Tissue samples from 19 people who died with COVID-19 gave researchers a close look at 91,068 microscopic regions. They found that cell layout and communication changed as damage progressed. Seven patients had acute diffuse alveolar damage, or DAD, and 12 had the proliferative form; the analysis also included control lung tissue. In proliferative DAD, fibrosis-linked signals were stronger even as alveolar repair processes remained active.
The study involved the Institut de Recerca Sant Pau, or IR Sant Pau, in Barcelona and was published in Nature Communications. Manel Esteller led the work. He heads the cancer epigenetics group at IR Sant Pau and is an ICREA researcher. He is also a professor of genetics at the University of Barcelona. Carlos A. García-Prieto and Eva Musulén were the first authors. The Josep Carreras Leukaemia Research Institute and Barcelona Supercomputing Center also took part. DAD is a form of lung injury associated with severe acute respiratory distress syndrome.
Spatial transcriptomics let the team track gene activity while preserving its position in the tissue. Using the Human Lung Cell Atlas as a reference, they identified 45 cell types. Conventional transcriptomic analysis requires tissue to be broken apart so cells can be studied separately. This approach preserved the location of each analysed region, letting researchers examine cell niches and signals exchanged by neighbouring cells across both DAD stages.
Alveolar type 1 cells became less common. They carry out much of the gas exchange between the lungs and blood.
In proliferative DAD, alveolar type 2 cells became more abundant. They can multiply and act as progenitors for type 1 cells after injury. Their increase points to an active repair response amid continuing tissue damage.
The researchers also found fewer capillary endothelial cells. Natural killer cells declined, while some macrophage populations increased. Peribronchial fibroblasts rose particularly sharply, forming distinct niches in the tissue. These cells produce components of the extracellular matrix. Their expansion was associated with the fibrotic response in advanced disease. As Manel Esteller told EFE, severe COVID-19 changes which cells are present and where they are distributed, as well as the signals they exchange.
Cell-to-cell signalling analysis brought the TGF-β pathway into focus. The pathway plays a role in tissue repair, but excessive or persistent activation can contribute to fibrosis. In proliferative DAD, SMAD3 activity increased, while SMAD7, which restrains profibrotic TGF-β/SMAD3 signalling, decreased. TIMP1-CD63 also emerged as a prominent interaction in the profibrotic signature.
The team reconstructed a signalling network in peribronchial fibroblasts. It linked activation of the ITGB1 receptor with changes in SMAD3 and SMAD7. The network also showed activity in ILK and AKT1, with MAP2K4 and MAPK14 involved. Researchers say some of these components could be studied as potential targets for limiting lung fibrosis. The work analysed post-mortem tissue and does not show that blocking TGF-β or any other pathway improves patient outcomes.
Signs of attempted alveolar repair persisted even in advanced disease. By combining gene activity with cell position, the researchers identified different stages in the transition from type 2 to type 1 alveolar cells. Some regions contained cells at intermediate stages; others showed CAV1, a marker of mature type 1 cells. Repair varied across the tissue and could remain incomplete.
Comparisons with eight cases of DAD unrelated to COVID-19 showed different fibroblast patterns. Peribronchial fibroblasts formed niches in proliferative COVID-19, while alveolar fibroblasts predominated in DAD from other causes. Peribronchial fibroblasts also appeared in idiopathic pulmonary fibrosis. Separately, data from more than 1.4 million Human Lung Cell Atlas cells showed that the SMAD3-high and SMAD7-low pattern was particularly associated with COVID-19.
The evidence has limits. Most samples came from people who had died, and the disease stages came from different patients, so the study cannot track progression within one person. Clinical differences between groups also make it difficult to separate infection-specific effects from comorbidities. Disease duration and secondary lung infections are further factors. The biological focus of this research is separate from the housing mobilisation report published earlier by RUSSPAIN.COM.
