Post-COVID19 Lung Fibrosis: An Worrying Experience of COVID19 Survivors

Patients recovering from confirmed COVID19 particularly moderate to severe disease, those treated in HDU / ICU support with high flow nasal cannula & Mechanical ventilation ,experienced different symptoms ranging from tiredness, fatigue to severe exertional dyspnea. High resolution CT scan of Chest of these such patients showed persistent radiological abnormalities simulating progressive fibrotic lung disease. Lung function including CO transfer factor revealed moderate to severe reduction. In case of patients recovered from moderate to severe COVID19 pneumonia, lung fibrosis is a big problem and it is one of the most worrying long-term complications. Lung fibrosis was documented in previous Severe Acute Respiratory Syndrome & Middle east Respiratory Syndrome pathology, and current observational studies suggests that pulmonary fibrosis could also complicate infection by SARSCOV2. The objective of our study was to set up a criteria of patients who are at risk to develop such serious complication, thus giving a chance for early detection of post-COVID19 lung fibrosis and thus preventing such disabling complication by proper andearly intervention . Bangladesh J Medicine July 2022; 33(1) : 114-119

Matricellular Protein Periostin Promotes Pericyte Migration in Fibrotic Airways

Introduction: Periostin is a matricellular protein that is currently used as a biomarker for asthma. However, its contribution to tissue remodeling in allergic asthma is currently unknown. We have previously demonstrated that tissue-resident mesenchymal stem cells known as pericytes are a key cell type involved in airway remodeling. This is thought to be caused the uncoupling of pericytes from the microvasculature supporting the large airways, facilitated by inflammatory growth factors and cytokines. It is hypothesized that periostin may be produced by profibrotic pericytes and contribute to the remodeling observed in allergic asthma.Methods: Lung sections from mice with allergic airway disease driven by exposure to house dust mite (HDM) were stained using an anti-periostin antibody to explore its involvement in fibrotic lung disease. Human pericytes were cultured in vitro and stained for periostin to assess periostin expression. Migration assays were performed using human pericytes that were pretreated with TGF-β or periostin. ELISAs were also carried out to assess periostin expression levels in bronchoalveolar lavage fluid as well as the induction of periostin production by IL-13.Results: Immunostaining indicated that pericytes robustly express periostin, with increased expression following treatment with TGF-β. Migration assays demonstrated that pericytes treated with periostin were more migratory. Periostin production was also increased in HDM exposed mice as well as in cultured pericytes treated with IL-13.Conclusion: Periostin is produced by pericytes in response to TGF-β or IL-13, and periostin plays a key role in inducing pericyte migration. The increase in periostin expression in TGF-β or IL-13 treated pericytes suggests that IL-13 may trigger periostin production in pericytes whilst TGF-β modulates periostin expression to promote pericyte migration in the context of tissue fibrosis.

Reversibility of clinical and computed tomographic lesions mimicking pulmonary fibrosis in a young cat

Background In humans with idiopathic pulmonary fibrosis (IPF), specific thoracic computed tomographic (CT) features in the correct clinical context may be used in lieu of histologic examination. Cats develop an IPF-like condition with similar features to humans. As few cats have invasive lung biopsies, CT has appeal as a surrogate diagnostic, showing features consistent with architectural remodeling supporting “end-stage lung”. Case presentation A 1-year-old female spayed Domestic Shorthair cat presenting with progressive respiratory clinical signs and thoracic CT changes (reticular pattern, parenchymal bands, subpleural interstitial thickening, pleural fissure thickening, subpleural lines and regions of increased attenuation with traction bronchiectasis and architectural distortion) consistent with reports of IPF was given a grave prognosis for long-term survival. The cat was treated with prednisolone, fenbendazole, pradofloxacin and clindamycin. Five months later, while still receiving an anti-inflammatory dose of prednisolone, the cat was re-evaluated with owner-reported absent respiratory clinical signs. Thoracic CT demonstrated resolution of lung patterns consistent with fibrosis. Conclusions Fibrotic lung disease is irreversible. Despite this cat having compatible progressive respiratory signs and associated lung patterns on thoracic CT scan, these abnormalities resolved with non-specific therapy and time, negating the possibility of IPF. While the cause of the distinct CT lesions that ultimately resolved was not determined, infection was suspected. Experimental Toxocara cati infection shows overlapping CT features as this cat and is considered a treatable disease. Improvement of CT lesions months after experimental heartworm-associated respiratory disease in cats has been documented. Reversibility of lesions suggests inflammation rather than fibrosis was the cause of the thoracic CT lesions. This cat serves as a lesson that although thoracic CT has been advocated as a surrogate for histopathology in people with IPF, additional studies in cats are needed to integrate CT findings with signalment, other clinicopathologic features and therapeutic response before providing a diagnosis or prognosis of fibrotic lung disease.

Involvement of the ACE2/Ang-(1–7)/MasR Axis in Pulmonary Fibrosis: Implications for COVID-19

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.

Bimodal fibrosis in a novel mouse model of bleomycin-induced usual interstitial pneumonia

Idiopathic pulmonary fibrosis is pathologically represented by usual interstitial pneumonia (UIP). Conventional bleomycin models used to study pathogenic mechanisms of pulmonary fibrosis display transient inflammation and fibrosis, so their relevance to UIP is limited. We developed a novel chronic induced-UIP (iUIP) model, inducing fibrosis in D1CC×D1BC transgenic mice by intra-tracheal instillation of bleomycin mixed with microbubbles followed by sonoporation (BMS). A bimodal fibrotic lung disease was observed over 14 wk, with an acute phase similar to nonspecific interstitial pneumonia (NSIP), followed by partial remission and a chronic fibrotic phase with honeycombing similar to UIP. In this secondary phase, we observed poor vascularization despite elevated PDGFRβ expression. γ2PF- and MMP7-positive epithelial cells, consistent with an invasive phenotype, were predominantly adjacent to fibrotic areas. Most invasive cells were Scgb1a1 and/or Krt5 positive. This iUIP mouse model displays key features of idiopathic pulmonary fibrosis and has identified potential mechanisms contributing to the onset of NSIP and progression to UIP. The model will provide a useful tool for the assessment of therapeutic interventions to oppose acute and chronic fibrosis.

Monocyte and neutrophil levels are potentially linked to progression to IPF for patients with indeterminate UIP CT pattern

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Identifying patients early may allow intervention which could limit progression. The ‘indeterminate for usual interstitial pneumonia’ (iUIP) CT pattern, defined in the 2018 IPF guidelines, could be a precursor to IPF but there is limited data on how patients with iUIP progress over time.ObjectiveTo evaluate the radiological progression of iUIP and explore factors linked to progression to IPF.MethodsWe performed a retrospective analysis of a lung fibrosis clinic cohort (n=230) seen between 2013 and 2017. Cases with iUIP were identified; first ever CTs for each patient found and categorised as 'non-progressor' or 'progressors' (the latter defined as increase in extent of disease or to 'definite' or 'probable' UIP CT pattern) during their follow-up. Lung function trends, haematological data and patient demographics were examined to explore disease evolution and potential contribution to progression.Results48 cases with iUIP CT pattern were identified. Of these, 32 had follow-up CT scans, of which 23 demonstrated progression. 17 patients in this cohort were diagnosed with IPF over a mean (SD) period of 3.9 (±1.9) years. Monocyte (HR: 23, 95% CI: 1.6 to 340, p=0.03) and neutrophil levels (HR: 1.8, 95% CI: 1.3 to 2.3, p<0.001), obtained around the time of initial CT, were associated with progression to IPF using Cox proportional hazard modelling.Conclusion53% of our evaluable patients with iUIP progressed to IPF over a mean of 4 years. Monocyte and neutrophil levels at initial CT were significantly associated with progression in disease. These data provide a single-centre analysis of the evolution of patients with iUIP CT pattern, and first signal for potential factors associated with progression to IPF.

Development of fibrosis and impairment of lung function in patients with a new coronavirus disease

The aim: review scientific research to find out whether the new coronavirus infection (NCI) causes fibrotic changes in the lungs and, if any, how long they persist and whether functional disorders of the respiratory system accompany them. Disruption of the functional state of the lungs in patients with severe novel coronavirus disease (COVID-19) is still seen 6 months after completion of inpatient treatment. High-resolution computed tomography (HRCT) demonstrates persistent pathological changes in the lungs, some of which are fibrosis-like. Pathomorphological features of the COVID-19 course, as well as the ability of the virus to activate connective tissue growth factor (CTGF) and enhance the signaling of transforming growth factor-beta (TGF-β), can contribute to lung tissue fibrosis. Increased titers of antinuclear autoantibodies and specific autoantibodies indirectly reveal dysregulation of the immune response leading to the progression of organizing pneumonia and fibrotic changes in the lung tissue. These increased titers can also indicate the need to prescribe immunosuppressive and antifibrotic drugs. Researchers are considering the possibility of including antifibrotic drugs in combination therapy for severe COVID-19 in the early stages of treatment in patients with risk factors for developing pulmonary fibrosis. However, further monitoring and determination of the role of antifibrotic drugs are required. Sometimes patients with COVID-19 develop severe, irreversible fibrotic lung disease, and lung transplantation is the only treatment option.Conclusion. There is no unequivocal opinion among researchers concerning the clinical significance and further prognosis of COVID-19 so far, which is a reason for further studies.

Nestin promotes pulmonary fibrosis via facilitating recycling of TGF-β receptor I

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is characterised by aberrant proliferation of activated myofibroblasts and pathological remodelling of the extracellular matrix. Previous studies have revealed that the intermediate filament protein Nestin plays key roles in tissue regeneration and wound healing in different organs. Whether Nestin plays a critical role in the pathogenesis of IPF needs to be clarified.Nestin expression in lung tissues from bleomycin-treated mice and IPF patients was determined. Transfection with Nestin shRNA vectors in vitro that regulated TGF-β/Smad signalling was conducted. Biotinylation assays to observe plasma membrane TβRI, TβRI endocytosis and TβRI recycling after Nestin knockdown were performed. Adeno-associated virus serotype 6 (AAV6)-mediated Nestin knockdown was assessed in vivo.We found that Nestin expression was increased in a murine pulmonary fibrosis model and IPF patients, and that the upregulated protein primarily localised in lung α-SMA+ myofibroblasts. Mechanistically, we determined that Nestin knockdown inhibited TGF-β signalling by suppressing recycling of TβRI to the cell surface and that Rab11 was required for the ability of Nestin to promote TβRI recycling. In vivo, we found that intratracheal administration of adeno-associated virus serotype 6 (AAV6)-mediated Nestin knockdown significantly alleviated pulmonary fibrosis in multiple experimental mice models.In conclusion, our findings reveal a pro-fibrotic function of Nestin partially through facilitating Rab11-dependent recycling of TβRI and shed new light on pulmonary fibrosis treatment.