COVID-19 and Pulmonary Angiogenesis: The Possible Role of Hypoxia and Hyperinflammation in the Overexpression of Proteins Involved in Alveolar Vascular Dysfunction.

COVID-19 has been considered a vascular disease, and inflammation, intravascular coagulation, and consequent thrombosis may be associated with endothelial dysfunction. These changes, in addition to hypoxia, may be responsible for pathological angiogenesis. This research investigated the impact of COVID-19 on vascular function by analyzing post-mortem lung samples from 24 COVID-19 patients, 10 H1N1pdm09 patients, and 11 controls. We evaluated, through the immunohistochemistry technique, the tissue immunoexpressions of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis (ICAM-1, ANGPT-2, and IL-6, IL-1ß, vWF, PAI-1, CTNNB-1, GJA-1, VEGF, VEGFR-1, NF-kB, TNF-α and HIF-1α), along with the histopathological presence of microthrombosis, endothelial activation, and vascular layer hypertrophy. Clinical data from patients were also observed. The results showed that COVID-19 was associated with increased immunoexpression of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis compared to the H1N1 and CONTROL groups. Microthrombosis and vascular layer hypertrophy were found to be more prevalent in COVID-19 patients. This study concluded that immunothrombosis and angiogenesis might play a key role in COVID-19 progression and outcome, particularly in patients who die from the disease.

IL-4/IL-13 remodeling pathway of COVID-19 lung injury.

The COVID-19 fatality rate is high when compared to the H1N1pdm09 (pandemic Influenza A virus H1N1 subtype) rate, and although both cause an aggravated inflammatory response, the differences in the mechanisms of both pandemic pneumonias need clarification. Thus, our goal was to analyze tissue expression of interleukins 4, 13, (IL-4, IL-13), transforming growth factor-beta (TGF-ß), and the number of M2 macrophages (Sphingosine-1) in patients who died by COVID-19, comparing with cases of severe pneumopathy caused by H1N1pdm09, and a control group without lung injury. Six lung biopsy samples of patients who died of SARS-CoV-2 (COVID-19 group) were used and compared with ten lung samples of adults who died from a severe infection of H1N1pdm09 (H1N1 group) and eleven samples of patients who died from different causes without lung injury (CONTROL group). The expression of IL-4, IL-13, TGF-ß, and M2 macrophages score (Sphingosine-1) were identified through immunohistochemistry (IHC). Significantly higher IL-4 tissue expression and Sphingosine-1 in M2 macrophages were observed in the COVID-19 group compared to both the H1N1 and the CONTROL groups. A different mechanism of diffuse alveolar damage (DAD) in SARS-CoV-2 compared to H1N1pdm09 infections were observed. IL-4 expression and lung remodeling are phenomena observed in both SARS-CoV-2 and H1N1pdm09. However, SARS-CoV-2 seems to promote lung damage through different mechanisms, such as the scarce participation Th1/Th17 response and the higher participation of the Th2. Understanding and managing the aggravated and ineffective immune response elicited by SARS-CoV-2 merits further clarification to improve treatments propose.

Immunoexpression of SOX-2 in oral leukoplakia.

OBJECTIVE: This study was conducted to correlate and compare the immunoexpression of sex-determining region Y-box 2 (SOX-2) in oral leukoplakia (OL) lesions with that in normal buccal mucosa (control). MATERIALS AND METHODS: In this observational study, OL with low-risk (n = 34) and high-risk (n = 33) dysplasia and control samples (n = 25) were subjected to immunohistochemical analysis for SOX-2. In the epithelium, SOX-2 positive and negative cells, as well as semiautomatic segmentation of the immunopositive nuclear area were counted. Statistical tests included chi-square, one-way analysis of variance, Tukey, and Games-Howell. The level of significance was 5%. RESULTS: Groups with OL lesions (low and high-risk) showed higher mean numbers of SOX-2 positive cells (63.47 ± 25.70 and 68.18 ± 21.17) compared to the control group (45.85 ± 27.38) (p = 0.00). Groups with OL lesions (low and high-risk) exhibited higher mean positive nuclear area (0.24 ± 0.47 and 1.09 ± 2.06) compared to the control group (0.00 ± 0.01) (p = 0.01). CONCLUSION: Oral leukoplakia lesions showed a higher expression of SOX-2, suggesting its contribution to the pathogenesis of OL.

Effect of the bone marrow derived-mononuclear stem cells transplantation in the growth, VEGF-R and TNF-alpha expression of endometrial implants in Wistar rats.

OBJECTIVE: To study the effect of bone marrow derived-mononuclear stem cells transplantation in the growth, VEGF-R and TNF-alpha expression of surgically induced endometriosis in an experimental model. STUDY DESIGN: This is an experimental study conducted in the Center for Health and Biological Sciences at the Pontifical Catholic University of Parana, Brazil. Endometriotic implants were surgically induced in 120 female Wistar rats. The animals with viable endometrial implant (larger than 25 mm(2)) were randomically divided into 3 groups to receive an intraperitoneal injection of 0.2 cc of saline solution (C group; n=30), a subcutaneous injection of 1mg/kg of leuprolide (L group; n=34), or an intraperitoneal injection of 5×10(6) bone marrow derived-mononuclear stem cells (SC group; n=36). They were sacrificed after 21 days to assess the implants' size and the tissue expression of vascular endothelial growth factor receptor (VEGF-R) and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Treatment with leuprolide decreased the surface area of the endometriotic implant compared to the SC group and the C group. The absolute reduction in the surface area of the implant was 16.5mm, 0mm, and 0mm (p=0.007), respectively, and the percent reduction was 40.2%, 0%, and 0% (p=0.001). VEGF-R expression in the endometriotic implant decreased after treatment in the L and SC groups compared to the C group (409.6 µm(2) vs. 465 µm(2) vs. 920.9 µm(2), respectively; p=0.021). TNF-alpha expression also reduced in the L and SC groups compared to the C group (585.7 µm(2) vs. 549.3 µm(2) vs. 2402.1 µm(2), respectively; p<0.001). CONCLUSION: Bone marrow derived-mononuclear stem cells transplantation decreased the expression of VEGF-R and TNF-alpha in the endometriotic implant but did not reduce the surface area of the lesion.