Asthma Associated Cytokines Regulate the Expression of SARS-CoV-2 Receptor ACE2 in the Lung Tissue of Asthmatic Patients

It is still controversial whether chronic lung inflammation increases the risk for COVID-19. One of the risk factors for acquiring COVID-19 is the level of expression of SARS-CoV-2 entry receptors, ACE2 and TMPRSS2, in lung tissue. It is, however, not clear how lung tissue inflammation affects expression levels of these receptors. We hence aimed to determine the level of SARS-CoV-2 receptors in lung tissue of asthmatic relative to age, gender, and asthma severity, and to investigate the factors regulating that. Therefore, gene expression data sets of well-known asthmatic cohorts (SARP and U-BIOPRED) were used to evaluate the association of ACE2 and TMPRSS2 with age, gender of the asthmatic patients, and also the type of the underlying lung tissue inflammatory cytokines. Notably, ACE2 and to less extent TMPRSS2 expression were upregulated in the lung tissue of asthmatics compared to healthy controls. Although a differential expression of ACE2, but not TMPRSS2 was observed relative to age within the moderate and severe asthma groups, our data suggest that age may not be a key regulatory factor of its expression. The type of tissue inflammation, however, associated significantly with ACE2 and TMPRSS2 expression levels following adjusting with age, gender and oral corticosteroids use of the patient. Type I cytokine (IFN-γ), IL-8, and IL-19 were associated with increased expression, while Type II cytokines (IL-4 and IL-13) with lower expression of ACE2 in lung tissue (airway epithelium and/or lung biopsies) of moderate and severe asthmatic patients. Of note, IL-19 was associated with ACE2 expression while IL-17 was associated with TMPRSS2 expression in sputum of asthmatic subjects. In vitro treatment of bronchial fibroblasts with IL-17 and IL-19 cytokines confirmed the regulatory effect of these cytokines on SARS-CoV-2 entry receptors. Our results suggest that the type of inflammation may regulate ACE2 and TMPRSS2 expression in the lung tissue of asthmatics and may hence affect susceptibility to SARS-CoV-2 infection.

Lung protective effect of Punicalagin on LPS-induced acute lung injury in mice

Background: Punicalagin (Pun) is one of the main bioactive compounds in pomegranate peel, it possesses many properties, including antioxidant, anti-inflammation, and immunosuppressive activities. The study was aimed to investigate the protective effect and mechanisms of Pun on lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice. Methods and Results: Forty-eight BALB/c male mice were used to establish ALI by intratracheal-instilled 2.4 mg/kg LPS, the mice were randomly divided into model and Pun (10, 20, 40 mg/kg) groups. The other twelve mice were intratracheal-instilled same volume of water as control. After 2 h of receiving LPS, mice were administrated drug through intraperitoneal injection. Lung index, histopathological changes, white blood cells and biomarkers in bronchoalveolar lavage fluid (BALF) were analyzed. The protein expression of total and phosphor p65, IκBα, ERK1/2, JNK and p38 in lung tissue was detected. The result showed that Pun could reduce the lung index and wet/dry weight ratio, improve lung histopathological injury. In addition, Pun decreased the inflammation cells and regulated the biomarkers in BALF. Furthermore, Pun dose-dependently reduced the phosphor protein levels of p65, IκBα, ERK1/2, JNK and p38 in lung tissue, which exhibited that the effect of Pun related to MAPKs pathway. More importantly, there is no toxicity was observed in the acute toxicity study of Pun. Conclusion: Pun improves LPS-induced ALI mainly through its anti-inflammatory properties, which is associated with NF-κB and MAPKs signaling pathways. The study implied that Pun maybe a potent agent against ALI in future clinic.

Label-Free Diagnosis of Pulmonary Fat Embolism Using Fourier Transform Infrared (FT-IR) Spectroscopic Imaging

The diagnosis of pulmonary fat embolism (PFE) is of great significance in the field of forensic medicine because it can be considered a major cause of death or a vital reaction. Conventional histological analysis of lung tissue specimens is a widely used method for PFE diagnosis. However, variable and labor-intensive tissue staining procedures impede the validity and informativeness of histological image analysis. To obtain complete information from tissues, a method based on infrared imaging of unlabeled tissue sections was developed to identify pulmonary fat emboli in the present study. We selected 15 PFE-positive lung samples and 15 PFE-negative samples from real cases. Oil red O (ORO) staining and infrared spectral imaging collection were both performed on all lung tissue samples. And the fatty tissue of the abdominal wall and the embolized lipid droplets in the lungs were taken for comparison. The results of the blind, evaluation by pathologists, showed good agreement between the infrared spectral imaging of the lung tissue and the standard histological stained images. Fourier transform infrared (FT-IR) spectroscopic imaging significantly simplifies the typical painstakingly laborious histological staining procedure. And we found a difference between lipid droplets embolized in abdominal wall fat and lung tissue.

c-Fos is a mechanosensor that regulates inflammatory responses and lung barrier dysfunction during ventilator-induced acute lung injury

Background As one of the basic treatments performed in the intensive care unit, mechanical ventilation can cause ventilator-induced acute lung injury (VILI). The typical features of VILI are an uncontrolled inflammatory response and impaired lung barrier function; however, its pathogenesis is not fully understood, and c-Fos protein is activated under mechanical stress. c-Fos/activating protein-1 (AP-1) plays a role by binding to AP-1 within the promoter region, which promotes inflammation and apoptosis. T-5224 is a specific inhibitor of c-Fos/AP-1, that controls the gene expression of many proinflammatory cytokines. This study investigated whether T-5224 attenuates VILI in rats by inhibiting inflammation and apoptosis. Methods The SD rats were divided into six groups: a control group, low tidal volume group, high tidal volume group, DMSO group, T-5224 group (low concentration), and T-5224 group (high concentration). After 3 h, the pathological damage, c-Fos protein expression, inflammatory reaction and apoptosis degree of lung tissue in each group were detected. Results c-Fos protein expression was increased within the lung tissue of VILI rats, and the pathological damage degree, inflammatory reaction and apoptosis in the lung tissue of VILI rats were significantly increased; T-5224 inhibited c-Fos protein expression in lung tissues, and T-5224 inhibit the inflammatory reaction and apoptosis of lung tissue by regulating the Fas/Fasl pathway. Conclusions c-Fos is a regulatory factor during ventilator-induced acute lung injury, and the inhibition of its expression has a protective effect. Which is associated with the antiinflammatory and antiapoptotic effects of T-5224.

Ten Years of Pediatric Lung Ultrasound: A Narrative Review

Lung diseases are the most common conditions in newborns, infants, and children and are also the primary cause of death in children younger than 5 years old. Traditionally, the lung was not thought to be a target for an ultrasound due to its inability to penetrate the gas-filled anatomical structures. With the deepening of knowledge on ultrasound in recent years, it is now known that the affected lung produces ultrasound artifacts resulting from the abnormal tissue/gas/tissue interface when ultrasound sound waves penetrate lung tissue. Over the years, the application of lung ultrasound (LUS) has changed and its main indications in the pediatric population have expanded. This review analyzed the studies on lung ultrasound in pediatrics, published from 2010 to 2020, with the aim of highlighting the usefulness of LUS in pediatrics. It also described the normal and abnormal appearances of the pediatric lung on ultrasound as well as the benefits, limitations, and possible future challenges of this modality.

Development of a method to measure regional perfusion of the lung in anesthetized ponies using computed tomography angiography and the maximum slope model

OBJECTIVE To develop a method based on CT angiography and the maximum slope model (MSM) to measure regional lung perfusion in anesthetized ponies. ANIMALS 6 ponies. PROCEDURES Anesthetized ponies were positioned in dorsal recumbency in the CT gantry. Contrast was injected, and the lungs were imaged while ponies were breathing spontaneously and while they were mechanically ventilated. Two observers delineated regions of interest in aerated and atelectatic lung, and perfusion in those regions was calculated with the MSM. Measurements obtained with a computerized method were compared with manual measurements, and computerized measurements were compared with previously reported measurements obtained with microspheres. RESULTS Perfusion measurements obtained with the MSM were similar to previously reported values obtained with the microsphere method. While ponies were spontaneously breathing, mean ± SD perfusion for aerated and atelectatic lung regions were 4.0 ± 1.9 and 5.0 ± 1.2 mL/min/g of lung tissue, respectively. During mechanical ventilation, values were 4.6 ± 1.2 and 2.7 ± 0.7 mL/min/g of lung tissue at end expiration and 4.1 ± 0.5 and 2.7 ± 0.6 mL/min/g of lung tissue at peak inspiration. Intraobserver agreement was acceptable, but interobserver agreement was lower. Computerized measurements compared well with manual measurements. CLINICAL RELEVANCE Findings showed that CT angiography and the MSM could be used to measure regional lung perfusion in dorsally recumbent anesthetized ponies. Measurements are repeatable, suggesting that the method could be used to determine efficacy of therapeutic interventions to improve ventilation-perfusion matching and for other studies for which measurement of regional lung perfusion is necessary.

Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock

We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GRdim/dim). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GRdim/dim mice compared to wildtype mice (GR+/+). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GRdim/dim mice. Lungs of GRdim/dim mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective Angpt1 compared to GR+/+ after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GRdim/dim mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GRdim/dim mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GRdim/dim mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage.

Identification and Semisynthesis of (–)-Anisomelic Acid as an Oral Antiviral Agent against SARS-CoV-2 in Mice

(–)-Anisomelic acid (AA), isolated from Anisomeles indica (L.) Kuntze (Labiatae) leaves, is a macrocyclic cembranolide with a trans-fused α-methylene-β-lactone motif. Cytopathic effect assays showed that the anti-SARS-CoV-2 effect of AA (IC50 = 4.3 μM) is comparable to that of remdesivir (IC50 = 2.1 μM), and more potent than that of molnupiravir (IC50 = 27.8 μM). Challenge studies in SARS-CoV-2-infected K18-hACE2 mice showed that oral administration of AA and remdesivir can both reduce the viral titers in the lung tissue at the same level. To facilitate drug discovery, we used a semisynthetic approach to shorten the project timelines. The enantioselective semisynthesis of AA from the naturally enriched and commercially available starting material (+)-costunolide was achieved in five steps with a 27% overall yield. The developed chemistry provides opportunities for developing AA-based novel ligands for selectively targeting proteins involved in viral infection.