01), and TEI (|r|= 0.485-0.742, p < 0.01). Receiver operating characteristic (ROC) analysis indicated MCTN averaged over the whole lung had the best performance for extensive CTD-ILD discrimination (AUC = 0.901, cut-off: - 762.30 HU, p < 0.001), with a sensitivity of 82.1% and a specificity of 85.4%. The Zeff value was the independent risk factor for dyspnea (OR = 3.644, 95% CI: 1.846-7.192, p < 0.001) and cough (OR = 3.101, 95% CI: 1.528-6.294, p = 0.002), and lung volume significantly contributed to the mental component summary (MCS) in SF-36 (standardized ß = 0.198, p < 0.05). CONCLUSIONS: DECT can be applied to evaluate the severity of CTD-ILD.

Histone arginine methylation by Prmt5 is required for lung branching morphogenesis through repression of BMP signaling.

Branching morphogenesis is essential for the successful development of a functional lung to accomplish its gas exchange function. Although many studies have highlighted requirements for the bone morphogenetic protein (BMP) signaling pathway during branching morphogenesis, little is known about how BMP signaling is regulated. Here, we report that the protein arginine methyltransferase 5 (Prmt5) and symmetric dimethylation at histone H4 arginine 3 (H4R3sme2) directly associate with chromatin of Bmp4 to suppress its transcription. Inactivation of Prmt5 in the lung epithelium results in halted branching morphogenesis, altered epithelial cell differentiation and neonatal lethality. These defects are accompanied by increased apoptosis and reduced proliferation of lung epithelium, as a consequence of elevated canonical BMP-Smad1/5/9 signaling. Inhibition of BMP signaling by Noggin rescues the lung branching defects of Prmt5 mutant in vitro Taken together, our results identify a novel mechanism through which Prmt5-mediated histone arginine methylation represses canonical BMP signaling to regulate lung branching morphogenesis.

Increased serum Th2 chemokine levels are associated with bronchopulmonary dysplasia in premature infants.

Bronchopulmonary dysplasia (BPD) is one of the most common chronic inflammatory lung disease of premature infants, with serious short- and long-term consequences. Early identification of premature infants at risk of BPD is critical to preventing the pathogenesis of disease. Thus, in the present study, we recruited 126 premature infants, collected peripheral blood samples at different time points during early life, and measured the concentration of Th1 (MCP-1, IP-10, and MIG) and Th2 (eotaxin-1, eotaxin-2, and MCP-4) chemokines in serum. We found serum eotaxin-2 levels were significantly higher in the BPD group than in the non-BPD group on day 1 [1662 pg/ml vs. 1221 pg/ml, P < 0.05], day 7 [1533 pg/ml vs. 1089 pg/ml, P < 0.05], and day 14 [1246 pg/ml vs. 704 pg/ml, P < 0.05] after birth, and serum MCP-4 levels were also significantly higher in the BPD group than in the non-BPD group on day 1 [186 pg/ml vs. 128 pg/ml, P < 0.05], day 7 [199 pg/ml vs. 101 pg/ml, P < 0.05], and day 14 [238 pg/ml vs. 106 pg/ml, P < 0.05] of life.Conclusions: Increased levels of Th2 chemokines, eotaxin-2, and MCP-4, are associated with BPD in premature infants. What is Known: • The pathogenesis of BPD is multifactorial and it is difficult to predict and prevent. • Previous studies have demonstrated that inflammation plays a major role in the pathogenesis of BPD. What is New: • Increased Th2 chemokines, eotaxin-2 and MCP-4, were associated with BPD in premature infants. • Abnormal Th1/Th2 response in early life maybe associated with the subsequent development of BPD, which provide a new insight to understand the pathogenesis of the disease.

WITHDRAWN: KLF5 promoted symmetric cell division in KRT5 positive keratinocytes through suppression of Notch1 expression.

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[Combined effect of gestational age and birth weight on metabolites related to inherited metabolic diseases in neonates].

OBJECTIVE: To study the combined effect of gestational age and birth weight on metabolites related to inherited metabolic diseases (IMD). METHODS: A total of 3 381 samples ruled out of IMD by follow-up were randomly selected from 38 931 newborns who participated in the neonatal IMD screening during 2014-2016. The 3 381 neonates were categorized into seven groups according to their gestational age and birth weight: extremely preterm appropriate-for-gestational age (AGA) group (n=12), preterm small-for-gestational age (SGA) group (n=18), preterm AGA group (n=219), preterm large-for-gestational age (LGA) group (n=18), full-term SGA group (n=206), full-term AGA group (n=2 677), and full-term LGA group (n=231). Heel blood samples were collected from each group on postnatal days 3-7 after adequate breastfeeding. Levels of 17 key IMD-related metabolic indices in dried blood spots were measured using tandem mass spectrometry. Spearman′s correlation analysis was used to investigate the relationships between 17 IMD-related metabolic indices and their influencing factors, while covariance analysis was used to compare the metabolic indices between these groups. RESULTS: After adjusting the influencing factors such as physiological and pathological status, compared with the full-term AGA group, the extremely preterm AGA, preterm SGA, and preterm AGA groups had significantly reduced levels of leucine\isoleucine\hydroxyproline and valine (P<0.05); the preterm AGA group had a significantly decreased ornithine level (P<0.05); the extremely preterm AGA and preterm AGA groups had a significantly reduced proline level (P<0.05). Besides, the phenylalanine level in the extremely preterm AGA and preterm AGA groups, the methionine level in the preterm SGA group, and the tyrosine level in the preterm AGA group all significantly increased (P<0.05). The increased levels of free carnitine, acetylcarnitine, and propionylcarnitine were found in the preterm SGA and preterm AGA groups. The oleylcarnitine level also significantly increased in the preterm SGA group (P<0.05). Most carnitine indices showed significant differences between the SGA group and the AGA/LGA group in both preterm and full-term infants (P<0.05). CONCLUSIONS: Low gestational age and low birth weight may result in abnormal results in IMD screening. Therefore, gestational age and birth weight should be considered to comprehensively judge the abnormal results in IMD screening.

[Identification of a novel GPR143 mutation in a Chinese family affected with X-linked ocular albinism].

OBJECTIVE: To detect mutation of GPR143 gene in a Chinese patient affected with ocular albinism. METHODS: Peripheral blood samples were collected from the proband and his parents. The coding regions of the GPR143 gene were subjected to PCR amplification and Sanger sequencing. RESULTS: A previously unreported mutation (c.758T>A) was found in exon 6 of the GPR143 gene in the proband and his mother. The same mutation was not found in his father. As predicted, the mutation has resulted in a stop codon, causing premature termination of protein translation. CONCLUSION: A novel mutation of the GPR143 gene related to X-linked ocular albinism has been identified.

Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation.

A blastocyst will implant only when the uterus becomes receptive. Following attachment, luminal epithelial cells undergo degeneration at the site of the blastocyst. Although many genes critical for uterine receptivity are primarily regulated by ovarian hormones, Kruppel-like factor 5 (KLF5), a zinc finger-containing transcription factor, is persistently expressed in epithelial cells independently of ovarian hormones. Loss of uterine Klf5 causes female infertility due to defective implantation. Cox2 is normally expressed in the luminal epithelium and stroma at the site of blastocyst attachment, but luminal epithelial COX2 expression is absent with loss of Klf5. This is associated with the retention of the epithelium around the implantation chamber with arrested embryonic growth. These results suggest that Klf5 is indispensable for normal implantation.

CDC42 is required for structural patterning of the lung during development.

The formation of highly branched epithelial structures is critical for the development of many essential organs, including lung, liver, pancreas, kidney and mammary glands. Elongation and branching of these structures require precise control of complex morphogenetic processes that are dependent upon coordinate regulation of cell shape, apical-basal polarity, proliferation, migration, and interactions among multiple cell types. Herein, we demonstrate that temporal-spatial regulation of epithelial cell polarity by the small GTPase, CDC42, is essential for branching morphogenesis of the developing lung. Epithelial cell-specific deletion of CDC42 in fetal mice disrupted epithelial cell polarity, the actin cytoskeleton, intercellular contacts, directional trafficking of proteins, proliferation and mitotic spindle orientation, impairing the organization and patterning of the developing respiratory epithelium and adjacent mesenchyme. Transition from a pseudostratified to a simple columnar epithelium was impaired, consistent with coordinate dysregulation of epithelial cell polarity, mitotic spindle orientation, and repositioning of mitotic cells within the epithelium during cell cycle progression. Expression of sonic hedgehog and its receptor, patched-1, was decreased, while fibroblast growth factor 10 expression in the mesenchyme was expanded, resulting in disruption of branching morphogenesis and bronchiolar smooth muscle formation in this model. CDC42 is required for spatial positioning of proliferating epithelial cells, as well as signaling interactions between the epithelium and mesenchyme and is, therefore, essential for formation and maintenance of the respiratory tract during morphogenesis of the fetal lung.

Disruption of precise regulation of αPKC expression and cellular localization is associated with cervical cancer progression.

PURPOSE: To understand the pathogenesis of cervical cancer (CC) associated with polarity protein αPKC and the potential roles of αPKC in clinical management of CC. METHODS: Tissue samples were collected from women who received colposcopy biopsy or hysterectomy surgery, including 9 CIN1, 8 CIN2, 15 CIN3, and 12 invasive cervical squamous cancer (ICC). 16 normal controls were from the normal region of tumor samples, HE and immunofluorescence staining of αPKC were performed on these samples. ANOVA and Kruslal-wallis test were used to quantitate the abnormal distribution and expression level of αPKC among different cervical lesions. RESULTS: Disruption of polarized apical localization and increased cytoplasmic accumulation of αPKC were identified in cervical lesions. In normal cervical epithelium, αPKC was detected on the apical membrane of endocervical columnar epithelial cells and of exocervical epithelial cells located at basal layer of squamous epithelium. While in squamous metaplasia, a precancerous lesion of cervical neoplasia, the polarized apical membrane localization of αPKC was disrupted, and intensed cytoplasmic accumulation was identified in the immature squamous metaplastic cells. Compared with normal cervix, number of epithelial cells with abnormal αPKC distribution was progressively increased in CINs and ICC (P < 0.05), and cytoplasmic accumulation of αPKC was increased in CIN2, CIN3, and ICC compared with CIN1 (P < 0.05). CONCLUSIONS: Disruption of polarized apical localization and increased cytoplasmic accumulation of αPKC were associated with CC progression, indicating that precise regulation of αPKC may play important roles in CC progression, and αPKC may be a potential molecular target for clinical diagnoses and treatment of CC.

Transcriptomic profiles of age-related genes in female trachea and bronchus.

Background: Studies demonstrated that age-related cellular and functional changes of airway significantly contribute to the pathogenesis of many airway diseases. However, our understanding on the age-related molecular alterations of human airway remains inadequate. Methods: Airway (trachea and bronchus) brushing specimens were collected from 14 healthy, female non-smokers with ages ranging from 20 to 60 years. Bulk RNA sequencing was performed on all the specimens (n = 28). Airway cell types and their relative proportions were estimated using CIBERSORTx. The cell type proportions were compared between the younger (age 20-40) and elder group (age 40-60) in the trachea and bronchus respectively. The linear association between cell type proportion and age was assessed using the Pearson correlation coefficient. Differentially expressed genes (DEGs) between the two age groups were identified using DESeq2. Three kinds of enrichment analysis of the age-related DEGs were performed, including Gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and disease enrichment analysis. Results: Sixteen and thirteen cell types were separately identified in tracheal and bronchial brushings, with the airway epithelial cells (including suprabasal, submucosal gland (SMG) goblet, serous, secretory, multiciliated, cycling.basal, basal cells) accounting for 85.1% in the trachea and 92.5% in the bronchus. The lymphatic cell and NK cells had a higher abundance ratio in the trachea, compared with the bronchus. The proportion of basal cells was negatively related to age both in the trachea and bronchus. Thirty-one and fifty-two age-related DEGs (p < 0.1) were identified in the trachea and bronchus, respectively. Among them, five common DEGs (CXCL2, CXCL8, TCIM, P4HA3, AQP10) were identified. Pathway enrichment analysis showed both tracheal and bronchial age-related DEGs were primarily involved in immune regulatory signaling pathways (TNF, NF-kappa B, IL-17 et al.). Disease enrichment analysis suggested that tracheal age-related DEGs significantly related to asthmatic pulmonary eosinophilia, and chronic airflow obstruction et al., and that bronchial age-related DEGs were enriched in airflow obstruction, bronchiectasis, pulmonary emphysema, and low respiratory tract infection et al. Conclusion: We found the proportion of basal cells decreased with age in both the trachea and bronchus, suggesting a weakening of their self-renew ability with age. We identified transcriptomic signature genes associated with the early aging process of the human trachea and bronchus, and provided evidence to support that changes in their immune regulatory function may play critical roles in age-related airway diseases.

Conditional disruption of mouse Klf5 results in defective eyelids with malformed meibomian glands, abnormal cornea and loss of conjunctival goblet cells.

Members of the Krüppel-like family of transcription factors regulate diverse developmental processes in various organs. Previously, we have demonstrated the role of Klf4 in the mouse ocular surface. Herein, we determined the role of the structurally related Klf5, using Klf5-conditional null (Klf5CN) mice derived by mating Klf5-LoxP and Le-Cre mice. Klf5 mRNA was detected as early as embryonic day 12 (E12) in the cornea, conjunctiva and eyelids, wherein its expression increased during development. Though the embryonic eye morphogenesis was unaltered in the Klf5CN mice, postnatal maturation was defective, resulting in smaller eyes with swollen eyelids that failed to separate properly. Klf5CN palpebral epidermis was hyperplastic with 7-9 layers of keratinocytes, compared with 2-3 in the wild type (WT). Klf5CN eyelid hair follicles and sebaceous glands were significantly enlarged, and the meibomian glands malformed. Klf5CN lacrimal glands displayed increased vasculature and large number of infiltrating cells. Klf5CN corneas were translucent, thicker with defective epithelial basement membrane and hypercellular stroma. Klf5CN conjunctiva lacked goblet cells, demonstrating that Klf5 is required for conjunctival goblet cell development. The number of Ki67-positive mitotic cells was more than doubled, consistent with the increased number of Klf5CN ocular surface epithelial cells. Co-ablation of Klf4 and Klf5 resulted in a more severe ocular surface phenotype compared with Klf4CN or Klf5CN, demonstrating that Klf4 and Klf5 share few if any, redundant functions. Thus, Klf5CN mice provide a useful model for investigating ocular surface pathologies involving meibomian gland dysfunction, blepharitis, corneal or conjunctival defects.

Foxa2 programs Th2 cell-mediated innate immunity in the developing lung.

After birth, the respiratory tract adapts to recurrent exposures to pathogens, allergens, and toxicants by inducing the complex innate and acquired immune systems required for pulmonary homeostasis. In this study, we show that Foxa2, expressed selectively in the respiratory epithelium, plays a critical role in regulating genetic programs influencing Th2 cell-mediated pulmonary inflammation. Deletion of the Foxa2 gene, encoding a winged helix/forkhead box transcription factor that is selectively expressed in respiratory epithelial cells, caused spontaneous pulmonary eosinophilic inflammation and goblet cell metaplasia. Loss of Foxa2 induced the recruitment and activation of myeloid dendritic cells and Th2 cells in the lung, causing increased production of Th2 cytokines and chemokines. Loss of Foxa2-induced expression of genes regulating Th2 cell-mediated inflammation and goblet cell differentiation, including IL-13, IL-4, eotaxins, thymus and activation-regulated chemokine, Il33, Ccl20, and SAM pointed domain-containing Ets transcription factor. Pulmonary inflammation and goblet cell differentiation were abrogated by treatment of neonatal Foxa2(Delta/Delta) mice with mAb against IL-4Ralpha subunit. The respiratory epithelium plays a central role in the regulation of Th2-mediated inflammation and innate immunity in the developing lung in a process regulated by Foxa2.

Association between Dietary Anthocyanidins and Risk of Lung Cancer.

Background: Anthocyanidins are a kind of water-soluble flavonoids widely found in flowers and fruits of many plants. Although the beneficial effect of anthocyanidins in cancer prevention has been discussed, the value of anthocyanidins in lung cancer prevention requires further investigation. In this study, we aimed to explore the role of dietary anthocyanidins in the prevention of lung cancer in population-based prospective studies. Methods: Data of participants in this study were collected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in Cox proportional hazards regression for the association of dietary anthocyanidins and lung cancer risk. The dose-response relationship was explored between total anthocyanidins and the incidence of lung cancer. Results: A total of 97,993 participants were included in this study. The calculated HRs showed a trend that a higher quartile of total anthocyanidins indicated lower risk of lung cancer after adjusting for covariates (HRQ4vsQ1: 0.63; 95% CI: 0.55,0.73; p for trend < 0.001). A non-linear association between total anthocyanidins and lung cancer risk was found in the restricted cubic spline model. Conclusion: A protective association between dietary anthocyanidins and risk of lung cancer in Americans was investigated.

Association Between Diabetes Risk Reduction Diet and Lung Cancer Risk in 98,159 Participants: Results From a Prospective Study.

Purpose: To evaluate the association between diabetes risk reduction diet (DRRD) score and the risk of lung cancer in a large population. Methods: Data of participants in this study were collected from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in the Cox proportional hazards regression model for the association of DRRD score and lung cancer incidence in all included participants. Prespecified subgroup analyses were performed to evaluate whether the observed association was modified by age, sex, BMI, race/ethnicity, family history of lung cancer, smoking status and history of diabetes. Results: A total of 98,159 participants were included in this study. The mean (SD) age of the study participants cohort at baseline was 65.5 (5.73) years old. The mean (SD) follow-up time was 8.83 (1.96) years. The mean (SD) score of DRRD was 26.82 (5.19), and ranged from 20.47 (2.3) to 33.65 (2.42) from the lowest quartile to the highest quartile of the DRRD score, inferring the possibility of highest through the lowest risk of type 2 diabetes. The calculated HRs showed there was a trend that higher quartile indicated lower risk of lung cancer after adjusted for covariates (HRQ4vsQ1: 0.85; 95% CI:0.73,0.98; p for trend =0.036). The inverse trend between higher DRRD score and the risk of squamous cell carcinoma was more evident (HRQ4vsQ1: 0.50; 95% CI:0.34,0.73; p for trend =0.002). The inverse association between DRRD score and the incidence of lung cancer was more pronounced in participants who had a clear family history of lung cancer (p for interaction=0.016). Conclusion: A protective association between DRRD score and risk of lung cancer is obtained. People are encouraged to adhere to higher DRRD score in their daily diet. Further studies should be conducted to confirm the result and explore the mechanism.