| Summary: |
Interstitial lung diseases (ILDs) comprise a heterogeneous group of diffuse parenchymal lung disorders, characterized by the infiltration of immune effector cells, fibroblasts,
myofibroblasts and extracellular matrix deposition. ILDs alter the normal respiratory physiology, eventually leading to disability and death. Some ILDs, such as idiopathic pulmonary
fibrosis (IPF), are primarily considered fibroproliferative disorders and associate to a dismal prognosis with median survival of only 2-5 years from diagnosis. Non-IPF ILDs show a
combination of inflammatory and self-sustained fibrotic processes, that may continue to progress in severity despite standard treatment with immunomodulatory drugs. These
disorders have been collectively named as progressive fibrosing ILDs (PF-ILDs), and are associated with high morbidity and mortality. A larger extent of fibrosis on high-resolution
computed tomography scans and greater decline in lung function are predictors of mortality, but the course of disease for an individual patient cannot be accurately predicted using
the currently available tools, which represents an unmet medical need.
PF-ILDs are multifactorial diseases, which involve complex interactions between host genetics and different environmental triggers, shaping the immune milieu that ultimately drives
the fibrotic cascade in a susceptible patient. Most research has been focused in IPF and has unveiled both genomic variants of risk and specific transcriptional signatures associated
with accelerated clinical course. In addition, advances in molecular sequencing technology allowed the study of the patient's microbiota composition in lung fibrosis pathology. Again,
greater evidence exists in IPF, in which an increased bacterial burden and/or abundance of potentially pathogenic bacteria may induce disease progression, acute exacerbations, and
mortality. Interestingly, recent findings highlight an interaction between the genetic background of the pat  |
Summary
Interstitial lung diseases (ILDs) comprise a heterogeneous group of diffuse parenchymal lung disorders, characterized by the infiltration of immune effector cells, fibroblasts,
myofibroblasts and extracellular matrix deposition. ILDs alter the normal respiratory physiology, eventually leading to disability and death. Some ILDs, such as idiopathic pulmonary
fibrosis (IPF), are primarily considered fibroproliferative disorders and associate to a dismal prognosis with median survival of only 2-5 years from diagnosis. Non-IPF ILDs show a
combination of inflammatory and self-sustained fibrotic processes, that may continue to progress in severity despite standard treatment with immunomodulatory drugs. These
disorders have been collectively named as progressive fibrosing ILDs (PF-ILDs), and are associated with high morbidity and mortality. A larger extent of fibrosis on high-resolution
computed tomography scans and greater decline in lung function are predictors of mortality, but the course of disease for an individual patient cannot be accurately predicted using
the currently available tools, which represents an unmet medical need.
PF-ILDs are multifactorial diseases, which involve complex interactions between host genetics and different environmental triggers, shaping the immune milieu that ultimately drives
the fibrotic cascade in a susceptible patient. Most research has been focused in IPF and has unveiled both genomic variants of risk and specific transcriptional signatures associated
with accelerated clinical course. In addition, advances in molecular sequencing technology allowed the study of the patient's microbiota composition in lung fibrosis pathology. Again,
greater evidence exists in IPF, in which an increased bacterial burden and/or abundance of potentially pathogenic bacteria may induce disease progression, acute exacerbations, and
mortality. Interestingly, recent findings highlight an interaction between the genetic background of the patient and the lung microbiome. In IPF patients, bacterial burden was
associated with a polymorphism in the promoter of the mucin gene MUC5B, which is a proven host susceptibility factor for lung fibrosis. Another genomic marker, the intronic TOLLIP
variant, was correlated to IPF mortality, and a possible link with microbial pathogens exists, given its role at regulating the innate immune responses mediated through toll-like
receptors (TLRs). For instance, TLR9 is overrepresented in lungs of IPF patients with rapidly progressive disease and its expression was positively correlated with Staphylococcal
OTU1348, suggesting that TLR9 signaling may depend on lung microbial communities. In fact, a combined analysis of the host transcriptome and microbial signatures demonstrated
that genes related to host defense response are upregulated in subjects with altered or more abundant microbiome. This overexpression is maintained overtime in subjects
experiencing disease progression, suggesting that the bacterial communities of the lower airways may induce persistent alveolar injury in IPF. However, as compared to IPF, our
knowledge on the molecular events underlying other PF-ILDs is minimal, calling for a deeper study of these pathologies.
The current proposal, FIBRA-Lung, aims at filling this void by establishing the first portuguese registry of PF-ILDs, enabling us to study their relative frequency in the region, and to
explore the molecular determinants of clinical outcomes, acute exacerbations and mortality. Furthermore, through the parallel creation of a biobank of peripheral blood,
bronchoalveolar lavage, pharyngeal swabs and lung tissue, we will analyze the interactions between host and environment in PF-ILDs, through an integrative approach linking the
transcriptional profiles and the respiratory microbiome. Through FIBRA-Lung, we expect to gain deeper insight into fibroproliferative common pathways, paving the way for new
biomarkers that reflect the progressive phenotype, supporting better treatment options in stratified populations of patients. |