The Role of Rosmarinic Acid in the Protection Against Inflammatory Factors in Rats Model With Monocrotaline-Induced Pulmonary Hypertension: Investigating the Signaling Pathway of NFκB, OPG, Runx2, and P-Selectin in Heart.

ABSTRACT: Shortness of breath and syncope are common symptoms of right ventricular failure caused by pulmonary arterial hypertension (PAH), which is the result of blockage and increased pressure in the pulmonary arteries. There is a significant amount of evidence supporting the idea that inflammation and vascular calcification (VC) are important factors in PAH pathogenesis. Therefore, we aimed to investigate the features of the inflammatory process and gene expression involved in VC in monocrotaline (MCT)-induced PAH rats. MCT (60 mg/kg, i.p.) was used to induce PAH. Animals were given normal saline or rosmarinic acid (RA) (10, 15, and 30 mg/kg, gavage) for 21 days. An increase in right ventricular systolic pressure was evaluated as confirming PAH. To determine the level of inflammation in lung tissue, pulmonary edema and the total and differential white blood cell counts in the bronchoalveolar lavage fluid were measured. Also, the expression of NFκB, OPG, Runx2, and P-selectin genes was investigated to evaluate the level of VC in the heart. Our experiment showed that RA significantly decreased right ventricular hypertrophy, inflammatory factors, NFκB, Runx2, and P-selectin gene expression, pulmonary edema, total and differential white blood cell count, and increased OPG gene expression. Therefore, our research showed that RA protects against MCT-induced PAH by reducing inflammation and VC in rats.

Single cell characteristics of patients with vaccine-related adverse reactions following inactivated COVID-19 vaccination.

A good safety and immunogenicity profile was reported in Phase I and II clinical trials of inactivated SARS-CoV-2 vaccines. Here, we report two cases associated with vaccine-associated adverse events, including one patient with fever and another with anaphylactic shock resulting from inactivated SARS-CoV-2 vaccination. Cell sub-types and the importance of genetic characteristics were assessed using single-cell mRNA sequencing and machine learning. Overall, the patient with fever showed a significant increase in the numbers of cytotoxic CD8 T cells and MKI67high CD8 T cells. A potential concurrent infection with the Epstein-Barr virus enhanced interferon type I responses to vaccination against the virus. STAT1, E2F1, YBX1, and E2F7 played a key role in the transcription regulation of MKI67high CD8 T cells. In contrast, the patient with allergic shock displayed predominant increases in the numbers of S100A9high monocytes, activated CD4 T cells, and PPBPhigh megakaryocytes. The decision tree showed that LYZ and S100A8 in S100A9high monocytes contributed to the degranulation of neutrophils and activation of neutrophils involved in allergic shock. PPBP and PF4 were major contributors to platelet degranulation. These findings highlight the diversity of adverse reactions following inactivated SARS-CoV-2 vaccination and show the emerging role of cellular subtypes and central genes in vaccine-associated adverse reactions.

The identification of cell sub-types may help in the diagnosis of COVID-19 vaccine-related adverse events.COVID-19 vaccination-related acute pulmonary edema may induce a higher risk of thrombosis.The long-term fever after vaccination may attribute to the excessive type I interferon responses.

Combination therapy with budesonide and acetylcysteine alleviates LPS-induced acute lung injury via the miR-381/NLRP3 molecular axis.

BACKGROUND: Acute lung injury (ALI) usually has a high morbidity and mortality rate, but the current treatment is relatively scarce. Both budesonide (Bud) and N-acetylcysteine (NAC) exhibit protective effects in ALI, so we further investigated whether they have a synergistic effect on ALI when used together. METHODS: Establishment of a rat model of ALI with Lipopolysaccharide (LPS). Bud and NAC were administered by nebulized inhalation alone or in combination. Subsequently, HE staining was performed to observe the pathological changes in lungs of rat. Evans blue staining was implemented to assess alveolar permeability, and the pulmonary edema was assessed by measuring the ratio of wet to dry weight of the lung. Moreover, a TUNEL kit was served to test apoptosis in lung tissues. Western blot and immunohistochemistry were analyzed for expression of scorch-related proteins and NLRP3 in lung tissue, respectively. ELISA was implemented to detect inflammatory factor levels in BALF. and RT-qPCR was utilized to assess the expression level of miR-381. After stable transfection of miR-381 inhibitor or OE-NLRP3 in BEAS-2B treated with LPS, Bud and NAC, miR-381 expression was assessed by RT-qPCR, scorch death-related protein expression was measured by western blot, cell proliferation/viability was assayed by CCK-8, apoptosis was measured by flow cytometry, and ELISA was implemented to assess inflammatory factor levels. Furthermore, the Dual-luciferase assay was used to verify the targeting relationship. RESULTS: Bud and NAC treatment alone or in combination with nebulized inhalation attenuated the increased alveolar permeability, pulmonary edema, inflammatory response and scorching in LPS-induced ALI rats, and combined treatment with Bud and NAC was the most effective. In addition, combined treatment with Bud and NAC upregulated miR-381 expression and inhibited NLRP3 expression in cellular models and LPS-induced ALI rats. Transfection of the miR-381 inhibitor and OE-NLRP3 partially reversed the protective effects of Bud and NAC combination treatment on BEAS-2B cell proliferation inhibition, apoptosis, focal death and the inflammatory response. CONCLUSION: Combined Bud and NAC nebulization therapy alleviates LPS-induced ALI by modulating the miR-381/NLRP3 molecular axis.

Reduning alleviates sepsis-induced acute lung injury by reducing apoptosis of pulmonary microvascular endothelial cells.

Introduction: Sepsis-induced acute lung injury (SALI) is a critical illness with high mortality, and pulmonary microvascular endothelial cells (PMECs) barrier dysfunction is a well-documented pathogenesis of SALI. The current study aimed to investigate the underlying mechanism of Reduning (RDN) in the treatment of SALI. Methods: Network pharmacology and molecular dynamics simulation (MDS) were used to confirm the possibility of key active components of RDN combining with AKT1. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to investigate the effect of RDN in vivo. Immunofluorescence (IF) and co-immunoprecipitation (CoIP) were used to investigate the relationship between mammalian target of rapamycin (mTOR) and Bax in PMECs. ELISA was used to test the level of TNF-α. Flow cytometry was used to detect apoptosis. JC-1 and electron microscopy were used to evaluate mitochondrial damage. The results showed that RDN likely alleviated SALI via targeting AKT1. Results: In vivo, RDN could evidently decrease the expression levels of apoptosis-related proteins, alleviate mitochondrial damage, reduce lung tissue edema, down-regulate the level of TNF-α in the serum, and improve the mortality of sepsis in mice. In vitro, RDN had a significant effect on reducing the level of apoptosis-related proteins and cell apoptosis rate, while also mitigated mitochondrial damage. Furthermore, RDN could effectively lower the level of Bax in PMECs and increase the level of mTOR both in vivo and in vitro. Notably, mTOR has the ability to directly bind to Bax, and RDN can enhance this binding capability. Discussion: RDN could attenuate SALI through reducing apoptosis of PMECs, which is a promising therapeutic strategy for SALI prevention.

Further explorations into the role of mast cells in deaths associated with fatal asphyxia: an immunohistochemical study utilizing CD 117 marker.

Asphyxia-related deaths have always been a challenging task in the speciality of forensic pathology. Apart from helpful macroscopical signs (e.g., strangulation mark, cyanosis, petechial haemorrhage, and lung oedema), recent literature indicates that prolonged asphyxia is sufficient to induce an increase in mast cells (MC). Inflammatory cells migrate from the bone marrow to the lungs, aiding in the diagnosis of fatal asphyxial deaths. HIF1-α, a key regulator protein, is released from lung tissue capillaries during catastrophic hypoxia circumstances, as previously demonstrated in immunohistochemistry (IHC) research. The present study analyzed lung samples from 164 medico-legal autopsy cases, including 57 asphyxia/hypoxia deaths and 107 controls (non-asphyxial deaths). Peribronchial, perivascular and perialveolar MCs were detected using CD117 antibody, and the average of MCs in each of these locations was noted in each case. The results indicated a statistically significant increase in peribronchial and perialveolar mast cells (MC) in fatal asphyxial deaths, including those caused by hanging, drowning, or postural asphyxia. Peri-bronchial MC in lung sections of asphyxial deaths were in the range of 0.2-5.4 and in non-asphyxial samples were in the range of 0.0-2.2. Peri-alveolar MCs in lung sections of asphyxial deaths were in the range of 0.0-0.6 and in non-asphyxial samples were in the range of 0.0-0.2. Our data suggest that mast cells (MC) play an important role in fatal hypoxia-related mortality and CD 117 may be a reliable marker for detection of mast cells in asphyxial deaths. It could be very beneficial to forensic pathologists tasked with differentiating fatal asphyxia fatalities from other causes of death.

Targeting EB3-IP3R3 Interface with Cognate Peptide Protects from Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a lung disease characterized by acute onset of noncardiogenic pulmonary edema, hypoxemia, and respiratory insufficiency. The current treatment for ARDS is mainly supportive in nature, providing a critical need for targeted pharmacological management. We addressed this medical problem by developing a pharmacological treatment for pulmonary vascular leakage, a culprit of alveolar damage and lung inflammation. Our novel therapeutic target is the microtubule accessory factor EB3 (end binding protein 3), which contributes to pulmonary vascular leakage by amplifying pathological calcium signaling in endothelial cells in response to inflammatory stimuli. EB3 interacts with IP3R3 (inositol 1,4,5-trisphosphate receptor 3) and orchestrates calcium release from endoplasmic reticulum stores. Here, we designed and tested the therapeutic benefits of a 14-aa peptide named CIPRI (cognate IP3 receptor inhibitor), which disrupted EB3-IP3R3 interaction in vitro and in lungs of mice challenged with endotoxin. Treatment with CIPRI or depletion of IP3R3 in lung microvascular endothelial monolayers mitigated calcium release from endoplasmic reticulum stores and prevented a disassembly of vascular endothelial cadherin junctions in response to the proinflammatory mediator α-thrombin. Furthermore, intravenous administration of CIPRI in mice mitigated inflammation-induced lung injury, blocked pulmonary microvascular leakage, prevented activation of NFAT (nuclear factor of activated T cells) signaling, and reduced production of proinflammatory cytokines in the lung tissue. CIPRI also improved survival of mice from endotoxemia and polymicrobial sepsis. Together, these data demonstrate that targeting EB3-IP3R3 interaction with a cognate peptide is a promising strategy to address hyperpermeability of microvessels in inflammatory lung diseases.

Discovery and pharmacological characterization of a novel benzimidazole TRPV4 antagonist with cyanocyclobutyl moiety.

GSK-Bz, a TPRV4 antagonist discovered by GSK, displayed potent in vitro TRPV4 inhibition activity, and demonstrated ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. In this study, a series of GSK-Bz derivatives were designed and synthesized based on our previous findings. Compound 2b with cyanocyclobutyl moiety (IC50 = 22.65 nM) was found to be 5.3-fold more potent than GSK-Bz (IC50 = 121.6 nM) in the calcium imaging experiment. Patch-clamp experiments confirmed that compound 2b (IR = 77.1%) also gave significantly improved potency on TRPV4 currents measured at -60 mV. Furthermore, 2b effectively suppressed the permeability response to LPS in HUVEC with negligible cytotoxicity (CC50 > 100 µM). The in vivo protective effects of compounds 2b on acute lung injury were finally assessed in an LPS-induced ALI mice model. Notably, 2b gave better results than HC-067047 against all of the tested indexes (lung W/D ratios, the concentrations of BALF protein and pathological scores), indicating that 2b is a novel and highly potent TRPV4 antagonist which is worth for further development. Currently, evaluation for the drug-like properties of 2b is underway.

Pinealectomy and melatonin administration in rats: their effects on pulmonary edema induced by α-naphthylthiourea.

We aimed to observe the possible effects of melatonin (MLT) deprivation (pinealectomy) and exogenous MLT administration on pulmonary edema induced by alpha-naphthylthiourea (ANTU), a toxic chemical agent, in rats. Seventy animals were assigned to seven groups: control, sham pinealectomy (PINX), PINX, ANTU (10 mg/kg intraperitoneal on day 30), ANTU + MLT (10 mg/kg/day i.p. for 30 days), ANTU + PINX, and ANTU + PINX + MLT.In this study, pleural effusion (PE) formation, lung weight/body weight (LW/BW) and PE/BW ratios (fluid accumulation and weight values in the lungs) increase detected. Pre-ANTU MLT administration led to significant decreases in PE, LW/BW, and PE/BW levels. The inhibited glutathione (GSH) and superoxide dismutase (SOD) levels and high malondialdehyde (MDA) levels that ANTU increase lipid peroxidation in the study. MLT administration eliminated oxidative stress by reducing MDA and ameliorating GSH and SOD levels.Pre-ANTU MLT administration led to a significant decrease in interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels in the lung when compared to the ANTU group without MLT administration. Post-pinealectomy ANTU administration significantly increased IL-1ß and TNF-α levels when compared to ANTU and MLT administration without pinealectomy. Diffused inflammatory cell infiltration, interstitial pulmonary edema, and histopathological congestion were observed after the administration of ANTU. Severity of the damage was elevated in the ANTU + PINX group. MLT treatment regressed pulmonary effusion and edema and improves lung structure. In brief, the findings suggested that MLT inhibited proinflammatory mediators and could serve as a therapeutic agent to prevent inflammatory disorders.

Aquaporin-1 inhibition exacerbates ischemia-reperfusion-induced lung injury in mouse.

BACKGROUND: Ischemia-reperfusion injury (IRI), which involves severe inflammation and edema, is an inevitable feature of the lung transplantation process and leads to primary graft dysfunction (PGD). The activation of aquaporin 1 (AQP1) modulates fluid transport in the alveolar space. The current study investigated the role of AQP1 in ischemia-reperfusion (IR)-induced lung injury. METHODS: A mouse model of lung IR was established by clamping the left lung hilar for 1 h and released for reperfusion for 24 h. The AQP1 inhibitor acetazolamide (AZA) was administered 3 days before lung ischemia with a dose of 100 mg/kg per day via gavage. Lung injury was evaluated using the ratio of wet-to-dry weight, peripheral bronchial epithelial thickness, degree of angioedema, acute lung injury score, neutrophil infiltration, and cytokine concentrations in bronchoalveolar lavage fluid. RESULTS: Compared with sham treatment, ischemia with no reperfusion (IR 0h) and ischemia with reperfusion for 24 h (IR 24 h) significantly upregulated AQP1 expression, increased the wet/dry weight ratio, angioedema, neutrophil infiltration and cytokine production (interleukin -6 and tumor necrosis factor -α) and thickened the peripheral bronchial epithelium. AZA exacerbated inflammation and pulmonary edema. CONCLUSION: AQP1 may exert a protective effect against IR-induced lung injury, which could be attributed to alleviating pulmonary edema and inflammation. AQP1 upregulation might be a potential application to alleviate lung IRI and decrease the incidence of PGD.

Endothelial TRPV4 channels in lung edema and injury.

The alveolo-capillary barrier is relatively impermeable, and facilitates gas exchange via the large alveolar surface in the lung. Disruption of alveolo-capillary barrier leads to accumulation of edema fluid in lung injury. Studies in animal models of various forms of lung injury provide evidence that TRPV4 channels play a critical role in disruption of the alveolo-capillary barrier and pathogenesis of lung injury. TRPV4 channels from capillary endothelial cells, alveolar epithelial cells, and immune cells have been implicated in the pathogenesis of lung injury. Recent studies in endothelium-specific TRPV4 knockout mice point to a central role for endothelial TRPV4 channels in lung injury. In this chapter, we review the findings on the pathological roles of endothelial TRPV4 channels in different forms of lung injury and future directions for further investigation.

Inflammation in Pulmonary Hypertension and Edema Induced by Hypobaric Hypoxia Exposure.

Exposure to high altitudes generates a decrease in the partial pressure of oxygen, triggering a hypobaric hypoxic condition. This condition produces pathophysiologic alterations in an organism. In the lung, one of the principal responses to hypoxia is the development of hypoxic pulmonary vasoconstriction (HPV), which improves gas exchange. However, when HPV is exacerbated, it induces high-altitude pulmonary hypertension (HAPH). Another important illness in hypobaric hypoxia is high-altitude pulmonary edema (HAPE), which occurs under acute exposure. Several studies have shown that inflammatory processes are activated in high-altitude illnesses, highlighting the importance of the crosstalk between hypoxia and inflammation. The aim of this review is to determine the inflammatory pathways involved in hypobaric hypoxia, to investigate the key role of inflammation in lung pathologies, such as HAPH and HAPE, and to summarize different anti-inflammatory treatment approaches for these high-altitude illnesses. In conclusion, both HAPE and HAPH show an increase in inflammatory cell infiltration (macrophages and neutrophils), cytokine levels (IL-6, TNF-α and IL-1ß), chemokine levels (MCP-1), and cell adhesion molecule levels (ICAM-1 and VCAM-1), and anti-inflammatory treatments (decreasing all inflammatory components mentioned above) seem to be promising mitigation strategies for treating lung pathologies associated with high-altitude exposure.

Evaluation of the Content of Aquaporin-5 and Epithelial Sodium Channel in the Lungs of Rats during the Development of Toxic Pulmonary Edema Caused by Intoxication with Acylating Pulmonotoxicants.

We studied the content of aquaporin-5 (AQP5) and epithelial sodium channel (ENaC) in rat lungs during the development of toxic pulmonary edema (TPE) caused by intoxication with phosgene and perfluoroisobutylene (1.5 LC50). The lung body weight index (LBI) was calculated and histological examination of the lung tissues was performed. Localization and expression of AQP5 and ENaC were determined by immunohistochemistry. Intoxication led to a significant (p<0.05) increase in LBI and histological changes typical of TPE 1 and 3 h after the exposure. In 1 and 3 h after phosgene intoxication, the AQP5 and ENaC content significantly (p<0.05) increased in comparison with the control. Similar changes in the AQP5 and ENaC content were observed 1 and 3 h after exposure to perfluoroisobutylene. It was hypothesized that AQP5 plays an important role in the formation of TPE caused by intoxication with acylating pulmonotoxicants. An increase in the content of ENaC can be considered as a compensatory reaction of the body aimed at clearance of the alveolar fluid.

Pulmonary toxicity of sodium dichloroisocyanurate after intratracheal instillation in sprague-dawley rats.

In water, sodium dichloroisocyanurate (NaDCC), a source for chlorine gas generation, releases free available chlorine in the form of hypochlorous acid, a strong oxidizing agent. NaDCC has been used as a disinfectant in humidifiers; however, its inhalation toxicity is a concern. Seven-week-old rats were exposed to NaDCC doses of 100, 500, and 2500 µg·kg-1 body weight by intratracheal instillation (ITI) to investigate pulmonary toxicity. The rats were sacrificed at 1 d (exposure group) or 14 d (recovery group) after ITI. Despite a slight decrease in body weight after exposure, there was no statistically significant difference between the control and NaDCC-treated groups. A significant increase in the total protein level of the bronchoalveolar lavage fluid (BALF) was observed in the exposure groups. Lactate dehydrogenase leakage into the BALF increased significantly (p < 0.01) in the exposure groups; however, recovery was observed after 14 d. The measurement of cytokines in the BALF samples indicated a significant increase in interleukin (IL)-6 in the exposure group and IL-8 in the recovery group. Histopathological examination revealed inflammatory foci and pulmonary edema around the terminal bronchioles and alveoli. This study demonstrated that ITI of NaDCC induced reversible pulmonary edema and inflammation without hepatic involvement in rats.

Imatinib alleviates lung injury and prolongs survival in ventilated rats.

Imatinib, a tyrosine kinase inhibitor, attenuates pulmonary edema and inflammation in lung injury. However, the physiological effects of this drug and their impact on outcomes are poorly characterized. Using serial computed tomography (CT), we tested the hypothesis that imatinib reduces injury severity and improves survival in ventilated rats. Hydrochloric acid (HCl) was instilled in the trachea (pH 1.5, 2.5 mL/kg) of anesthetized, intubated supine rats. Animals were randomized (n = 17 each group) to receive intraperitoneal imatinib or vehicle immediately prior to HCl. All rats then received mechanical ventilation. CT was performed hourly for 4 h. Images were quantitatively analyzed to assess the progression of radiological abnormalities. Injury severity was confirmed via hourly blood gases, serum biomarkers, bronchoalveolar lavage (BAL), and histopathology. Serial blood drug levels were measured in a subset of rats. Imatinib reduced mortality while delaying functional and radiological injury progression: out of 17 rats per condition, 2 control vs. 8 imatinib-treated rats survived until the end of the experiment (P = 0.02). Imatinib attenuated edema after lung injury (P < 0.05), and survival time in both groups was negatively correlated with increased lung mass (R2 = 0.70) as well as other physiological and CT parameters. Capillary leak (BAL protein concentration) was significantly lower in the treated group (P = 0.04). Peak drug concentration was reached after 70 min, and the drug half-life was 150 min. Imatinib decreased both mortality and lung injury severity in mechanically ventilated rats. Pharmacological inhibition of edema could be used during mechanical ventilation to improve the severity and outcome of lung injury.

Fatal diving: could it be an immersion pulmonary edema? Case report.

Immersion pulmonary edema is a rare, underrecognized, and potentially lethal pathology developing during scuba diving and other immersion-related activities (swimming or apnoea). Physiopathology is complex and not fully understood, but its mechanisms involve an alteration of the alveolo-capillary barrier caused by transcapillary pressure elevation during immersion, leading to an accumulation of fluid and blood in the alveolar space. Diagnosis remains a challenge for clinicians and forensic practionner. The symptoms begin during ascent, with cough, frothy sputum, and hemoptysis. Auscultation reveals signs of pulmonary edema. Pulmonary CT scan, which is the radiological exam of choice, shows ground glass opacities and interlobular thickening, eventually demonstrating a patterned distribution, likely in the anterior segments of both lungs. Apart from the support of vital functions, there is no specific treatment and hyperbaric oxygen therapy is not systematically recommended. We present a case of fatal IPE occurring in a recreational diver who unfortunately died shortly after his last dive. Diagnosis was made after complete forensic investigations including post-mortem-computed tomography, complete forensic autopsy, histological examination, and toxicological analysis.

Entrapment within an ottoman storage bed: an unusual accidental asphyxial death.

Herein, we present an uncommon forensic case of death by asphyxia. The victim was a woman whose body at death scene investigation (DSI) was discovered beside an ottoman storage bed. According to the rescue team, who had moved the body before our arrival, the body was originally found in the prone position and stuck with the neck, thorax and arms within the bed. Examination of the body showed hypostasis that was mainly distributed to the face and the lower chest while sparing the neck and the upper chest. The face was markedly swollen, and the eyes were congested with blood. Dissection and histology revealed pulmonary oedema and emphysema of both lungs. Integrating circumstantial, radiology and autopsy data, it was established that the victim, while trapped between the mattress and the edge of the ottoman storage bed, died by mechanical asphyxia due to cervical-thoracic compression and postural asphyxia acting simultaneously.

ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury.

Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.

Endothelial Dysfunction through Oxidatively Generated Epigenetic Mark in Respiratory Viral Infections.

The bronchial vascular endothelial network plays important roles in pulmonary pathology during respiratory viral infections, including respiratory syncytial virus (RSV), influenza A(H1N1) and importantly SARS-Cov-2. All of these infections can be severe and even lethal in patients with underlying risk factors.A major obstacle in disease prevention is the lack of appropriate efficacious vaccine(s) due to continuous changes in the encoding capacity of the viral genome, exuberant responsiveness of the host immune system and lack of effective antiviral drugs. Current management of these severe respiratory viral infections is limited to supportive clinical care. The primary cause of morbidity and mortality is respiratory failure, partially due to endothelial pulmonary complications, including edema. The latter is induced by the loss of alveolar epithelium integrity and by pathological changes in the endothelial vascular network that regulates blood flow, blood fluidity, exchange of fluids, electrolytes, various macromolecules and responses to signals triggered by oxygenation, and controls trafficking of leukocyte immune cells. This overview outlines the latest understanding of the implications of pulmonary vascular endothelium involvement in respiratory distress syndrome secondary to viral infections. In addition, the roles of infection-induced cytokines, growth factors, and epigenetic reprogramming in endothelial permeability, as well as emerging treatment options to decrease disease burden, are discussed.

The Disruption of the Endothelial Barrier Contributes to Acute Lung Injury Induced by Coxsackievirus A2 Infection in Mice.

Sporadic occurrences and outbreaks of hand, foot, and mouth disease (HFMD) caused by Coxsackievirus A2 (CVA2) have frequently reported worldwide recently, which pose a great challenge to public health. Epidemiological studies have suggested that the main cause of death in critical patients is pulmonary edema. However, the pathogenesis of this underlying comorbidity remains unclear. In this study, we utilized the 5-day-old BALB/c mouse model of lethal CVA2 infection to evaluate lung damage. We found that the permeability of lung microvascular was significantly increased after CVA2 infection. We also observed the direct infection and apoptosis of lung endothelial cells as well as the destruction of tight junctions between endothelial cells. CVA2 infection led to the degradation of tight junction proteins (e.g., ZO-1, claudin-5, and occludin). The gene transcription levels of von Willebrand factor (vWF), endothelin (ET), thrombomodulin (THBD), granular membrane protein 140 (GMP140), and intercellular cell adhesion molecule-1 (ICAM-1) related to endothelial dysfunction were all significantly increased. Additionally, CVA2 infection induced the increased expression of inflammatory cytokines (IL-6, IL-1ß, and MCP-1) and the activation of p38 mitogen-activated protein kinase (MAPK). In conclusion, the disruption of the endothelial barrier contributes to acute lung injury induced by CVA2 infection; targeting p38-MAPK signaling may provide a therapeutic approach for pulmonary edema in critical infections of HFMD.

Therapeutic effects of high molecular weight hyaluronic acid in severe Pseudomonas aeruginosa pneumonia in ex vivo perfused human lungs.

We previously reported that extracellular vesicles (EVs) released during Escherichia coli (E. coli) bacterial pneumonia were inflammatory, and administration of high molecular weight hyaluronic acid (HMW HA) suppressed several indices of acute lung injury (ALI) from E. coli pneumonia by binding to these inflammatory EVs. The current study was undertaken to study the therapeutic effects of HMW HA in ex vivo perfused human lungs injured with Pseudomonas aeruginosa (PA)103 bacterial pneumonia. For lungs with baseline alveolar fluid clearance (AFC) <10%/h, HMW HA 1 or 2 mg was injected intravenously after 1 h (n = 4-9), and EVs released during PA pneumonia were collected from the perfusate over 6 h. For lungs with baseline AFC > 10%/h, HMW HA 2 mg was injected intravenously after 1 h (n = 6). In vitro experiments were conducted to evaluate the effects of HA on inflammation and bacterial phagocytosis. For lungs with AFC < 10%/h, administration of HMW HA intravenously significantly restored AFC and numerically decreased protein permeability and alveolar inflammation from PA103 pneumonia but had no effect on bacterial counts at 6 h. However, HMW HA improved bacterial phagocytosis by human monocytes and neutrophils and suppressed the inflammatory properties of EVs released during pneumonia on monocytes. For lungs with AFC > 10%/h, administration of HMW HA intravenously improved AFC from PA103 pneumonia but had no significant effects on protein permeability, inflammation, or bacterial counts. In the presence of impaired alveolar epithelial transport capacity, administration of HMW HA improved the resolution of pulmonary edema from Pseudomonas PA103 bacterial pneumonia.