Alveolar Wall Thickness Research Articles

Systemic Immune Modulation Induced by Ephedrine in Obese-Diabetes (db/db) Mice.

Immune-modulatory effects in obese-diabetes (db/db) mice were observed to understand the possible mechanism(s) of ephedrine-induced unfavorable responses. The ephedrine doses were selected based on the FDA report (NTP Tech Rep Ser NO 307; CAS# 134-72-5), which showed the non-toxic dose for B6C3F1 mice. In db/db mice, higher doses (6 and 12 mg/mouse) of ephedrine significantly harmed the liver and lung morphology, including fatty liver with multiple blood vessel engorgement, alveolar wall thickening, and inflammatory response in the lung. The immune micro-environment of db/db mice was an inflammatory state with suppressed adaptive cellular immunity. After the administration of ephedrine, significant deterioration of NK activity was observed with lowered gene transcription of klrk1 encoding NKG2D, and of ccl8, a NK cell targeting chemokine. Suppressed cellular immunity in db/db mice was lowered ever further by single ephedrine treatment, as was evidenced by mitogen-induced T or B cell proliferations. These observations demonstrate that at the non-toxic doses in normal B6C3F1 mice, ephedrine clearly suppressed systemic immunity of db/db mice. The data suggest that the immune micro-environment of obese individuals is fragile and susceptible to ephedrine-related pathologic response, and this may be a prelude to the induction of obesity-related secondary immunological disorders.

Potential mechanisms of lung injury and repair after hexavalent chromium [Cr(VI)] aerosol whole-body dynamic exposure

Hexavalent chromium [Cr(VI)], known as "Top Hazardous Substances", poses a significant threat to the respiratory system. Nevertheless, the potential mechanisms of toxicity and the lung's repair ability after injury remain incompletely understood. In this study, Cr(VI) aerosol whole-body dynamic exposure system simulating real exposure scenarios of chromate workers was constructed to evaluate the lung injury and repair effects. Subsequently, miRNA sequencing, mRNA sequencing and metabolomics analyses on lung tissue were performed to explore the underlying mechanisms. Our results revealed that Cr(VI) exposure led to an increase in lactic dehydrogenase activity and a time-dependent decline in lung function. Notably, after 13 w of Cr(VI) exposure, alveolar hemorrhage, thickening of alveolar walls, emphysema-like changes, mitochondrial damage of alveolar epithelial cells and macrophage polarization changes were observed. Remarkably, a two-week repair intervention effectively ameliorated lung function decline and pulmonary injury. Furthermore, significant disruptions in the expressions of miRNAs and mRNAs involved in oxidative phosphorylation, glycerophospholipid metabolism and inflammatory signaling pathways were found. The two-week repair period resulted in the reversal of expression of oxidative phosphorylation related genes, and inhibited the inflammatory signaling pathways. This study concluded that the inhibition of the mitochondrial oxidative phosphorylation pathway and the subsequent enhancement of inflammatory response might be key mechanisms underlying Cr(VI) pulmonary toxicity, and timely cessation of exposure could effectively alleviate the pulmonary injury. These findings shed light on the potential mechanisms of Cr(VI) toxicity and provide crucial insights into the health protection for occupational populations exposed to Cr(VI).

Qualitative Histopathological Analysis of Bleomycin-Induced Lung Injury

Recent evidence has suggested that the accumulation of cholesterol-laden “fatty macrophages” in the lung may play a key role in the presentation of ALI 1, a condition that affects nearly 200,000 people per year in the United States. Studying the pathways of these cells suggests that preventing the formation and build-up of these macrophages could prevent many of the characteristic symptoms of acute lung injury. Specifically, this experiment aims to explore the effect that ACAT1 inhibition by K604 has on fatty macrophage formation and outcomes of ALI. To test this, different groups of mice were administered either PBS (as control), ITB (intratracheal bleomycin), PBS + K604, or ITB + K604. After the mice were sacrificed, the left lung lobes were extracted, inflated, embedded, and sectioned for microscopic scanning and analysis with the ImageJ software. The lung tissue was characterized using 3 unbiased parameters: alveolar wall thickness (µm), cell infiltration (number of nuclei), and percent white space. Simultaneously, a cholesterol assay was performed using cells extracted from mouse bronchoalveolar lavage (BAL). The results show that K604 was successful at preventing ITB-induced increases in cell infiltration, consolidation, and alveolar thickening as well as lipid accumulation in macrophages by limiting the formation of cholesterol esters through ACAT1 inhibition. In this respect, this experiment shows that K604 might be a viable pharmaceutical target in the treatment of ALI.

Particulate matter-mediated oxidative stress induces airway inflammation and pulmonary dysfunction through TXNIP/NF-κB and modulation of the SIRT1-mediated p53 and TGF-β/Smad3 pathways in mice

Exposure to particulate matter is currently recognized as a serious aggravating factor of respiratory diseases. In this study, we investigated the effects of particulate matter (PM) on the respiratory system in BALB/c mice and NCI-H292 cells. PM (0, 2.5, 5 and 20 mg/kg) was administered to mice by intra-tracheal instillation for 7 days. After a 7 day-repeated treatment of PM, we evaluated inflammatory cytokines/cell counts in bronchoalveolar lavage fluid (BALF) and conducted pulmonary histology and functional test. We also investigated the role of TXNIP/NF-κB and SIRT1-mediated p53 and TGF-β/Smad3 pathways in PM-induced airway inflammation and pulmonary dysfunction. PM caused a significant increase in pro-inflammatory cytokines, inflammatory cell counts in bronchoalveolar lavage fluid. PM-mediated oxidative stress down-regulated thioredoxin-1 and up-regulated thioredoxin-interacting protein and activation of nuclear factor-kappa B in the lung tissue and PM-treated NCI-H292 cells. PM suppressed sirtuin1 protein levels and increased p53 acetylation in PM-exposed mice and PM-treated NCI-H292 cells. In addition, PM caused inflammatory cell infiltration and the thickening of alveolar walls by exacerbating the inflammatory response in the lung tissue. PM increased levels of transforming growth factor-β, phosphorylation of Smad3 and activation of α-smooth muscle actin, and collagen type1A2 in PM-exposed mice and PM-treated NCI-H292 cells. In pulmonary function tests, PM exposure impaired pulmonary function resembling pulmonary fibrosis, characterized by increased resistance and elastance of the respiratory system, and resistance, elastance, and damping of lung tissues, whereas decreased compliance of the respiratory system, forced expired volume and forced vital capacity. Overall, PM-mediated oxidative stress caused airway inflammation and pulmonary dysfunction with pulmonary fibrosis via TXNIP pathway/NF-κB activation and modulation of the SIRT1-mediated TGF-β/Smad3 pathways. The results of this study can provide fundamental data on the potential adverse effects and underlying mechanism of pulmonary fibrosis caused by PM exposure as a public health concern. Due to the potential toxicity of PM, people with respiratory disease must be careful with PM exposure.

Alterations in the gene expression of SARS-COV-2 entry receptors and enzymes in lungs and hearts of controlled and uncontrolled diabetic mice.

The entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin-converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin-L (CTSL). COVID-19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality. The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse Ace2, Tmprss2, and Ctsl and correlate it with the pathological alterations in the lungs and the heart of DM mice. Balb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of Ace2, Tmprss2, Ctsl, Cyp4a11, and Adrb1 genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real-time polymerase chain reaction (RT-PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination. After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (P<0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of Ace2 gene expression (P< 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of Ctsl gene expression in their hearts (P<0.05). Notably, Cyp4a12 gene expression was significantly downregulated (P<0.05) in UDM mice but returned to normal levels in CDM mice. We conclude from this study that T1DM downregulates Ace2 receptor and Cyp4a12 gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the lungs. Insulin administration for controlling T1DM ameliorated these pathological alterations. These results can help increase our understanding of the impact of controlled and uncontrolled T1DM on the lungs and may explain, at least in part, why DM patients with COVID-19 experience exacerbation of symptoms.

Relationship Between Sagittal Root Position and Alveolar Wall Thickness of Maxillary Teeth in the Esthetic Area for Immediate Implant Treatment Planning in a Peruvian Population.

The purpose of this retrospective study was to assess facial and palatal alveolar wall thickness (AWT) in relation to sagittal root position (SRP) of maxillary anterior teeth using cone-beam computed tomography (CBCT). 102 CBCT images (60 females, 42 males) of anterior maxillary teeth were reviewed. SRP was classified according to Kan's classification, and AWT was evaluated at coronal (4 mm from the cementoenamel junction), mid-root, and apical (2 mm from the apex) levels of the facial and palatal. Secondary variables of sex, age and tooth type were analyzed. The SRP distribution was 76.6% class I, 11.3% class II, 0.8% class III, and 11.3% class IV. AWT, from thickest to thinnest, was found in palatal apical>mid>coronal, followed by facial coronal>mid>apical. AWT was thickest in SRP class II, followed by class I and III, and least thick in class IV at all measured areas (P<.05). A significantly higher AWT was associated with class I in central incisors, class II in canine teeth and in males, and class IV in central incisors and canines.

Potential Therapeutic Targets of Resveratrol in the Prevention and Treatment of Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a feared component in over 200 interstitial pulmonary diseases, which are characterized by increased alveolar wall thickness, excessive scarring, and aberrant extracellular matrix restructuring that, ultimately, affect lung compliance and capacity. As a result of its broad range of biological activities, including antioxidant, anti-inflammatory, antiapoptotic, and many others, resveratrol has been shown to be an effective treatment for respiratory system diseases, including interstitial lung disease, infectious diseases, and lung cancer. This work reviews the known molecular therapeutic targets of resveratrol and its potential mechanisms of action in attenuating PF in respiratory diseases, including cancer, COVID-19, interstitial lung diseases (ILDs) of known etiologies, idiopathic interstitial pneumonia, and ILDs associated with systemic disorders, such as rheumatoid arthritis, systemic sclerosis, Schrödinger's syndrome, systemic lupus erythematosus, and pulmonary hypertension. The current issues and controversies related to the possible use of resveratrol as a pharmaceutical drug or supplement are also discussed.

Integrin α10β1-selected mesenchymal stem cells reduced hypercoagulopathy in a porcine model of acute respiratory distress syndrome

Mesenchymal stem cells (MSCs) have been studied for their potential benefits in treating acute respiratory distress syndrome (ARDS) and have reported mild effects when trialed within human clinical trials. MSCs have been investigated in preclinical models with efficacy when administered at the time of lung injury. Human integrin α10β1-selected adipose tissue-derived MSCs (integrin α10β1-MSCs) have shown immunomodulatory and regenerative effects in various disease models. We hypothesized that integrin α10β1 selected-MSCs can be used to treat a sepsis-induced ARDS in a porcine model when administering cells after established injury rather than simultaneously. This was hypothesized to reflect a clinical picture of treatment with MSCs in human ARDS. 12 pigs were randomized to the treated or placebo-controlled group prior to the induction of mild to moderate ARDS via lipopolysaccharide administration. The treated group received 5 × 106 cells/kg integrin α10β1-selected MSCs and both groups were followed for 12 h. ARDS was confirmed with blood gases and retrospectively with histological changes. After intervention, the treated group showed decreased need for inotropic support, fewer signs of histopathological lung injury including less alveolar wall thickening and reduction of the hypercoagulative disease state. The MSC treatment was not associated with adverse events over the monitoring period. This provides new opportunities to investigate integrin α10β1-selected MSCs as a treatment for a disease which does not yet have any definitive therapeutic options.

Lung infection by Pseudomonas aeruginosa induces neuroinflammation and blood–brain barrier dysfunction in mice

BackgroundSevere lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood–brain barrier (BBB) leakage and behavioral impairment.MethodsLung infection in mice was induced by instilling Pseudomonas aeruginosa (PA) intratracheally. We determined bacterial colonization in tissue, microvascular leakage, expression of cytokines and leukocyte infiltration into the brain.ResultsLung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell–cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 h and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b + CD45+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell–cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1β induced a significant reduction of barrier function coupled with tight junction (TJ) and adherens junction (AJ) diffusion and disorganization. Combined treatment with IL-1β and TNFα augmented the barrier injury.ConclusionsLung bacterial infection is associated with BBB disruption and behavioral changes, which are mediated by systemic cytokine release.

Extracellular vesicles: A promising therapy against SARS-CoV-2 infection

Extracellular vesicles: A promising therapy against SARS-CoV-2 infection

Interstitial lung disease and mycobacteriosis in children with inherited CCR2 deficiency

Tissue-resident alveolar macrophages are important for lung homeostasis and innate immunity. They originate from fetal monocytes and are maintained in the lung through self-renewal or may arise from recruited circulating monocytes. Disturbance of alveolar macrophage function, their numbers or loss of GM-CSF signaling can all underlie pulmonary alveolar proteinosis (PAP). Here, we report eight patients (aged 8–21 years) from four kindreds and three ancestries suffering from recurrent pneumonia, progressive interstitial fibrosis, and PAP. All patients are deficient for the monocyte-chemoattractant protein-1 (CCL-2) receptor 2 (CCR2). Five patients are homozygous and three are compound heterozygous for private or rare CCR2 variants. The variants are loss-of-function for Ca2 +-release and cell migration upon CCL-2 stimulation, when tested by overexpression in monocytic THP-1 cells. Moreover, CCL-2-dependent migration and Ca2+-release of the patients’ monocytes are abolished, while their plasma CCL-2 levels are elevated. Yet, CCR2-deficient cells respond normally to GM-CSF. In addition, the counts, frequencies, and transcriptomes of blood lymphoid and myeloid subsets are normal. Mice deficient for CCR2 display alveolar septal wall thickening and increased number of alveolar type II cells producing surfactant protein C causing increased lung tissue hysteresis. CCR2-deficient mice are vulnerable to mycobacteria, with impaired attraction of blood monocytes to infected tissues. These findings suggest that human CCR2 is essential for the recruitment of monocytes to both pulmonary alveoli and tissues infected with mycobacteria.

High-fat intake alleviates lung injury induced by Paragonimus proliferus infection in rats through up-regulating CYP 4A1 expression in lung tissues

To explore the improvements of high-fat intake on lung injury induced by Paragonimus proliferus infection in rats, and to preliminarily explore the mechanisms underlying the role of cytochrome P450 4A1 (CYP 4A1) in the improve ments. SD rats were randomly assigned into three groups, including the normal control group (n = 10), the infection and normal diet group (n = 12) and the infection and high-fat diet group (n = 12). Rats in the normal control group were fed with normal diet and without any other treatments, and animals in the infection and normal diet group were subcutaneously injected with 8 excysted metacercariae of P. proliferus via the abdominal wall, followed by feeding with normal diet, while rats in the infection and high-fat diet group were subcutaneously injected with 8 excysted metacercariae of P. proliferus via the abdominal wall, followed by feeding with high-fat diet. All rats were sacrificed 28 weeks post-infection, and serum samples and lung specimens were collected. Following hematoxylin-eosin (HE) staining of rat lung specimens, the rat lung injury was observed under an optical microscope, and alveolitis was evaluated using semi-quantitative scoring. Serum interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assay (ELISA), and the cytochrome P450 4A1 (CYP 4A1) expression was quantified in rat lung specimens at transcriptional and translational levels using quantitative real-time PCR (qPCR) and Western blotting assays. Alveolar wall thickening, edema and inflammatory cell infiltration were alleviated 28 weeks post-infection with P. proliferus in rats in the infection and high-fat diet group relative to the infection and normal diet group, and no alveolar consolidation was seen in the infection and high-fat diet group. The semi-quantitative score of alveolitis was significantly higher in the infection and normal diet group [(2.200 ± 0.289) points] than in the normal control group [(0.300 ± 0.083) points] and the infection and high-fat diet group [(1.300 ± 0.475) points] (both P values < 0.05), and higher serum IL-1β [(151.586 ± 20.492)] pg/mL and TNF-α levels [(180.207 ± 23.379) pg/mL] were detected in the infection and normal diet group than in the normal control group [IL-1β: (103.226 ± 3.366) pg/mL; TNF-α: (144.807 ± 1.348) pg/mL] and the infection and high-fat diet group [IL-1β: (110.131 ± 12.946) pg/mL; TNF-α: (131.764 ± 27.831) pg/mL] (all P values < 0.05). In addition, lower CYP 4A1 mRNA (3.00 ± 0.81) and protein expression (0.40 ± 0.02) was quantified in lung specimens in the infection and normal diet group than in the normal control group [(5.03 ± 2.05) and (0.84 ± 0.14)] and the infection and high-fat diet group [(11.19 ± 3.51) and (0.68 ± 0.18)] (all P values < 0.05). High-fat intake may alleviate lung injuries caused by P. proliferus infection in rats through up-regulating CYP 4A1 expression in lung tissues at both translational and transcriptional levels.

Derrone Targeting the TGF Type 1 Receptor Kinase Improves Bleomycin-Mediated Pulmonary Fibrosis through Inhibition of Smad Signaling Pathway.

Transforming growth factor-β (TGF-β) has a strong impact on the pathogenesis of pulmonary fibrosis. Therefore, in this study, we investigated whether derrone promotes anti-fibrotic effects on TGF-β1-stimulated MRC-5 lung fibroblast cells and bleomycin-induced lung fibrosis. Long-term treatment with high concentrations of derrone increased the cytotoxicity of MRC-5 cells; however, substantial cell death was not observed at low concentrations of derrone (below 0.05 μg/mL) during a three-day treatment. In addition, derrone significantly decreased the expressions of TGF-β1, fibronectin, elastin, and collagen1α1, and these decreases were accompanied by downregulation of α-SMA expression in TGF-β1-stimulated MRC-5 cells. Severe fibrotic histopathological changes in infiltration, alveolar congestion, and alveolar wall thickness were observed in bleomycin-treated mice; however, derrone supplementation significantly reduced these histological deformations. In addition, intratracheal administration of bleomycin resulted in lung collagen accumulation and high expression of α-SMA and fibrotic genes-including TGF-β1, fibronectin, elastin, and collagen1α1-in the lungs. However, fibrotic severity in intranasal derrone-administrated mice was significantly less than that of bleomycin-administered mice. Molecular docking predicted that derrone potently fits into the ATP-binding pocket of the TGF-β receptor type 1 kinase domain with stronger binding scores than ATP. Additionally, derrone inhibited TGF-β1-induced phosphorylation and nuclear translocations of Smad2/3. Overall, derrone significantly attenuated TGF-β1-stimulated lung inflammation in vitro and bleomycin-induced lung fibrosis in a murine model, indicating that derrone may be a promising candidate for preventing pulmonary fibrosis.

Macrophage Inactivation by Small Molecule Wedelolactone via Targeting sEH for the Treatment of LPS-Induced Acute Lung Injury.

Soluble epoxide hydrolase (sEH) plays a critical role in inflammation by modulating levels of epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs). Here, we investigate the possible role of sEH in lipopolysaccharide (LPS)-mediated macrophage activation and acute lung injury (ALI). In this study, we found that a small molecule, wedelolactone (WED), targeted sEH and led to macrophage inactivation. Through the molecular interaction with amino acids Phe362 and Gln384, WED suppressed sEH activity to enhance levels of EETs, thus attenuating inflammation and oxidative stress by regulating glycogen synthase kinase 3beta (GSK3β)-mediated nuclear factor-kappa B (NF-κB) and nuclear factor E2-related factor 2 (Nrf2) pathways in vitro. In an LPS-stimulated ALI animal model, pharmacological sEH inhibition by WED or sEH knockout (KO) alleviated pulmonary damage, such as the increase in the alveolar wall thickness and collapse. Additionally, WED or sEH genetic KO both suppressed macrophage activation and attenuated inflammation and oxidative stress in vivo. These findings provided the broader prospects for ALI treatment by targeting sEH to alleviate inflammation and oxidative stress and suggested WED as a natural lead candidate for the development of novel synthetic sEH inhibitors.

Problems and Perspectives on Accelerated Orthodontic Tooth Movement by Low-Level Laser Photobiomodulation

Objective: To determine whether there is any relationship between the thickness of the labial alveolar bone wall in the anterior portion of the maxilla and arch shape.

Selenium alleviates cadmium-induced mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep

Cadmium (Cd) is a poisonous metal element that causes mitochondrial dysfunction. Selenium (Se) can reduce the damage of Cd to various organs of animals, but the protective mechanism of Se in Cd-induced lung injury has not been fully elucidated. For purpose of further illustrating the specific mechanism of Se alleviated Cd-triggered pulmonary toxicity, 48 sheep were divided into 4 groups, of which the sheep in the treatment group were taken 1 mg/kg body weight (BW) of Cd, 0.34 mg/kg BW of Se, and 0.34 mg Se + 1 mg/kg BW of Cd by intragastric administration for 50 d, respectively. The results indicated that Cd caused inflammatory cell infiltration and alveolar wall thickening, which facilitated mitochondrial vacuolation and formation of mitophagosomes in lung tissues. Simultaneously, Cd treatment impaired the antioxidant capacity of sheep lung tissue. Additionally, Cd treatment down-regulated the expression levels of mitochondrial biogenesis and mitochondrial fusion, but up-regulated the levels of mitochondrial fission and mitophagy mediated by FUNDC1. Moreover, the immunofluorescence co-localization puncta of LC3B/COX IV, LC3B/FUNDC1 were increased after Cd treatment. Nevertheless, co-treatment with Se improved effectively the above variation caused by Cd exposure. In summary, Se could mitigate Cd-generated mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep.

Comparative study of the pathogenicity of SARS-CoV-2 B.1 AND B.1.617.2 lineages for syrian hamsters

BACKGROUND: Syrian hamsters are the most sensitive model for studying the pathogenesis of a new coronavirus infection and testing prophylactic and therapeutic drugs against SARS-CoV-2. Accordingly, it is important to identify pathomorphological indicators of tissue damage in coronavirus-infected animals, which would correlate with the severity of the disease.&#x0D; AIM: Comprehensive assessment of the pathogenicity of SARS-CoV-2 viruses of B.1 and B.1.167.2 lineages on the model of Syrian hamsters to identify the most sensitive criteria that correlate with the clinical manifestation of the disease.&#x0D; MATERIALS AND METHODS: Intranasal infection of animals with SARS-CoV-2, followed by the assessment of the clinical picture of the disease and detailed pathomorphological studies of various organs collected on the 5th day after infection.&#x0D; RESULTS: The SARS-CoV-2 Delta virus (B.1.617.2) was shown to be less pathogenic for Syrian hamsters compared to the ancestral strain that circulated during the first wave of the COVID-19 pandemic (B.1). The histopathological characterization of lung tissue sections of infected animals revealed the most sensitive morphometric indicator that correlates with the severity of SARS-CoV-2-induced pathology, namely, the alveolar wall thickness.&#x0D; CONCLUSIONS: The use of this indicator makes it possible to determine even slight differences in the severity of virus-induced pathology in the Syrian hamster model, which can be critical in the preclinical evaluation of prophylactic and therapeutic drugs for COVID-19.

Type I Interferon Signaling is Required for Oncostatin-M Driven Inflammatory Responses in Mouse Lung

Type I interferons (IFNs) consist of a group of structurally similar cytokines that play an integral role in regulating the immune response to combat lung infections. In certain models type I IFNs have also been associated with suppression of Th2-skewed immune and inflammatory responses. Transient pulmonary overexpression of the gp130 cytokine Oncostatin M (OSM) by Adenovirus vector (AdOSM) induces a robust Th2-skewed cytokine/inflammatory profile in C57Bl/6 murine lungs. In this study we assessed type I IFN function in OSM-mediated inflammation in vivo using Ifnar1-/- C57Bl/6 mice and Ifnar1-deficient cells in vitro. Ifnar1-/- mice showed a significant reduction in AdOSM-induced histopathology (epithelial hyperplasia, alveolar septal wall thickening, cellular infiltration), and levels of IL-6 and chemokine protein (CXCL-1/KC and CCL24/eotaxin-2) in lungs compared with wild-type. Ifnar1-/- murine fibroblasts and human type I IFN receptor (Ifnar)-knockdown fibroblasts were also less responsive to OSM in STAT3 activation and cytokine production compared with Ifnar-sufficient cells in vitro. Exogenous type I IFN induced IL-6 responses in mouse and human fibroblasts and in combination with OSM further stimulated IL-6 production, suggesting a concerted action of type I IFNs and OSM. Taken together, these results demonstrate that cross-talk between IFNAR and OSM signaling enhances cell responses and modulates OSM-driven responses in lung inflammation.

Mechanics of lung cancer: A finite element model shows strain amplification during early tumorigenesis.

Early lung cancer lesions develop within a unique microenvironment that undergoes constant cyclic stretch from respiration. While tumor stiffening is an established driver of tumor progression, the contribution of stress and strain to lung cancer is unknown. We developed tissue scale finite element models of lung tissue to test how early lesions alter respiration-induced strain. We found that an early tumor, represented as alveolar filling, amplified the strain experienced in the adjacent alveolar walls. Tumor stiffening further increased the amplitude of the strain in the adjacent alveolar walls and extended the strain amplification deeper into the normal lung. In contrast, the strain experienced in the tumor proper was less than the applied strain, although regions of amplification appeared at the tumor edge. Measurements of the alveolar wall thickness in clinical and mouse model samples of lung adenocarcinoma (LUAD) showed wall thickening adjacent to the tumors, consistent with cellular response to strain. Modeling alveolar wall thickening by encircling the tumor with thickened walls moved the strain amplification radially outward, to the next adjacent alveolus. Simulating iterative thickening in response to amplified strain produced tracks of thickened walls. We observed such tracks in early-stage clinical samples. The tracks were populated with invading tumor cells, suggesting that strain amplification in very early lung lesions could guide pro-invasive remodeling of the tumor microenvironment. The simulation results and tumor measurements suggest that cells at the edge of a lung tumor and in surrounding alveolar walls experience increased strain during respiration that could promote tumor progression.

Prenatal Heparin-Binding Epidermal Growth Factor–Like Growth Factor Administration Decreases Lung Inflammation in the Experimental Model of Necrotizing Enterocolitis

INTRODUCTION: Necrotizing enterocolitis (NEC) is the leading gastrointestinal cause of death in premature infants. Postnatal enteral and prenatal intraperitoneal Heparin-Binding EGF-like Growth Factor (HB-EGF) administration has decreased the incidence and severity of intestinal injury in a neonatal rat model of NEC. The aim was to determine the effect of prenatally administered HB-EGF on lung injury in neonatal rats exposed to the experimental model of NEC. METHODS: Pregnant rats and pups were separated into 3 groups: control (natural birth, no NEC protocol, no HB-EGF), NEC (cesarean section, NEC protocol), and HB-EGF (prenatal HB-EGF administration, cesarean section, NEC protocol). Pregnant rats were given HB-EGF (800 μg/kg/dose) via intraperitoneal injection 2 hours before timed cesarean section. After delivery, the premature rat pups were exposed to the NEC model (hypercaloric feds, hypothermia, and hypoxia). Pups were sacrificed upon clinical signs of NEC; the intestines and lungs were hematoxylin and eosin stained for grading. RESULTS: The median alveolar wall thicknesses were significantly different between control (71,646 μm2) vs NEC (75,398 μm2; p < 0.0001) and HB-EGF (71,646 μm2) vs NEC (p < 0.0001); however, the control and HB-EGF groups were similar (p = 0.307; Fig. 1A). The median alveolar areas were significantly different between control (85.23 μm2) vs NEC (66.40 μm2; p < 0.0001) and HB-EGF (64.14 μm2) vs NEC (p < 0.0001); however, again, the control and HB-EGF were similar (p = 0.215; Fig. 1B).CONCLUSION: Our results support the prenatal HB-EGF role in preventing lung injury by means of preserving alveolar wall thickness and alveolar surface area in this animal model of NEC; therefore, maternal administration of HB-EGF before delivery in prematurity could protect lungs from NEC-related injury.