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Background: Persistent respiratory symptoms and lung abnormalities post‐COVID‐19 are public health problems. This study evaluated biomarkers to stratify high‐risk patients to the development or persistence of post‐COVID‐19 interstitial lung disease. Methods: One hundred eighteen patients discharged with residual lung abnormalities compatible with interstitial lung disease (COVID‐ILD patients) after a severe COVID‐19 were followed for 1 year (post‐COVID‐ILD patients). Physical examination, pulmonary function tests, and chest high‐resolution computed tomography (HRCT) were performed. Soluble forms (s) of PD‐L1, PD‐L2, TIM‐3, and GAL‐9 were evaluated in serum and cell culture supernatant, as well as T‐cells subsets and the transmembrane expression of PD‐L1 and PD‐L2 on the cell surface. Results: Eighty percent of the post‐COVID‐ILD patients normalized their lung function at 1‐year follow‐up, 8% presented COVID‐independent ILD, and 12% still showed functional and HRCT alterations. PD‐L2 levels were heterogeneous during acute COVID‐19 (aCOVID); patients who increased (at least 30%) their sPD‐L2 levels at 1 year post‐COVID‐19 and exhibited altered CD4/CD8 ratio showed persistence of chest tomographic and functional alterations. By contrast, patients who decreased sPD‐L2 displayed a complete lung recovery. sPD‐L1, sTIM‐3, and sGAL‐9 increased significantly during aCOVID and decreased in all patients after 1‐year follow‐up. Conclusion: Increased sPD‐L2 and an altered CD4/CD8 ratio after 12 months of aCOVID are associated with the persistence of lung lesions, suggesting that they may contribute to lung damage post‐COVID‐19. [ABSTRACT FROM AUTHOR]

In severe COVID-19, a rapid deterioration at the pulmonary level may lead to organ dysfunction and even death. Initially, this was attributed to the cytokine storm. However, it has been identified in a murine model that more than the overall action of a broad panel of cytokines could be the synergism between TNF and IFN-γ, which triggers a process of inflammatory cell death. Here, we evaluated the impact of the TNF/IFN-γ axis in COVID-19 patients. A cohort of 138 vaccine naïve COVID-19 patients were classified into four groups (G) according to the plasma level of TNF and IFN-γ (High [H] or Normal-Low [N-L]), as follows: G1: TNFH/IFNH; G2: TNFH/IFN- N-L; G3: TNFN-L/IFN- H; and G4: TNFN-L/IFN- N-L. Apoptosis, cell death, inflammation, and senescence-related proteins were evaluated at transcriptional, soluble levels, or both. According to the patient group, we identify a specific profile of apoptosis and inflammatory-involved proteins. The p21/CDKN1A, a protein impacting the cell cycle and senescence, was increased in G2 and G3. G1 showed a higher level of TNFR1, MLKL, RIPK1, NLRP3, Caspase 1, and HMGB-1. Interestingly, a high percentage of the Gp 1 patients (81 %) had severe COVID-19, and 44 % died. Overall results suggest that an increased level of both cytokines simultaneously promotes the convergence of cell death pathways as pyroptosis, apoptosis, and necroptosis, which may converge in a cell death process called PANoptosis. This could be associated with the severity of the disease and death of patients. Additionally, some events of senescence and cell cycle deregulation could participate. [ABSTRACT FROM AUTHOR]

Telomeres are localized at the end of chromosomes to provide genome stability; however, the telomere length tends to be shortened with each cell division inducing a progressive telomere shortening (TS). In addition to age, other factors, such as exposure to pollutants, diet, stress, and disruptions in the shelterin protein complex or genes associated with telomerase induce TS. This phenomenon favors cellular senescence and genotoxic stress, which increases the risk of the development and progression of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, SARS-CoV-2 infection, and lung cancer. In an infectious environment, immune cells that exhibit TS are associated with severe lymphopenia and death, whereas in a noninfectious context, naïve T cells that exhibit TS are related to cancer progression and enhanced inflammatory processes. In this review, we discuss how TS modifies the function of the immune system cells, making them inefficient in maintaining homeostasis in the lung. Finally, we discuss the advances in drug and gene therapy for lung diseases where TS could be used as a target for future treatments. [ABSTRACT FROM AUTHOR]