Converging pathways in pulmonary fibrosis and Covid-19 - The fibrotic link to disease severity : Common molecular pathways in Covid-19 and pulmonary fibrosis

As Covid-19 affects millions of people worldwide, the global health care will encounter an increasing burden of the aftermaths of the disease. Evidence shows that up to a fifth of the patients develop fibrotic tissue in the lung. The SARS outbreak in the early 2000 resulted in chronic pulmonary fibrosis in a subset (around 4%) of the patients, and correlated to reduced lung function and forced expiratory volume (FEV). The similarities between corona virus infections causing SARS and Covid-19 are striking, except that the novel coronavirus, SARS-CoV-2, has proven to have an even higher communicability. This would translate into a large number of patients seeking care for clinical signs of pulmonary fibrosis, given that the Covid-19 pandemic has up till now (Sept 2020) affected around 30 million people. The SARS-CoV-2 is dependent on binding to the angiotensin converting enzyme 2 (ACE2), which is part of the renin-angiotensin system (RAS). Downregulation of ACE2 upon virus binding disturbs downstream activities of RAS resulting in increased inflammation and development of fibrosis. The poor prognosis and risk of developing pulmonary fibrosis are therefore associated with the increased expression of ACE2 in risk groups, such as obesity, heart disorders and aging, conferring plenty of binding opportunity for the virus and subsequently the internalization of ACE2, thus devoiding the enzyme from acting counter-inflammatory and antifibrotic. Identifying pathways that are associated with Covid-19 severity that result in pulmonary fibrosis may enable early diagnosis and individualized treatment for these patients to prevent or reduce irreversible fibrotic damage to the lung

Glycosaminoglycans: a link between development and regeneration in the lung : a link between development and regeneration in the lung

What can we learn from embryogenesis to increase our understanding of how regeneration of damaged adult lung tissue could be induced in serious lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and asthma? The local tissue niche determines events in both embryogenesis and repair of the adult lung. Important constituents of the niche are extracellular matrix (ECM) molecules including proteoglycans and glycosaminoglycans (GAG). GAGs, strategically located in the pericellular and extracellular space, bind developmentally active growth factors and morphogenes such as fibroblast growth factors (FGF), transforming growth factor- (TGF-) and bone morphogenetic proteins (BMPs) aside from cytokines. These interactions affect activities in many cells, including stem cells, important in development and tissue regeneration. Moreover, it is becoming clear that the "inherent code", such as sulfation of disaccharides of GAGs is a strong determinant of cellular outcome. Sulfation pattern, deacetylations and epimerizations of GAG chains function as tuning forks in gradient formation of morphogens, growth factors and cytokines. Learning to tune these fine instruments, i.e. interactions between growth factors (GF), chemokines and cytokines with the specific disaccharide code of GAGs in the adult lung, could become the key to unlock inherent regenerative forces to override pathological remodeling. This review aims to give an overview of the role GAGs play during development and similar events in regenerative efforts in the adult lung

Pulmonary 5-HT 2B receptor expression in fibrotic interstitial lung diseases.

Pulmonary fibrosis is a severe condition in interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-ILD, where the underlying mechanism is not well defined and with no curative treatments available. Serotonin (5-HT) signaling via the 5-HT 2B receptor has been recognized as a promising preclinical target for fibrosis. Despite this, the involvement of the 5-HT 2B receptor in fibrotic ILD is widely unexplored. This work highlights the spatial pulmonary distribution of the 5-HT 2B receptor in patients with IPF and systemic sclerosis-ILD. We show that the 5-HT 2B receptor is located in typical pathological structures e.g. honeycomb cysts and weakly in fibroblast foci. Together with immunohistochemistry and immunofluorescence stainings of patient derived distal lung tissues, we identified cell targets for 5-HT 2B receptor interference in type II alveolar epithelial cells, endothelial cells and M2 macrophages. Our results emphasize the role of 5-HT 2B receptor as a target in lung fibrosis, warranting further consideration in targeting fibrotic ILDs

Pathological insight into 5-ht2b receptor activation in fibrosing interstitial lung diseases

Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 con-ditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT)2 receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT2B receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT2B receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies

Harnessing the ECM Microenvironment to Ameliorate Mesenchymal Stromal Cell-Based Therapy in Chronic Lung Diseases

It is known that the cell environment such as biomechanical properties and extracellular matrix (ECM) composition dictate cell behaviour including migration, proliferation, and differentiation. Important constituents of the microenvironment, including ECM molecules such as proteoglycans and glycosaminoglycans (GAGs), determine events in both embryogenesis and repair of the adult lung. Mesenchymal stromal/stem cells (MSC) have been shown to have immunomodulatory properties and may be potent actors regulating tissue remodelling and regenerative cell responses upon lung injury. Using MSC in cell-based therapy holds promise for treatment of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, so far clinical trials with MSCs in COPD have not had a significant impact on disease amelioration nor on IPF, where low cell survival rate and pulmonary retention time are major hurdles to overcome. Research shows that the microenvironment has a profound impact on transplanted MSCs. In our studies on acellular lung tissue slices (lung scaffolds) from IPF patients versus healthy individuals, we see a profound effect on cellular activity, where healthy cells cultured in diseased lung scaffolds adapt and produce proteins further promoting a diseased environment, whereas cells on healthy scaffolds sustain a healthy proteomic profile. Therefore, modulating the environmental context for cell-based therapy may be a potent way to improve treatment using MSCs. In this review, we will describe the importance of the microenvironment for cell-based therapy in chronic lung diseases, how MSC-ECM interactions can affect therapeutic output and describe current progress in the field of cell-based therapy

Protein Signatures of Remodeled Airways in Transplanted Lungs with Bronchiolitis Obliterans Syndrome Obtained Using Laser-Capture Microdissection

Bronchiolitis obliterans syndrome (BOS), a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation. The histological correlate is progressive, fibrotic occlusion of small airways, obliterative bronchiolitis lesions, ultimately leading to organ failure. The molecular composition of these lesions is unknown. By laser-capture microdissection and optimized sample preparation protocols for mass spectrometry the protein composition of the lesions in explanted lungs from four end-stage BOS patients were analysed. Immunohistochemistry and immunofluorescence were used to determine the spatial distribution of commonly identified proteins on the tissue level, protein signatures for in total 14 OB-lesions were established. A set of 39 proteins identified in more than 75% of lesions included distinct structural proteins (collagen type IV and VI) and cellular components (actins, vimentin, tryptase). Each respective lesion exhibited a unique composition of proteins (on average n=66 proteins), thereby mirroring the morphological variation of the lesions. Antibody-based staining confirmed these MS-based findings. The 14 analyzed OB-lesions showed variations in their protein content, but also common features. This study provides molecular and morphological insights into the development of chronic rejection after lung transplantation. The protein patterns in the lesions were correlated to pathways of extracellular matrix organization, tissue development and wound healing processes