Molecular Pathogenesis of Fibrosis, Thrombosis and Surfactant Dysfunction in the Lungs of Severe COVID-19 Patients

Abstract

The global scope and scale of the SARS-CoV-2 pandemic led to huge amounts of important data from clinical observations and experimental analyses being collected, in particular, regarding the long-term impact of COVID-19 on lung tissue. Visible changes in lung tissue mainly relate to the destruction of the alveolar architecture, dense cellularity, and pulmonary fibrosis with myofibroblast proliferation and collagen deposition. These changes are the result of infection, mainly with virus variants from the first pandemic waves (Alpha to Delta). In addition, proper regulation of immune responses to pathogenic viral stimuli is critical for the control of and recovery from tissue/organ damage, including in the lungs. We can distinguish three main processes in the lungs during SARS-CoV-2 infection: damage or deficiency of the pulmonary surfactant, coagulation processes, and fibrosis. Understanding the molecular basis of these processes is extremely important in the context of elucidating all pathologies occurring after virus entry. In the present review, data on the abovementioned three biochemical processes that lead to pathological changes are gathered together and discussed. Systematization of the knowledge is necessary to explore the three key pathways in lung tissue after SARS-CoV-2 virus infection as a result of a prolonged and intense inflammatory process in the context of pulmonary fibrosis, hemostatic disorders, and disturbances in the structure and/or metabolism of the surfactant. Despite the fact that the new Omicron variant does not affect the lungs as much as the previous variants, we cannot ignore the fact that other new mutations and emerging variants will not cause serious damage to the lung tissue. In the future, this review will be helpful to stratify the risk of serious complications in patients, to improve COVID-19 treatment outcomes, and to select those who may develop complications before clinical manifestation.

Role of GM-CSF in lung balance and disease

“…Approximately 80–90% of the lipids are phospholipids, and surfactant-related proteins include SP-A, SP-B, SP-C, and SP-D. These proteins are involved in the intracellular transport of phospholipid components and contribute to the maintenance of surfactant properties in the alveoli ( 48 , 49 ). Surfactant phospholipids and proteins are synthesized and secreted by AT2s ( 50 , 51 ).…”

Molecular mechanisms of COVID-19-induced pulmonary fibrosis and epithelial-mesenchymal transition

“…By cleaving angiotensin 1 (Ang-1), ACE produces Ang-2, which activates a wide range of signaling pathways. ACE2/Ang-(1-7)/MasR axis, as one of the branches of RAS, plays an important role in antiinflammation and anti-fibrosis (Delpino and Quarleri, 2020;Krygier et al, 2022). When SARS-CoV-2 binds to ACE2 receptors on the cell membrane of type II lung cells, ACE2 receptors of host cells undergo endocytosis, which reduces the expression of ACE2 and leads to the ability decrease of the host to balance RAS, thereby inhibiting the activity of ACE2/Ang-(1-7)/ MasR axis, leading to pro-inflammation and pro-fibrosis (Krygier et al, 2022).…”

“…ACE2/Ang-(1-7)/MasR axis, as one of the branches of RAS, plays an important role in antiinflammation and anti-fibrosis (Delpino and Quarleri, 2020;Krygier et al, 2022). When SARS-CoV-2 binds to ACE2 receptors on the cell membrane of type II lung cells, ACE2 receptors of host cells undergo endocytosis, which reduces the expression of ACE2 and leads to the ability decrease of the host to balance RAS, thereby inhibiting the activity of ACE2/Ang-(1-7)/ MasR axis, leading to pro-inflammation and pro-fibrosis (Krygier et al, 2022). The former mainly includes the activation of IL-6 and TNF-α as well as the increased recruitment of neutrophils and macrophages, while the latter mainly involves two key factors, MAPK/ERK and TGF-β (Vianello et al, 2022).…”

“…In severe cases, it can lead to lung tissue remodeling and PF (Schmitt et al, 2022). In detail, after virus entry into the epithelial cells of the respiratory tract, Th-1 are activated, which stimulate the production of proinflammatory cytokines such as GM-CSF and IL-6 (Krygier et al, 2022). In response to GM-CSF stimulation, monocytes produce a large number of cytokines such as IL-1β, IL-6, IL-7, IL-8, IL-9, IL-10, and TNFα, which is called cytokine storm (Hu et al, 2021;Vianello et al, 2022).…”

Exhaled breath condensate contains extracellular vesicles (EVs) that carry miRNA cargos of lung tissue origin that can be selectively purified and analyzed

“…Contrarily to the terminal bronchioles, the alveoli are only composed of two types of cells, the alveolar type I cells that are involved in gas exchange and the alveolar type II cells that are progenitors of type I cells but that produce all pulmonary surfactant, whose purpose is to reduce the air‐liquid surface tension to enhance gas exchange and to actively contribute to the immune defense of the lungs (Whitsett et al., 2010 ). The surfactant Protein C (SFTPC) is one of these molecules and it is uniquely produced by alveolar type II cells (Krygier et al., 2022 ; Leibel et al., 2019 ). Although the exact cellular origin of lung cancer initiating cells remains unknown, both Clara cells and alveolar type II cells have been experimentally implicated in the initiation of lung adenocarcinoma (Dermer, 1982 ; Jackson et al., 2001 ; Xu et al., 2012 ).…”