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.

The inflammasome complex is a key part of chronic diseases and acute infections, being responsible for cytokine release and cell death mechanism regulation. The SARS-CoV-2 infection is characterized by a dysregulated cytokine release. In this context, the inflammasome complex analysis within SARS-CoV-2 infection may prove beneficial to understand the disease’s mechanisms. Post-mortem minimally invasive autopsies were performed in patients who died from COVID-19 (n = 24), and lung samples were compared to a patient control group (n = 11) and an Influenza A virus H1N1 subtype group from the 2009 pandemics (n = 10). Histological analysis was performed using hematoxylin-eosin staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: ACE2, TLR4, NF-κB, NLRP-3 (or NALP), IL-1β, IL-18, ASC, CASP1, CASP9, GSDMD, NOX4, TNF-α. Data obtained from digital analysis underwent appropriate statistical tests. IHC analysis showed biomarkers that indicate inflammasome activation (ACE2; NF-κB; NOX4; ASC) were significantly increased in the COVID-19 group (p < 0.05 for all) and biomarkers that indicate cell pyroptosis and inflammasome derived cytokines such as IL-18 (p < 0.005) and CASP1 were greatly increased (p < 0.0001) even when compared to the H1N1 group. We propose that the SARS-CoV-2 pathogenesis is connected to the inflammasome complex activation. Further studies are still warranted to elucidate the pathophysiology of the disease.

Disorders of the Achilles tendon are common and have a major socio-economic impact. Current treatments (drugs, physiotherapy, and surgery) do not provide lasting relief, leading to chronicity and recurrence. In this context, experimental studies on regenerative therapies, such as stem cells, and natural and synthetic membranes, have shown promising results in the treatment of tendon lesions. Background/Objectives: The present study analyzes the response of tissue to a combination of bone marrow mononuclear cells (BMMCs) and human decellularized amniotic membrane (AM) for the treatment of Achilles tendon lesions in rats. Methods: Forty male Wistar rats were randomized into four treatment groups: SC (stem cells), AM (amniotic membrane), SC + AM (stem cells + amniotic membrane), and C (control). All underwent Achilles tendon sectioning and tenorrhaphy. In the AM and SC + AM groups, the amniotic membrane was sutured over the lesion after the tendon was sutured; in the SC and SC + AM groups, 2 mL of autologous blood from the iliac crest containing BMMCs was applied around the lesion. Animals in Group C received only 2 mL of 0.9% saline around the lesion. After four weeks, the animals were euthanized, and the tendons were sent for histological analysis (Picrosirius Red) and immunohistochemistry (IL-6, IL-4, and IL-13). Results: Analysis of type I and type III collagen fibers showed no differences between groups. However, the SC + AM group showed the highest expressions of IL-4 and IL-13. Conclusions: IL-4 and IL-13 are cytokines known to be associated with tissue repair and organization. This suggests that the therapy associated with SC and AM is potentially beneficial in the treatment of injured Achilles tendons. However, further studies are necessary to clarify the benefits of this treatment for the function and biomechanical properties of the tendon and prove whether this association could represent a combined Advanced Therapy Medicinal Product (cATMP). Such a product would contain SC and a biological membrane, providing a mechanical structure for the injured tendon and active biological cells. Another possible medical approach could be immunobiological drugs targeting IL-4 and IL-13.

Tendon disorders are common and have a major socio-economic impact. Current treatments (drugs, physiotherapy, surgery) do not provide lasting relief, leading to chronicity and recurrence. In this context, studies on regenerative therapies, such as stem cells, platelet-rich plasma and natural and synthetic membranes, have shown promising results in the treatment of tendon lesions. The present study analyzes the tissue response to a combination of bone marrow mononuclear cells BMMCs) and human decellularized amniotic membrane for treatment of Achilles tendon lesions in rats. Forty male Wistar rats were randomized into four treatment groups: SC (stem cells), AM (amniotic membrane), SC + AM (stem cells + amniotic membrane) and C (control). All underwent Achilles tendon sectioning and tenorrhaphy. In the AM and SC + AM groups, amniotic membrane was sutured over the lesion after the tendon was sutured; in the SC and SC + AM groups, 2 ml of autologous blood from the iliac crest containing BMMCs was applied around the lesion. Group C animals received only 2 ml of 0.9% saline around the lesion. After four weeks, the animals were euthanized, and the tendons were sent for histological analysis (Picrosirius Red) and immunohistochemistry (IL-6, IL-4 and IL-13). Analysis of type I and type III collagen fibers showed no differences between groups. However, the SC + AM group showed a better immunohistochemical profile, with greater expression of IL-4 and IL-13. In this experiment, animals treated with amniotic membrane and autologous stem cells had a better immunohistochemical profile than controls, with increased expression of cytokines associated with tissue repair and organization.