Dynamic Characteristics of Blood Platelet Count in COVID-19 Patients

Background and purpose: Coronavirus disease 2019 (COVID-19) was spreading all over the world. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) primarily invades and infects the lungs of humans leading to COVID-19. Mild to severe clinical symptoms such as fever, cough, and shortness of breath were existed in those patients. One of the most common changes in these patients was abnormal blood routine. However, uncertainty remains regarding the dynamic characteristics of platelet in COVID-19 patients due to limited data. Therefore, we aimed to analyze the association between dynamic characteristics of blood platelet and disease severity, and to identify new monitoring indicators to treat the COVID-19 patients. Methods: In this cohort study, 398 COVID-19 patients treated in the Shenzhen Third People’s hospital from December 16, 2019 to March 26, 2020 were collected and participated. All data of participants including the clinical characteristics, imaging and laboratory information were collected. All patients included in our study were classified as four groups (mild, common, severe, and critical types) regarding clinical symptoms and relevant severe failures based on the Diagnosis Criteria. Platelet count was examined at the baseline and every 3–5 days during hospitalization. Results: The platelet count varied with clinical classifications. The platelet count in mild type was normal without significant fluctuation. While the blood platelet count of most common and severe patients had obvious fluctuations, showing as a dynamic change that first rose and then fell to the level at admission, which was consistent with the trend of lung inflammation. Bone marrow smears further showed that bone marrow hyperplasia was normal in mild, common and severe type patients, and megakaryocytes and their platelet-producing functions were not abnormal. Conclusions: Our results suggested that the dynamic changes of platelet count might be a predictor of lung inflammation alteration for COVID-19 patients. The changes in platelet count might be a responsive pattern secondary to lung inflammation. The function of bone marrow may be slightly affected by SARS-CoV-2 infection.

The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome

Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of Coronavirus Disease 2019 (COVID-19) and an increase in complications including Acute Respiratory Distress Syndrome (ARDS). Due to the lack of therapeutic options for Acute Respiratory Distress Syndrome, recent attention has focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help define effective therapeutic strategies. Interleukin 8 (IL-8) is a pro-inflammatory cytokine that has a role in neutrophil activation and has been identified within the pathogenesis and progression of this disease. The aim of this review is to highlight the role of IL-8 as a biomarker and prognostic factor in modulating the hyperinflammatory response in ARDS. The crucial role of IL-8 in lung inflammation and disease pathogenesis might suggest IL-8 as a possible new therapeutic target to efficiently modulate the hyperinflammatory response in ARDS.

Contribution of Kazal-Like Domains of the Serine Protease Inhibitor-1 from Toxoplasma gondii in Asthma Therapeutic Vaccination Effectiveness

<b><i>Background:</i></b> We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. <b><i>Objectives:</i></b> In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. <b><i>Methods:</i></b> BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. <b><i>Results:</i></b> Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. <b><i>Conclusions:</i></b> Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.

Neutrophil Cathepsin G Enhances Thrombogenicity of Mildly Injured Arteries via ADP-Mediated Platelet Sensitization

Inhalation of particulate matter in polluted air causes direct, size-restricted passage in the circulation and pronounced lung inflammation, provoking platelet activation and (non)-fatal cardiovascular complications. To determine potency and mechanism of platelet sensitization via neutrophil enzymes, we performed in vitro aggregation studies in washed human platelets and in murine and human blood, in the presence of elastase, cathepsin G and regular platelet agonists, present in damaged arteries. The impact of both enzymes on in vivo thrombogenicity was studied in the same thrombosis mouse model, previously having demonstrated that neutrophil activation enhances peripheral thrombogenicity. At 0.05 U/mL, cathepsin G activated washed human platelets via PAR1, whereas at 0.35 U/mL, aggregation occurred via PAR4. In Swiss mouse platelet-rich plasma no aggregation occurred by cathepsin G at 0.4 U/mL. In human and murine blood, aggregations by 0.05–0.1 U/mL cathepsin G were similar and not PAR-mediated, but platelet aggregation was inhibited by ADP antagonists, advocating cathepsin G-released ADP in blood as the true agonist of sustained platelet activation. In the mouse thrombosis model, cathepsin G and elastase amplified mild thrombogenicity at blood concentrations that activated platelets in vitro. This study shows that cathepsin G and elastase secreted in the circulation during mild air pollution-induced lung inflammation lyse red blood cell membrane proteins, leading to ADP-leakage into plasma, sensitizing platelets and amplifying their contribution to cardiovascular complications of ambient particle inhalation.

Exosomes derived from adipose-derived stem cells alleviate cigarette smoke-induced lung inflammation and injury by inhibiting alveolar macrophages pyroptosis

Background Chronic obstructive pulmonary disease (COPD) is a frequently encountered disease condition in clinical practice mainly caused by cigarette smoke (CS). The aim of this study was to investigate the protective roles of human adipose-derived stem cells-derived exosomes (ADSCs-Exo) in CS-induced lung inflammation and injury and explore the underlying mechanism by discovering the effects of ADSCs-Exo on alveolar macrophages (AMs) pyroptosis. Methods ADSCs were isolated from human adipose tissues harvested from three healthy donors, and then ADSCs-Exo were isolated. In vivo, 24 age-matched male C57BL/6 mice were exposed to CS for 4 weeks, followed by intratracheal administration of ADSCs-Exo or phosphate buffered saline. In vitro, MH-S cells, derived from mouse AMs, were stimulated by 2% CS extract (CSE) for 24 h, followed by the treatment of ADSCs-Exo or phosphate buffered saline. Pulmonary inflammation was analyzed by detecting pro-inflammatory cells and mediators in the bronchoalveolar lavage fluid. Lung histology was assessed by hematoxylin and eosin staining. Mucus production was determined by Alcian blue-periodic acid-Schiff staining. The profile of AMs pyroptosis was evaluated by detecting the levels of pyroptosis-indicated proteins. The inflammatory response in AMs and the phagocytic activity of AMs were also investigated. Results In mice exposed to CS, the levels of pro-inflammatory cells and mediators were significantly increased, mucus production was markedly increased and lung architecture was obviously disrupted. AMs pyroptosis was elevated and AMs phagocytosis was inhibited. However, the administration of ADSCs-Exo greatly reversed these alterations caused by CS exposure. Consistently, in MH-S cells with CSE-induced properties modelling those found in COPD, the cellular inflammatory response was elevated, the pyroptotic activity was upregulated while the phagocytosis was decreased. Nonetheless, these abnormalities were remarkably alleviated by the treatment of ADSCs-Exo. Conclusions ADSCs-Exo effectively attenuate CS-induced airway mucus overproduction, lung inflammation and injury by inhibiting AMs pyroptosis. Therefore, hADSCs-Exo may be a promising cell-free therapeutic candidate for CS-induced lung inflammation and injury.

Quanzhenyiqitang Reverses LPS-Induced Inflammation via Inhibiting PYK2/p38MAPK/HDAC2/CK2 Signaling Pathway in Rat Alveolar Macrophage

Chronic obstructive pulmonary disease (COPD) is a common chronic pulmonary disease with multiple etiologies and pathological changes. PYK2 expression is significantly increased in lipopolysaccharide-induced lung injury, but it mediates chronic lung inflammation. The mechanism of its occurrence remains unclear. Quanzhenyiqitang is often used in clinical treatment of COPD, so this study explored the mechanism of its treatment of lipopolysaccharide-induced lung injury. In this study, transfection, flow cytometry, QRT-PCR, and Western blotting methods were used to study the mechanism of Quanzhenyiqitang lipopolysaccharide-induced lung injury. The results showed that the mechanism of occurrence remains unclear. Our novel observations imply that the PYK2/p38MAPK/HDAC2/CK2 pathway is one of the fundamental underlying mechanisms that mediate the pathogenic progression of COPD, and Quanzhenyiqitang may be the therapeutic drug to prevent chronic inflammation and delay the progression of COPD by inhibiting PYK2 signaling pathways.

Protective Role of Nrf2 in Zinc Oxide Nanoparticles-Induced Lung Inflammation in Female Mice and Sexual Dimorphism in Susceptibility

Background Zinc oxide nanoparticles (ZnO-NPs) are used in various products such as rubber, paint, and cosmetics. Our group reported recently that Nrf2 protein provides protection against ZnO-NPs-induced pulmonary inflammation in male mice. The present study investigated the effect of Nrf2 deletion on the lung inflammatory response in female mice exposed to ZnO-NPs. Methods Twenty-four female Nrf2−/− mice and the same number of female Nrf2+/+ mice were each divided into three equal groups and each exposed to ZnO-NPs at either 0, 10 or 30 µg/mouse by pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and lungs were collected 14 days later to quantify protein level, number of inflammatory cells, and for scoring inflammation histopathologically. The mRNA levels of Nrf2-depedent antioxidant enzymes and proinflammatory cytokine in lung tissue were measured. Results Exposure to ZnO-NPs increased all types of BALF cells and lung inflammation scores in both of female Nrf2−/− and Nrf2+/+ mice, and Nrf2 deletion enhanced ZnO-NPs-induced increase in the number of eosinophils in BALF. Nrf2 deletion enhanced ZnO-NPs-induced downregulation of GR and upregulation of HO-1 and TNFα. Nrf2 deletion decreased mRNA levels of CAT, GcLc and NQO1 and increased that for GcLm and MT-2. ZnO-NPs dose-dependently increased the level of oxidized glutathione (GSSG), and mRNA levels of proinflammatory cytokines/chemokines; KC, MIP-2, IL-6, IL-1β and MCP-1 only in wild-type mice, and Nrf2 deletion decreased total glutathione levels and upregulated the above proinflammatory cytokines/chemokines regardless of level of exposure to ZnO-NPs. Taken together with our previous results in male mice, our results showed a lower susceptibility of females to lung inflammation, relative to males, irrespective of Nrf2 deletion, and that enhancement of ZnO-NPs-induced upregulation of HO-1 and TNFα and downregulation of GR by deletion of Nrf2 is specific to female mice. Conclusion We conclude that Nrf2 provides protection in female mice against increase in BALF eosinophils, probably through down-regulation of proinflammatory cytokines/chemokines and upregulation of oxidative stress-related genes. The study also suggests lower susceptibility to lung inflammation in female mice relative to their male counterparts and the synergistic effects of sex and exposure to ZnO-NPs on mRNA expression of GR, HO-1 or TNFα.