The Role of Pulmonary Surfactant Phospholipids in Fibrotic Lung Diseases.

Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress to fibrosis. Within this group of pneumonias, idiopathic pulmonary fibrosis (IPF) is considered the most common. This disease has no known cause, is devastating and has no cure. Chronic lesion of alveolar type II (ATII) cells represents a key mechanism for the development of IPF. ATII cells are specialized in the biosynthesis and secretion of pulmonary surfactant (PS), a lipid-protein complex that reduces surface tension and minimizes breathing effort. Some differences in PS composition have been reported between patients with idiopathic pulmonary disease and healthy individuals, especially regarding some specific proteins in the PS; however, few reports have been conducted on the lipid components. This review focuses on the mechanisms by which phospholipids (PLs) could be involved in the development of the fibroproliferative response.

Bioinformatics-based investigation on the genetic influence between SARS-CoV-2 infections and idiopathic pulmonary fibrosis (IPF) diseases, and drug repurposing.

Some recent studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other through the shared genes. Therefore, in this study, an attempt was made to explore common genomic biomarkers for SARS-CoV-2 infections and IPF disease highlighting their functions, pathways, regulators and associated drug molecules. At first, we identified 32 statistically significant common differentially expressed genes (cDEGs) between disease (SARS-CoV-2 and IPF) and control samples of RNA-Seq profiles by using a statistical r-package (edgeR). Then we detected 10 cDEGs (CXCR4, TNFAIP3, VCAM1, NLRP3, TNFAIP6, SELE, MX2, IRF4, UBD and CH25H) out of 32 as the common hub genes (cHubGs) by the protein-protein interaction (PPI) network analysis. The cHubGs regulatory network analysis detected few key TFs-proteins and miRNAs as the transcriptional and post-transcriptional regulators of cHubGs. The cDEGs-set enrichment analysis identified some crucial SARS-CoV-2 and IPF causing common molecular mechanisms including biological processes, molecular functions, cellular components and signaling pathways. Then, we suggested the cHubGs-guided top-ranked 10 candidate drug molecules (Tegobuvir, Nilotinib, Digoxin, Proscillaridin, Simeprevir, Sorafenib, Torin 2, Rapamycin, Vancomycin and Hesperidin) for the treatment against SARS-CoV-2 infections with IFP diseases as comorbidity. Finally, we investigated the resistance performance of our proposed drug molecules compare to the already published molecules, against the state-of-the-art alternatives publicly available top-ranked independent receptors by molecular docking analysis. Molecular docking results suggested that our proposed drug molecules would be more effective compare to the already published drug molecules. Thus, the findings of this study might be played a vital role for diagnosis and therapies of SARS-CoV-2 infections with IPF disease as comorbidity risk.

Thalidomide interaction with inflammation in idiopathic pulmonary fibrosis.

The "Thalidomide tragedy" is a landmark in the history of the pharmaceutical industry. Despite limited clinical trials, there is a continuous effort to investigate thalidomide as a drug for cancer and inflammatory diseases such as rheumatoid arthritis, lepromatous leprosy, and COVID-19. This review focuses on the possibilities of targeting inflammation by repurposing thalidomide for the treatment of idiopathic pulmonary fibrosis (IPF). Articles were searched from the Scopus database, sorted, and selected articles were reviewed. The content includes the proven mechanisms of action of thalidomide relevant to IPF. Inflammation, oxidative stress, and epigenetic mechanisms are major pathogenic factors in IPF. Transforming growth factor-ß (TGF-ß) is the major biomarker of IPF. Thalidomide is an effective anti-inflammatory drug in inhibiting TGF-ß, interleukins (IL-6 and IL-1ß), and tumour necrosis factor-α (TNF-α). Thalidomide binds cereblon, a process that is involved in the proposed mechanism in specific cancers such as breast cancer, colon cancer, multiple myeloma, and lung cancer. Cereblon is involved in activating AMP-activated protein kinase (AMPK)-TGF-ß/Smad signalling, thereby attenuating fibrosis. The past few years have witnessed an improvement in the identification of biomarkers and diagnostic technologies in respiratory diseases, partly because of the COVID-19 pandemic. Hence, investment in clinical trials with a systematic plan can help repurpose thalidomide for pulmonary fibrosis.

Developing PI3K Inhibitors for Respiratory Diseases.

A number of different experimental models using both non-selective and selective PI3K inhibitors have shown that many pathogenic steps of respiratory disorders, such as bronchial asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF), Acute Respiratory Distress Syndrome (ARDS) and Lung Cancer (LC) are, at least in part, regulated by the PI3K signaling pathway, suggesting that the inhibition of PI3K could represent an ideal therapeutic target for the treatment of respiratory diseases. This chapter summarizes the current state of the therapeutic strategies aimed to exploit the inhibition of PI3K in this context. In animal models of asthma, selective δ and γ inhibitors have shown to be effective, and when administered by inhalation, reasonably safe. Nevertheless, very few clinical trials have been performed so far. The efficacy of current traditional therapies for allergic bronchial asthma has likely diminished the need for new alternative treatments. Surprisingly, in COPD, where instead there is an urgent need for new and more effective therapeutic approaches, the number of clinical studies is still low and not capable yet, with the exception for an acceptable safety profile, to show a significant improvement of clinical outcomes. In IPF, a disease with a disappointing prognosis, PI3K inhibitors have been bound to a FAP ligand with the aim to selectively target myofibroblasts, showing to significantly reduce collagen production and the development of lung fibrosis in an animal model of lung fibrosis. Due to its role in cell activation and cell replication, the PI3K pathway is obviously largely involved in lung cancer. Several studies, currently ongoing, are testing the effect of PI3K inhibitors mainly in NSCLC. Some evidence in the treatment of cancer patients suggests the possibility that PI3K inhibitors may enhance the response to conventional treatment. The involvement of PI3Kδ in the modulation of airway neutrophil recruitment and bronchial epithelial functional alterations also suggest a potential role in the treatment of ARDS, but at the current state the ongoing trials are aimed to the treatment of ARDS in COVID-19 patients. In general, few clinical trials investigating PI3K inhibitors in respiratory disorders have been performed so far. This relatively new approach of treatment is just at its beginning and certainly needs further efforts and additional studies.

Real-Time Measurement of Cell Mechanics as a Clinically Relevant Readout of an In Vitro Lung Fibrosis Model Established on a Bioinspired Basement Membrane.

Lung fibrosis, one of the major post-COVID complications, is a progressive and ultimately fatal disease without a cure. Here, an organ- and disease-specific in vitro mini-lung fibrosis model equipped with noninvasive real-time monitoring of cell mechanics is introduced as a functional readout. To establish an intricate multiculture model under physiologic conditions, a biomimetic ultrathin basement (biphasic elastic thin for air-liquid culture conditions, BETA) membrane (<1 µm) is developed with unique properties, including biocompatibility, permeability, and high elasticity (<10 kPa) for cell culturing under air-liquid interface and cyclic mechanical stretch conditions. The human-based triple coculture fibrosis model, which includes epithelial and endothelial cell lines combined with primary fibroblasts from idiopathic pulmonary fibrosis patients established on the BETA membrane, is integrated into a millifluidic bioreactor system (cyclic in vitro cell-stretch, CIVIC) with dose-controlled aerosolized drug delivery, mimicking inhalation therapy. The real-time measurement of cell/tissue stiffness (and compliance) is shown as a clinical biomarker of the progression/attenuation of fibrosis upon drug treatment, which is confirmed for inhaled Nintedanib-an antifibrosis drug. The mini-lung fibrosis model allows the combined longitudinal testing of pharmacodynamics and pharmacokinetics of drugs, which is expected to enhance the predictive capacity of preclinical models and hence facilitate the development of approved therapies for lung fibrosis.

Nintedanib vs pirfenidone in the management of COVID-19 lung fibrosis: A single-centre study.

BACKGROUND: COVID-19 pneumonia is complicated with residual lung fibrosis, as evidenced by imaging and postmortem pathological findings. In addition to steroids, we compared the efficacy of nintedanib and pirfenidone in the management of COVID-19 lung fibrosis measured by CT severity score (CTSS). METHODS: All cases of COVID-19 pneumonia diagnosed as COVID-19 positive by RT-PCR having SpO2 ⩽ 96% and CTSS ⩾ 10 even after 15 days were included in the study. The patients were divided into three groups. All three groups received steroids at a dose of 1 mg/kg body weight of prednisolone or equivalent. The first group received steroids alone, the second group received pirfenidone with steroids and the third group received nintedanib with steroids. All patients were followed up at 6 and 12 weeks. The primary endpoint of our study was to find out any improvement in CTSS. RESULTS: Out of 90 patients, 56 patients completed the study. Among three groups, 19 (33.9%) patients received steroids (control) only, 16 (28.6%) patients received steroids with pirfenidone and 21 (37.5%) patients received steroids with nintedanib. The study population had a mean (±SD) age of 52.5 ± 10.1 years, mean (±SD) C-reactive protein of 97.1 ± 102.2 mg/L (normal <6 mg/L), mean (±SD) serum ferritin 459.4 ± 305.5 ng/mL (normal <250 ng/mL), mean (±SD) serum d-dimer level 2.1 ± 2.6 µg/mL (normal <0.5 µg/mL) and mean (±SD) CTSS of 16.9 ± 4.3. There was significant improvement in CTSS in group receiving nintedanib compared to pirfenidone at 12 weeks (3.67 ± 1.21 vs 9.07 ± 1.12) with a p-value <0.01. CONCLUSION: Along with steroids in the treatment of COVID-19 lung fibrosis, there was a significant improvement in lung CTSS with nintedanib compared to pirfenidone.

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis.

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.

Phase 2B Study of Inhaled RVT-1601 for Chronic Cough in Idiopathic Pulmonary Fibrosis: A Multicenter, Randomized, Placebo-controlled Study (SCENIC Trial).

Rationale: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2A study, inhaled RVT-1601 (cromolyn sodium) reduced daytime cough and 24-hour average cough counts in patients with IPF. Objectives: To determine the efficacy, safety, and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF. Methods: In this multicenter, randomized, placebo-controlled phase 2B study, patients with IPF and chronic cough for ⩾8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough-specific quality of life. Safety was monitored throughout the study. Measurements and Main Results: The study was prematurely terminated owing to the impact of the coronavirus disease (COVID-19) pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-square mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and the placebo group. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated. Conclusions: Treatment with inhaled RVT-1601 (10, 40, and 80 mg three times a day) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF.

The impact of SARS-COV2 pandemic on the management oF IPF patients: Our narrative experience.

BACKGROUND: The SARS-CoV-2 pandemic has changed the health-care systems around the world in a remarkable way. We describe the strategies adopted to cope with the limitations imposed by the pandemic to the access to health care by patients diagnosed with idiopathic Pulmonary Fibrosis (IPF). MATERIAL AND METHODS: We conducted a retrospective observational analysis including IPF patients under antifibrotic drugs (nintedanib and pirfenidone) that accessed to the Outpatient clinic of the University of Palermo, Italy. Patients received a phone number and an email address in case of any urgency and a virtual meeting was settled up monthly. RESULTS: 40 patients (M/F: 30/10) were followed up, 33 under nintedanib treatment, 7 under pirfenidone. Among patients under nintedanib, 1 patient reported high fever (T max 39 °C) and purulent sputum with no sign of infections, 1 had hemoptysis that was spontaneously resolved. 2 patients accessed to the emergency department for the worsening of dyspnea; 5 patients had diarrhea that resolved with symptomatic drugs in few days. 3 patients had an increase of alkaline phosphatase levels, leading to the withdrawal of the antifibrotic drug for 15 days, and subsequent normalization of the plasmatic levels. Among patients under pirfenidone, one subject had an increase of ferritin serum levels with no symptoms. The remaining subjects were in stable clinical conditions. None of the patients reported hospitalization or exacerbations, and did not experience antifibrotic withdrawal. CONCLUSIONS: We were able to demonstrate that by implementing alternative ways to monitor the disease, patients did not incur in increased rates of acute exacerbations or higher frequency of side effects and antifibrotic treatment withdrawal.

Successful Treatment with High-dose Steroids for Acute Exacerbation of Idiopathic Pulmonary Fibrosis Triggered by COVID-19.

We herein report a case of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) triggered by COVID-19. An 87-year-old woman tested positive for COVID-19 on a polymerase chain reaction test, and computed tomography revealed ground-glass opacity (GGO) superimposed on a background pattern consistent with usual interstitial pneumonia. Considering these data, we diagnosed her with AE-IPF. She experienced worsening of dyspnea and expansion of the GGO. Therefore, we introduced high-dose steroids (methylprednisolone 250 mg/day for 3 days). After the treatment, the pulmonary infiltrates improved. She was discharged from our hospital without severe disability. High-dose steroids can be a viable treatment option for AE-IPF triggered by COVID-19.

Identification of hub genes associated with COVID-19 and idiopathic pulmonary fibrosis by integrated bioinformatics analysis.

INTRODUCTION: The coronavirus disease 2019 (COVID-19), emerged in late 2019, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The risk factors for idiopathic pulmonary fibrosis (IPF) and COVID-19 are reported to be common. This study aimed to determine the potential role of differentially expressed genes (DEGs) common in IPF and COVID-19. MATERIALS AND METHODS: Based on GEO database, we obtained DEGs from one SARS-CoV-2 dataset and five IPF datasets. A series of enrichment analysis were performed to identify the function of upregulated and downregulated DEGs, respectively. Two plugins in Cytoscape, Cytohubba and MCODE, were utilized to identify hub genes after a protein-protein interaction (PPI) network. Finally, candidate drugs were predicted to target the upregulated DEGs. RESULTS: A total of 188 DEGs were found between COVID-19 and IPF, out of which 117 were upregulated and 71 were downregulated. The upregulated DEGs were involved in cytokine function, while downregulated DEGs were associated with extracellular matrix disassembly. Twenty-two hub genes were upregulated in COVID-19 and IPF, for which 155 candidate drugs were predicted (adj.P.value < 0.01). CONCLUSION: Identifying the hub genes aberrantly regulated in both COVID-19 and IPF may enable development of molecules, encoded by those genes, as therapeutic targets for preventing IPF progression and SARS-CoV-2 infections.

Early experience of nintedanib in COVID-19 ARDS-related pulmonary fibrosis: a case series.

The current COVID-19 pandemic has spread like wildfire worldwide and has affected millions of people. The novel corona virus mainly affects the lungs leading to life threatening disease like acute respiratory distress syndrome (ARDS). The aftermath of the disease in form of pulmonary fibrosis is upcoming cause of further increase in morbidity and mortality. Nintedanib is an oral antifibrotics with proven role in idiopathic pulmonary fibrosis, however its use in COVID-19 related pulmonary fibrosis has not been studied. We report our early experience of use of nintedanib in COVID-19 related pulmonary fibrosis.

Comparison of pirfenidone and corticosteroid treatments at the COVID-19 pneumonia with the guide of artificial intelligence supported thoracic computed tomography.

AIM: We aimed to investigate the effect of short-term pirfenidone treatment on prolonged COVID-19 pneumonia. METHOD: Hospital files of patients hospitalised with a diagnosis of critical COVID-19 pneumonia from November 2020 to March 2021 were retrospectively reviewed. Chest computed tomography images taken both before treatment and 2 months after treatment, demographic characteristics and laboratory parameters of patients receiving pirfenidone + methylprednisolone (n = 13) and only methylprednisolones (n = 9) were recorded. Pulmonary function tests were performed after the second month of the treatment. CT involvement rates were determined by machine learning. RESULTS: A total of 22 patients, 13 of whom (59.1%) were using methylprednisolone + pirfenidone and 9 of whom (40.9%) were using only methylprednisolone were included. When the blood gas parameters and pulmonary function tests of the patients were compared at the end of the second month, it was found that the FEV1, FEV1%, FVC and FVC% values were statistically significantly higher in the methylprednisolone + pirfenidone group compared with the methylprednisolone group (P = .025, P = .012, P = .026 and P = .017, respectively). When the rates of change in CT scans at diagnosis and second month of treatment were examined, it was found that the involvement rates in the methylprednisolone + pirfenidone group were statistically significantly decreased (P < .001). CONCLUSION: Antifibrotic agents can reduce fibrosis that may develop in the future. These can also help dose reduction and/or non-use strategy for methylprednisolone therapy, which has many side effects. Further large series and randomised controlled studies are needed on this subject.

Therapeutic Rationale for Endotoxin Removal with Polymyxin B Immobilized Fiber Column (PMX) for Septic Shock.

Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicenter, randomized and controlled trial. Following the findings derived from a large sepsis clinical trial with PMX in North America, a new trial is ongoing to determine if PMX has a long-term survival benefit when administered to septic patients. Another approach to support a survival benefit from intervention with PMX is to utilize a detailed analysis available from a large clinical data base. The endotoxin adsorption capacity of PMX columns in vitro and the effectiveness of PMX columns can be further demonstrable in animal models. The capability of PMX and details of its mechanism of action to intervene in the sepsis cascade and impede organ dysfunction in septic patients is not fully understood. The surface antigen expression in monocytes and neutrophils are improved after PMX therapy. Immunomodulatory effects as a result of endotoxin removal and/or other mechanisms of action have been suggested. These effects and other potential immune effects may explain some of the improved effects upon organ dysfunction of sepsis and septic shock patients. Endotoxemia may be involved in the pathophysiology of other diseases than sepsis. A rapid diagnostic method to detect and target endotoxemia could allow us to practice precision medicine and expand the clinical indications of endotoxin removal therapy.

Effects of the COVID-19 pandemic on the follow-up and treatment of patients with idiopathic pulmonary fibrosis: a cross-sectional, multicentre phone call survey.

OBJECTIVE: To learn about the attitudes and behaviours of patients with idiopathic pulmonary fibrosis (IPF) in relation to the difficulties experienced during the COVID-19 pandemic. DESIGN: A cross-sectional, multicentre phone call survey. SETTING: Four university hospitals in Turkey. PARTICIPANTS: The study included patients with IPF receiving antifibrotics for at least 3 months and with doctor appointment and/or scheduled routine blood analysis between March and May 2020 (the first 3 months after the official announcement of the COVID-19 pandemic in Turkey). INTERVENTIONS: Phone calls (a 5 min interview) were performed in June 2020. A questionnaire and the Hospital Anxiety-Depression Scale were applied. MAIN OUTCOME MEASURES: Patients' preferences for disease monitoring, patients' attitudes and behaviours towards IPF, drug continuation, COVID-19 diagnosis and anxiety/depression status. RESULTS: The study included 115 patients with IPF (82 male; mean age, 68.43±7.44 years). Of the patients, 73.9% had doctor appointment and 52.2% had scheduled routine blood testing; 54.5% of patients with doctor appointment self-cancelled their appointments and 53.3% of patients with scheduled routine blood testing did not undergo testing. Of the patients, 32.2% were on nintedanib and 67.8% were on pirfenidone; self-initiated drug discontinuation rate was 22.6%. The percentage of patients communicating with their physicians was 35.7%. The route of communication was by phone (34.8%). The frequency of depression and anxiety was 27.0% and 38.3%, respectively. The rates of drug discontinuation (35.1% vs 16.7%, p<0.05) and depression (37.8% vs 21.8%, p=0.07) were higher in nintedanib users than in pirfenidone users. Only two (1.7%) patients had COVID-19 diagnosis. CONCLUSIONS: During the COVID-19 pandemic, a significant proportion (>50%) of patients self-cancelled their appointments and nearly a quarter of patients discontinued their medications. Providing a documentation of the problems experienced by patients with IPF about management of the necessary requirements during the COVID-19 pandemic, this study may be a model for patients with chronic diseases.

Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial.

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. Objective: To assess the effect of antimicrobial therapy on clinical outcomes. Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group. Main Outcomes and Measures: The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. Results: Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%). Conclusions and Relevance: Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02759120.

Therapeutic targets in lung tissue remodelling and fibrosis.

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-ß induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.