Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair.

Inflammatory lung injury is characterized by lung endothelial cell (LEC) death, alveolar epithelial cell (AEC) death, LEC-LEC junction weakening, and leukocyte infiltration, which together disrupt nutrient and oxygen transport. Subsequently, lung vascular repair is characterized by LEC and AEC regeneration and LEC-LEC junction re-annealing, which restores nutrient and oxygen delivery to the injured tissue. Pulmonary hypoxia is a characteristic feature of several inflammatory lung conditions, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19). The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs) 1 and 2. These transcription factors control the expression of a wide variety of target genes, which in turn mediate key pathophysiological processes including cell survival, differentiation, migration, and proliferation. HIF signaling in pulmonary cell types such as LECs and AECs, as well as infiltrating leukocytes, tightly regulates inflammatory lung injury and repair, in a manner that is dependent upon HIF isoform, cell type, and injury stimulus. The aim of this review is to describe the HIF-dependent regulation of inflammatory lung injury and vascular repair. The review will also discuss potential areas for future study and highlight putative targets for inflammatory lung conditions such as ALI/ARDS and severe COVID-19. In the development of HIF-targeted therapies to reduce inflammatory lung injury and/or enhance pulmonary vascular repair, it will be vital to consider HIF isoform- and cell-specificity, off-target side-effects, and the timing and delivery strategy of the therapeutic intervention.

Emerging and Established Histological Techniques for the Analysis of Thrombosis in COVID-19 Lungs.

Coronavirus disease 2019 (COVID-19) is the potentially lethal disease that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 have an increased risk of thrombosis, but the role of thrombosis in the pathogenesis and progression of severe COVID-19 remains unclear. A better understanding of the contribution of thrombosis to the development and progression of COVID-19 could lead to the development of novel COVID-19 treatments. For this reason, established and emerging histological techniques have recently been used to analyze COVID-19 lungs quantitatively and visually and in two and three dimensions. The gold standard and novel state-of the-art histological techniques that have been used to assess thrombosis in COVID-19 lungs are described in this Mini Review.

Nasal Delivery of Hesperidin/Chitosan Nanoparticles Suppresses Cytokine Storm Syndrome in a Mouse Model of Acute Lung Injury.

The cytokine storm or cytokine storm syndrome (CSS) is associated with high mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), for example following sepsis or infectious diseases including COVID-19. However, there are no effective treatments for CSS-associated ALI or ALI/ARDS. Thus, there remains an urgent need to develop effective drugs and therapeutic strategies against CSS and ALI/ARDS. Nasal and inhaled drug delivery methods represent a promising strategy in the treatment of inflammatory lung disease as a result of their ability to improve drug delivery to lungs. Improving the nasal mucosa absorption of poorly water-soluble drugs with poor mucosa bioavailability to a therapeutically effective level is another promising strategy in the fight against ALI/ARDS. Here, chitosan nanoparticles loaded with hesperidin (HPD/NPs) were developed for nasal delivery of the anti-inflammatory HPD compound to inflammatory lungs. In vitro and in vivo, HPD/NPs exhibited enhanced cellular uptake in the inflammatory microenvironment compared with free HPD. In a mouse model of inflammatory lung disease, the HPD/NPs markedly inhibited lung injury as evidenced by reduced inflammatory cytokine levels and suppressed vascular permeability compared with free HPD. Collectively, our study demonstrates that nasal delivery of HPD/NPs suppresses CSS and ALI/ARDS in a murine model of inflammatory lung disease, and that nanoparticle-based treatment strategies with anti-inflammatory effects could be used to reduce CSS and ALI in patients with inflammatory lung injury.

Surviving and Thriving in Thrombosis Research During a Global Pandemic: Experiences of a Vascular Scientist Diagnosed with COVID-19

The 2019-2020 COVID-19 outbreak resulted in widespread suffering along with major changes in the ways that researchers carry out their work. This article profiles the experiences of an early-career investigator in thrombosis research who worked through the COVID-19 pandemic and a COVID-19 diagnosis. The aims of this article are to normalize concern regarding COVID-19 in the research community, to provide a perspective on maintaining productivity during stay-at-home periods, and to discuss how the COVID-19 pandemic might alter common research practices in the future. While the COVID-19 outbreak was clearly disruptive and debilitating on a global level, some research practices that were heavily employed during the pandemic may continue to be utilized in scientific research for many years to come.

Requests from primary care for chest X-ray and CA125 measurements during the COVID-19 emergency: An observational study.

During the first 3 months of 2020, as the COVID-19 pandemic developed, it was noticed that requests from primary care for investigations were decreasing, including those that form part of the diagnostic process for cancers. We therefore obtained data on the requests from primary care for chest X-rays (CXRs) and CA125 measurement our hospital received in the first half of 2020 and compared them with 2019. The number of CXRs declined by 93% in April 2020 compared with 2019, with the decline being greater for patient living in outlying areas. Requests from the emergency department also declined. Requests for CA125 measurement similarly fell by 77% from all areas. The requests increased in June, CA125 more than CXR. If this phenomenon is widespread it may have an impact on diagnosis of major conditions, particularly cancers and tuberculosis.