Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-β is intimately involved in the fibrogenic process. When activated, TGF-β promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 tissue expression) involved in the TGF-β1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-β pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-β inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.

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-1β, 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.

The COVID-19 pandemic, driven by SARS-CoV-2, has led to a global health crisis, highlighting the virus’s unique molecular mechanisms that distinguish it from other respiratory pathogens. It is known that the Hypoxia-Inducible Factor 1α (HIF-1α) activates a complex network of intracellular signaling pathways regulating cellular energy metabolism, angiogenesis, and cell survival, contributing to the wide range of clinical manifestations of COVID-19, including Post-Acute COVID-19 Syndrome (PACS). Emerging evidence suggests that dysregulation of HIF-1α is a key driver of systemic inflammation, silent hypoxia, and pathological tissue remodeling in both the acute and post-acute phases of the disease. This scoping review was conducted following PRISMA-ScR guidelines and registered in INPLASY. It involved a literature search in Scopus and PubMed, supplemented by manual reference screening, with study selection facilitated by Rayyan software. Our analysis clarifies the dual role of HIF-1α, which may either worsen inflammatory responses and viral persistence or support adaptive mechanisms that reduce cellular damage. The potential for targeting HIF-1α therapeutically in COVID-19 is complex, requiring further investigation to clarify its precise role and translational applications. This review deepens the molecular understanding of SARS-CoV-2-induced cellular and tissue dysfunction in hypoxia, offering insights for improving clinical management strategies and addressing long-term sequelae.

Background/Objectives: This study aimed to evaluate sociodemographic factors, features of the acute infection, and post-infection health status in survivors of COVID-19, assessing their association with post-acute COVID-19 syndrome (PACS). Methods: A multidisciplinary public clinic in Brazil assessed COVID-19 survivors between June 2020 and February 2022. Patients were classified as having PACS or subacute infection (SI). Data on the history of the acute infection, current symptoms, physical examination, and laboratory findings were collected and analyzed using multivariate models with PACS as the outcome. Results: Among the 113 participants, 63.71% were diagnosed with PACS at a median of 130 days (IQR: 53–196) following acute symptom onset. Admission to the intensive care unit was more frequent among individuals with PACS than those with SI (83.3% vs. 65.0% respectively; p = 0.037). Symptoms significantly more prevalent in the PACS group when compared to the SI cohort included hair loss (44.4% vs. 17.1% respectively; p = 0.004), lower limb paresthesia (34.7% vs. 9.8% respectively; p = 0.003), and slow thinking speed (28.2% vs. 0.0% respectively; p < 0.001). Logistic regression revealed that only the time interval between the onset of acute symptoms and the clinical evaluation was independently associated with a PACS diagnosis (β = 0.057; 95% CI: 1.03–1.08; p < 0.001). Conclusions: Patients with PACS had a higher frequency of intensive care unit admission compared to those with subacute infection. However, in the multivariate analysis, the severity of the acute infection did not predict the final diagnosis of PACS, which was associated only with the time elapsed since symptom onset.

Perinatal asphyxia is a major contributor to neonatal morbidity and mortality, particularly among preterm infants, whose brains are highly vulnerable to hypoxic–ischemic injury. The germinal matrix (GM), owing to its vascular fragility and high metabolic demand, is especially susceptible in this context. This study analyzed 118 germinal matrix samples from neonates, stratified into three groups according to gestational age—Extremely Preterm (EP), Late Preterm (LP), and Term (T)—to investigate the immunopositivity of hypoxia-inducible factor 1-alpha (HIF-1α) and brain-derived neurotrophic factor (BDNF), correlating these findings with gestational age, the presence of asphyxia, neuronal injury, and survival time. BDNF expression showed a positive association with postnatal survival in neonates without neuronal injury (ρ = 0.309; p = 0.012). Linear regression analysis further demonstrated that BDNF immunopositivity was a significant predictor of survival time, with each 11.82% increase in positive staining corresponding to an additional predicted hour of survival (p < 0.001). HIF-1α expression was positively associated with survival in asphyxiated extremely preterm neonates (ρ = 0.492; p = 0.024) and demonstrated a strong correlation that approached, but did not reach, conventional statistical significance in late preterm neonates with neuronal injury (ρ = 0.949; p = 0.051). Collectively, these findings suggest a complementary role for BDNF and HIF-1α in neonatal neuroprotective responses, with BDNF showing potential as a prognostic biomarker in neonates without neuronal injury and HIF-1α reflecting adaptive responses to hypoxic–ischemic stress in a gestational age-dependent manner. However, additional studies are required to validate these associations and further clarify their prognostic and therapeutic relevance in neonatal hypoxic–ischemic conditions.

Objective: Given the high proliferative activity of germinal matrix and its direct correlation with hypoxemia, it is necessary to investigate the possible molecular regulation pathways, to understand the existing clinical relationship between the hypoxic-ischemic insult and the biomarkers NF-kB, AKT-3, Parkin, TRK-C and VEGFR-1. Methods: A hundred and eighteen germinal matrix samples of the central nervous system of patients who died in the first 28 days of life were submitted to histological and immunohistochemistry analysis to identify the tissue immunoexpression of those biomarkers related to asphyxia, prematurity, and death events within 24h. Results: A significantly increased tissue immunoexpression of NF-kB, AKT-3 and Parkin was observed in the germinal matrix of preterm infants. In addition, significantly decreased tissue immunoexpression of VEGFR-1 and NF-kB was observed in patients who experienced asphyxia followed by death within 24 hours. Conclusions: The results suggest a direct involvement between the hypoxic-ischemic insult and NF-kB and VEGFR-1 markers since a decreased immunoexpression of these biomarkers was observed in asphyxiated patients. Furthermore, it is suggested that there was not enough time for VEGFR-1 to be transcribed, translated and expressed on the surface of the plasma membrane. This temporality can be observed in the relationship between NF-kB expression and the survival time of individuals who died within 24 hours, suggesting that this factor is essential for the production of VEGFR-1 and, therefore, to carry out the necessary remodeling effect to neovascularize the affected region.