SARS-CoV-2-Triggered Mast Cell Rapid Degranulation Induces Alveolar Epithelial Inflammation and Lung Injury

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. Here we showed that SARS-CoV-2-triggeed MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation alterred various signaling pathways in alveolar epithelial cells, particularly, led to the production of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/449680v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@899996org.highwire.dtl.DTLVardef@1c26c0eorg.highwire.dtl.DTLVardef@1442cdcorg.highwire.dtl.DTLVardef@dd4204_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefSARS-CoV-2 triggers an immediate mast cell (MC) degranulation, which initiates the alveolar epithelial inflammation and disrupts the tight junction. MC stabilizers that block degranulation reduce virus-induced lung inflammation and injury. HighlightsO_LIThe binding of RBD of Spike protein of SARS-CoV-2-to ACE2 receptor protein triggers an immediate MC degranulation C_LIO_LIMC degranulation induces transcriptomic changes include an upregulated inflammatory signaling and a downregulated cell-junction signaling C_LIO_LIMC degranulation leads to alveolar epithelial inflammation and disruption of tight junctions C_LIO_LIMC stabilizer that inhibits degranulation reduces SARS-CoV-2-induced lung inflammation and injury in vivo C_LI

Effects of yiqi huoxue qufeng decoction on the diamine oxidase and immunoglobin E of patients with chronic urticaria / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe effects of Yiqi Huoxue Qufeng Decoction (YHQD, with the actions of replenishing qi, activating blood, and dispelling wind) on diamine oxidase (DAO) and immunoglobulin E (IgE) of patients with chronic urticaria.</p><p><b>METHODS</b>Eighty-five chronic urticaria patients from the clinics of dermatology, Shaanxi Hospital of Traditional Chinese Medicine were randomly assigned to the treatment group (50 cases) and the control group (35 cases). Besides, another 15 healthy volunteers were recruited as the healthy group. Patients in the treatment group took YHQD, one dose daily, once in the morning and once in the evening. Patients in the control group took Fuyang Granule (FYG), 6 g each time, three times daily. The therapeutic course for the two groups was 8 weeks. The effective rates of the two groups were observed after treatment and 2 months after quitting treatment. The levels of DAO and IgE were observed in the three groups before and after treatment.</p><p><b>RESULTS</b>The post-treatment recovery rate (20 cases, 44.0%) and the effective rate 2 months after quitting treatment (62.0%) were higher in the treatment group than in the control group (7 cases, 20.0%; 31.4%) with statistical difference (P<0.05). The DAO level in the two treatment groups (6.9 +/- 1.8 in the treatment group and 6.5 +/- 1.8 in the control group) was obviously higher than that in the healthy group (1.1 +/- 0.4), showing statistical difference (P<0.05). The post-treatment DAO and IgE both decreased in the treatment group and the control group when compared with before treatment in the same group. Those were lower in the treatment group than in the control group with statistical difference (P<0.05).</p><p><b>CONCLUSION</b>YHQD could improve the symptoms of chronic urticaria patients, ameliorate the intestines mucosa barrier function and the immunity.</p>

Effects of intranasal interferon gamma on transforming growth factor-β1/Smad in rats with allergic rhinitis / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the effects of intranasal interferon gamma (IFN-γ) on nasal mucosa remodeling and expression of transforming growth factor-β1 (TGF-β1), Smad2, Smad3, Smad7 in allergic rhinitis (AR) rat model.</p><p><b>METHODS</b>Ovalbumin (OVA) and aluminum hydroxide were used to construct the AR model. Thirty AR rats were randomly divided into positive control group (group B, n = 10), IFN-γ treatment group (group C, n = 10) and negative control group (normal rats, n = 10). After the AR models were built, 50 µl PBS, 1 µg IFN-γ was dropped into the nasal cavity of each rat in group B and group C, from the fouth week to tenth week, twice a week. The nasal mucosa was collected on day 71 in order to observe the pathologic changes, and the expression of TGF-β1, TGF-β1 mRNA, Smad2 mRNA, Smad3 mRNA and Smad7 mRNA by immunohistochemistry and reverse transcriptase-polymerase chain reaction.</p><p><b>RESULTS</b>Decreases of TGF-β1, Smad2 and Smad3 mRNA were seen in nasal tissue of group C (0.59 ± 0.04, 0.39 ± 0.08, 0.46 ± 0.15) as compared with group B (0.82 ± 0.12, 0.70 ± 0.18, 0.95 ± 0.26), the differences were significant (q value were 3.15, 4.47, 3.03, all P < 0.05). The levels of Smad7 mRNA expression increased significantly (q = 2.98, P < 0.05) in group C (0.31 ± 0.05) as compared with group B (0.25 ± 0.06). Immunohistochemistry showed significant decrease of TGF-β1 expression in the nasal tissue of group C much lesser than that in group B.</p><p><b>CONCLUSIONS</b>Intranasal IFN-γ could decrease the expression of TGF-β1, TGF-β1 mRNA, Smad2 mRNA, Smad3 mRNA, increase the expression of Smad7 mRNA in AR rats model and inhibit the nasal mucosa remodeling.</p>