Pathophysiological relevance of sputum MUC5AC and MUC5B levels in patients with mild asthma

[Background] Airway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans. [Methods] In this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays. [Results] Sputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = −0.33, p = 0.004). [Conclusions] Sputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma

Association of Eosinophilic Inflammation with FKBP51 Expression in Sputum Cells in Asthma.

[Background]: Airway eosinophilia is a predictor of steroid responsiveness in steroid-naı¨ve asthma. However, the relationship between airway eosinophilia and the expression of FK506-binding protein 51 (FKBP51), a glucocorticoid receptor cochaperone that plays a role in steroid insensitivity in asthma, remains unknown. [Objective]: To evaluate the relationship between eosinophilic inflammation and FKBP51 expression in sputum cells in asthma. [Methods]: The FKBP51 mRNA levels in sputum cells from steroid-naı¨ve patients with asthma (n = 31) and stable asthmatic patients on inhaled corticosteroid (ICS) (n = 28) were cross-sectionally examined using real-time PCR. Associations between FKBP51 levels and clinical indices were analyzed. [Results]: In steroid-naı¨ve patients, the FKBP51 levels were negatively correlated with eosinophil proportions in blood (r =20.52) and sputum (r =20.57), and exhaled nitric oxide levels (r =20.42) (all p,0.05). No such associations were observed in patients on ICS. In steroid-naı¨ve patients, improvement in forced expiratory volume in one second after ICS initiation was correlated with baseline eosinophil proportions in blood (r = 0.74) and sputum (r = 0.76) and negatively correlated with FKBP51 levels (r =20.73) (all p,0.0001) (n = 20). Lastly, the FKBP51 levels were the lowest in steroid-naı¨ve asthmatic patients, followed by mild to moderate persistent asthmatic patients on ICS, and the highest in severe persistent asthmatic patients on ICS (p,0.0001). [Conclusions]: Lower FKBP51 expression in sputum cells may reflect eosinophilic inflammation and glucocorticoid responsiveness in steroid-naı¨ve asthmatic patients

Effects of 24-week add-on treatment with ciclesonide and montelukast on small airways inflammation in asthma.

[Background]Eosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients. The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown.Objective To examine the effects of add-on therapy with either ciclesonide, an inhaled corticosteroid with extrafine particles, or montelukast on small airway inflammation. [Methods]Sixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a randomized, open-label, parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast. Patients were randomly assigned to 3 groups: ciclesonide (n = 19), montelukast (n = 22), or no add-on as controls (n = 19). At baseline and at weeks 4, 12, and 24, extended nitric oxide analysis; pulmonary function tests, including impulse oscillometry; blood eosinophil counts; and asthma control tests (ACTs) were performed. [Results]A total of 18 patients in the ciclesonide group, 19 in the montelukast group, and 15 in the control group completed the study and were analyzed. With repeated-measures analysis of variance, ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time. Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores, whereas no such changes were observed in the control group. Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control. [Conclusion]Ciclesonide add-on therapy and montelukast add-on therapy may act differently, but both separately can improve small airway abnormalities and provide better asthma control

Mechanical stimulation by postnasal drip evokes cough

Cough affects all individuals at different times, and its economic burden is substantial. Despite these widespread adverse effects, cough research relies on animal models, which hampers our understanding of the fundamental cause of cough. Postnasal drip is speculated to be one of the most frequent causes of chronic cough; however, this is a matter of debate. Here we show that mechanical stimuli by postnasal drip cause chronic cough. We distinguished human cough from sneezes and expiration reflexes by airflow patterns. Cough and sneeze exhibited one-peak and two-peak patterns, respectively, in expiratory airflow, which were also confirmed by animal models of cough and sneeze. Transgenic mice with ciliary dyskinesia coughed substantially and showed postnasal drip in the pharynx; furthermore, their cough was completely inhibited by nasal airway blockade of postnasal drip. We successfully reproduced cough observed in these mice by injecting artificial postnasal drip in wild-type mice. These results demonstrated that mechanical stimulation by postnasal drip evoked cough. The findings of our study can therefore be used to develop new antitussive drugs that prevent the root cause of cough

A multicenter prospective observational study of lymph node metastasis patterns and short‐term outcomes of extended lymphadenectomy in right‐sided colon cancer

Abstract Background The lymph node metastasis rate in right‐sided colon cancer is unknown, and the optimal central vascular ligation level remains controversial. We aimed to determine the lymph node metastasis rate and short‐term results of radical surgery with extended lymph node dissection in right‐sided colon cancer. Methods This prospective multicenter observational study included patients with stage II/III right‐sided colon cancer from five cancer hospitals. The metastasis rate of each node station was analyzed according to tumor location and main feeding artery. Results Between April 2018 and August 2021, 208 patients underwent dissection around the superior mesenteric artery (SMA) and vein (SMV). In transverse colon cancer, 7.5% and 2.5% of metastases occurred around the SMV and SMA at the root of the middle colic artery (MCA), respectively; 6.7% and 6.7% at the root of the right colic artery. In caecal cancer, 1.9% of metastases occurred around the SMV and 1.9% around the SMA. In ascending colon cancer, the rate was 1.1% around the SMV. Of the tumors, 17% fed mainly by the ileocolic artery had node metastases along the middle or right colic artery, as did 66.7% fed mainly by the right colic artery and 41.2% fed by the MCA (p = 0.01). Postoperative complications occurred in 42 patients (20.2%). Conclusion Routine prophylactic extended lymphadenectomy around the SMA might not be necessary in caecum and ascending colon cancer. Dissection around the SMA may be necessary in cases of transverse colon cancer or when the feeding artery is the MCA