SARS-CoV-2 spike protein receptor binding domain promotes IL-6 and IL-8 release via ATP/P2Y2 and ERK1/2 signaling pathways in human bronchial epithelia.

The spike protein of SARS-CoV-2 as well as its receptor binding domain (RBD) has been demonstrated to be capable of activating the release of pro-inflammatory mediators in endothelial cells and immune cells such as monocytes. However, the effects of spike protein or its RBD on airway epithelial cells and mechanisms underlying these effects have not been adequately characterized. Here, we show that the RBD of spike protein alone can induce bronchial epithelial inflammation in a manner of ATP/P2Y2 dependence. Incubation of human bronchial epithelia with RBD induced IL-6 and IL-8 release, which could be inhibited by antibody. The incubation of RBD also up-regulated the expression of inflammatory indicators such as ho-1 and mkp-1. Furthermore, ATP secretion was observed after RBD treatment, P2Y2 receptor knock down by siRNA significantly suppressed the IL-6 and IL-8 release evoked by RBD. Additionally, S-RBD elevated the phosphorylation level of ERK1/2, and the effect that PD98059 can inhibit the pro-inflammatory cytokine release suggested the participation of ERK1/2. These novel findings provide new evidence of SARS-CoV-2 on airway inflammation and introduce purinergic signaling as promising treatment target.

Pro-inflammatory action of formoterol in human bronchial epithelia.

Despite the wide usage of ß2-adrenoceptor agonists in asthma treatment, they do have side effects such as aggravating inflammation. We previously reported that isoprenaline induced Cl- secretion and IL-6 release via cAMP-dependent pathways in human bronchial epithelia, but the mechanisms underlying the inflammation-aggravation effects of ß2-adrenoceptor agonists remain pooly understood. In this study, we investigated formoterol, a more specific ß2-adrenoceptor agonist, -mediated signaling pathways involved in the production of IL-6 and IL-8 in 16HBE14o- human bronchial epithelia. The effects of formoterol were detected in the presence of PKA, exchange protein directly activated by cAMP (EPAC), cystic fibrosis transmembrane conductance regulator (CFTR), extracellular signal-regulated protein kinase (ERK)1/2 and Src inhibitors. The involvement of ß-arrestin2 was determined using siRNA knockdown. Our results indicate that formoterol can induce IL-6 and IL-8 secretion in concentration-dependent manner. The PKA-specific inhibitor, H89, partially inhibited IL-6 release, but not IL-8. Another intracellular cAMP receptor, EPAC, was not involved in either IL-6 or IL-8 release. PD98059 and U0126, two ERK1/2 inhibitors, blocked IL-8 while attenuated IL-6 secretion induced by formoterol. Furthermore, formoterol-induced IL-6 and IL-8 release was attenuated by Src inhibitors, namely dasatinib and PP1, and CFTRinh172, a CFTR inhibitor. In addition, knockdown of ß-arrestin2 by siRNA only suppressed IL-8 release when a high concentration of formoterol (1 µM) was used. Taken together, our results suggest that formoterol stimulates IL-6 and IL-8 release which involves PKA/Src/ERK1/2 and/or ß-arrestin2 signaling pathways.

Prevalence of strongyloidiasis and schistosomiasis among migrants: a systematic review and meta-analysis.

BACKGROUND: Global migration from regions where strongyloidiasis and schistosomiasis are endemic to non-endemic countries has increased the potential individual and public health effect of these parasitic diseases. We aimed to estimate the prevalence of these infections among migrants to establish which groups are at highest risk and who could benefit from screening. METHODS: We did a systematic review and meta-analysis of strongyloidiasis and schistosomiasis prevalence among migrants born in endemic countries. Original studies that included data for the prevalence of Strongyloides or Schistosoma antibodies in serum or the prevalence of larvae or eggs in stool or urine samples among migrants originating from countries endemic for these parasites and arriving or living in host countries with low endemicity-specifically the USA, Canada, Australia, New Zealand, Israel, and 23 western European countries-were eligible for inclusion. Pooled estimates of the prevalence of strongyloidiasis and schistosomiasis by stool or urine microscopy for larvae or eggs or serum antibodies were calculated with a random-effects model. Heterogeneity was explored by stratification by age, region of origin, migrant class, period of study, and type of serological antigen used. FINDINGS: 88 studies were included. Pooled strongyloidiasis seroprevalence was 12·2% (95% CI 9·0-15·9%; I2 96%) and stool-based prevalence was 1·8% (1·2-2·6%; 98%). Migrants from east Asia and the Pacific (17·3% [95% CI 4·1-37·0]), sub-Saharan Africa (14·6% [7·1-24·2]), and Latin America and the Caribbean (11·4% [7·8-15·7]) had the highest seroprevalence. Pooled schistosomiasis seroprevalence was 18·4% (95% CI 13·1-24·5; I2 97%) and stool-based prevalence was 0·9% (0·2-1·9; 99%). Sub-Saharan African migrants had the highest seroprevalence (24·1·% [95% CI 16·4-32·7]). INTERPRETATION: Strongyloidiasis affects migrants from all global regions, whereas schistosomiasis is focused in specific regions and most common among sub-Saharan African migrants. Serological prevalence estimates were several times higher than stool estimates for both parasites. These data can be used to inform screening decisions for migrants and support the use of serological screening, which is more sensitive and easier than stool testing. FUNDING: None.

[Analysis of clinical features of concomitant vertigo in idiopathic sudden deafness].

OBJECTIVE: To analyze the clinical characteristics of concomitant vertigo in patients with sudden deafness (SD). METHODS: Ninety-six cases of SD were reviewed retrospectively from January 2005 to July 2009. SD and benign paroxysmal positional vertigo (BPPV) were diagnosed according to the guides of China Medical Association. The characteristics of vestibular function and the order of the onset of cochlear and vestibular symptoms were analyzed. RESULTS: Of all 96 cases, 23 (24.0%) cases presented with BPPV; 58 (60.4%) cases took the form of unilateral vestibular hypofunction and 15 (15.6%) cases had normal vestibular function. Time interval between cochlear and vestibular symptoms was as follows: 46 patients could tell the exact time of onset of cochlear and vestibular symptoms, of which 6 (13.0%) cases occurred simultaneously; 4 (8.7%) cases presented vertigo within 1 hour after onset of cochlear symptom hypofunction; 21 (45.7%) cases showed time interval between 1 hour and 24 hours; and 13 (28.3%) cases presented vertigo at several days (less than 10 days) after cochlear symptoms. And only in 2 (4.3%) cases did vertigo occur before cochlear symptoms. CONCLUSIONS: Concomitant vertigo in idiopathic SD took the forms of normal or abnormal vestibular function, some of which were BPPV. Occurrence of vertigo was after cochlear symptoms.

[Complications of canalith repositioning procedure for benign paroxysmal positional vertigo].

OBJECTIVE: To investigate the incidence of complications of canalith repositioning procedure (CRP) for benign paroxysmal positional vertigo (BPPV) in order to recognize and intervene the complication. METHODS: Totally 430 cases of BPPV were treated by CRP between Jan., 2005 and Nov., 2007. The patients with complication were retreated with CRP according to the new canals otolith falling into. RESULTS: There were 313 patients with posterior canal BPPV, among which 5 had complications during CRP for posterior canal BPPV and 3 for horizontal canal BPPV. And 1 patient transformed from cupulolithiasis to canalithiasis during Semont CRP, which made CRP possible. Three patients had horizontal BPPV during CRP for posterior canal BPPV. Horizontal BPPV emerged during CRP for anterior canal BPPV in 1 patient. CRP for the posterior BPPV had more patients with complication than that of CRP for the anterior BPPV, but the percentage was on the contrary, and they were 1.9% (8/313) and 28.6% (2/7) respectively. The rate of complication during CRP was 3.3% (14/430) and all of them recovered well with CRP. CONCLUSIONS: There are possibility for canal otolith transferred from one canal to another. Careful observation of nystagmus and reevaluation of the patients with BPPV in case of unsuccessful treatments are crucial to determine the complications.

Preferential recruitment of neutrophils by endothelin-1 in acute lung inflammation induced by lipopolysaccharide or cigarette smoke.

This study examined the role of endothelin-1 (ET-1) in recruiting inflammatory cells to the lung after induction of injury with either lipopolysaccharide (LPS) or cigarette smoke. Hamsters injected with either ET-1 or its precursor peptide (Big ET-1) prior to treatment with LPS or cigarette smoke had markedly increased concentrations of neutrophils in bronchoalveolar lavage fluid (BALF) despite a reduction in total numbers of BALF leukocytes. Furthermore, the effect of ET-1 on smoke-exposed animals was reversed by addition of an endothelin-A receptor antagonist. These results are consistent with preferential recruitment of neutrophils by ET-1, and suggest that inhibition of this proinflammatory mediator may decrease acute pulmonary inflammation associated with cigarette smoke and other pulmonary toxins.

[Benign paroxysmal positioning vertigo related to inner ear disorders].

OBJECTIVE: To investigate the incidence of benign paroxysmal positional vertigo(BPPV) and to further understand the possible mechanism of BPPV. METHODS: To observe the incidence of BPPV among vestibular neuritis, sudden deafness, Meniere's disease and Bell's palsy at vertigo clinic from January at 2004 to November at 2006 and to compare the therapeutic results with that of the primary BPPV. RESULTS: There are 4 types of inner ear disorders involved in the concomitant BPPV, ie, vestibular neuritis, sudden deafness, Meniere's disease and Bell's palsy and the incidence are 9.5% (5/53), 38.9% (35/90) and 0.3% (1/381) respectively; and there was 1 case of BPPV concomitant to Bell's palsy. Among the 42 concomitant BPPV, 5 cases were horizontal canal BPPV, 37 cases were posterior canal BPPV, and 1 cases had complicated anterior BPPV during repositioning maneuver. 39 cases of concomitant BPPV were canalithiasis and 3 cases were cupuliothiathitis, of which 75% (27/36) of concomitant BPPV emerged within 1/2 years after the onset of primary inner ear disorders. The therapeutic efficacy of the concomitant BPPV with canalith repositioning was similar to that of the primary type of BPPV. CONCLUSIONS: Following some inner ear disorder, BPPV could emerge, such as sudden deafness, vestibular neuritis and Meniere's disease. The most common type of BPPV was canalithiasis of posterior canal, and the cupulolithiasis of horizontal canal was uncommon. The anterior canal therapeutic efficacy of the concomitant BPPV with canalith repositioning was similar to that of the primary type of BPPV. The therapeutic efficacy of the concomitant BPPV with canalith repositioning was similar to that of the primary type of BPPV.

[Neurootological manifestation of migrainous vertigo].

OBJECTIVE: To analyzed the characteristics of migrainous vertigo (MV), a kind of paroxysmal vertigo, in order to demonstrate the extent of damage and dysfunction in MV and to judge whether MV is peripheral or central vertigo. METHODS: Twenty-two cases of acute (5 cases) or subacute (17 cases) MV were examined with oto-neurological tests, spontaneous nystagmus, positional nystagmus and auditory tests. RESULTS: There were 6 males and 16 females. Among those patients, 15 had migraine, 17 motion sickness, 15 family history of migraine or motion sickness, 1 visual aura, 7 motion intolerance (vertigo from head movement and body movement), 4 photophobia, 6 phonophobia and 5 vertigo from insomnia and emotion. There were likely to have vertigo in menstrual period in 2 cases. The duration of vertigo lasted from minutes to days. For pure-tone audiometric, 9 were normal which from mild to moderate hearing loss. Three cases had abnormal high frequency ABR bilaterally and 10 abnormal unilaterally. Subjective visual vertical were normal in all of the cases. Vestibular evoked myogenic potentials were abnormal in 14 cases (13 had low amplitude and 1 had longer latency of P13 wave). Bithermal caloric test was abnormal in 3 cases and 11 had abnormal ocular movement (9 with low gain of optokinetic nystagmus, 1 with overshoot in saccade and 1 with vertical nystagmus after head shaking), in which 10 had abnormal high frequency ABR and 1 was normal. CONCLUSIONS: MV could be peripheral or central vertigo and MV should be included in the differentiation of peripheral and central vertigo.

[Audio-vestibular function in patients with benign paroxysmal positional vertigo].

OBJECTIVE: To investigate the audio-vestibular function and the possible mechanism of benign paroxysmal positional vertigo (BPPV) and to raise the therapeutic strategy. METHODS: Patients with BPPV were tested with pure tone audiometry, high frequency ABR audiometry, bithermal caloric test and vestibular evoked myogenic potential test (VEMP). The positive rate of these otologic function test were analyzed. RESULTS: Primary BPPV comprised 82 percent (70/86) of patients with BPPV. Among all of the patients, the results of pure tone audiometry were abnormal in 52 percent (45/86) of the cases. High frequency auditory brainstem response (ABR) was abnormal in 60 percent (30/50) of cases. Vestibular evoked myogenic potential (VEMP) was abnormal in 34 percent (11/32) of cases who had this examination. And bithermal caloric test were abnormal in 28 percent (20/72) of cases. In the abnormal cases, 67 percent (12/18) of cases were ipsilateral with BPPV. The majority of the BPPV with abnormal results of bithermal caloric test (89%, 16/18) belong to posterior semicircular canal BPPV. CONCLUSIONS: The incidence of primary BPPV was higher than that of secondary BPPV. The abnormality in superior labyrinth was much more correlated with the occurrence of BPPV. The inner ear ischemia might be a factor in the morbidity of BPPV, especially for the primary BPPV.