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Published in final edited form as: Matrix Biol. 2018 Mar 19;68-69:422–434. doi: 10.1016/j.matbio.2018.03.014

Fibrosis: Lessons from OMICS analyses of the human lung

Guoying Yu 1, Gabriel H Ibarra 1, Naftali Kaminski 1
PMCID: PMC6015529  NIHMSID: NIHMS955021  PMID: 29567123

Abstract

In recent decades there has been a significant shift in our understanding of Idiopathic Pulmonary fibrosis (IPF), a progressive and lethal disorder. While initially much of the mechanistic understanding was derived from hypotheses generated from animal models of disease, in recent decades new insights derived from humans with IPF have taken precedence. This is mainly because of the establishment of large collections of IPF lung tissues and patient cohorts, and the emergence of high throughput profiling technologies collectively termed ‘omics’ technologies based on their shared suffix. In this review we describe impacts of ‘omics’ analyses of human IPF samples on our understanding of the disease. In particular, we discuss the results of genomics and transcriptomics studies, as well as proteomics, epigenomics and metabolomics. We then describe how these findings can be integrated in a modified paradigm of human idiopathic pulmonary fibrosis, that introduces the ‘hallmarks of aging’ as a central theme in the IPF lung. This allows resolution of all the disparate cellular and molecular features in IPF, from the central role of epithelial cells, through the dramatic phenotypic alterations observed in fibroblasts and the numerous aberrations that inflammatory cells exhibit. We end with reiterating a call for renewed efforts to collect and analyze carefully characterized human tissues, in ways that would facilitate implementation of novel technologies for high resolution single cell omics profiling.

Keywords: Pulmonary Fibrosis, Mitochondria, Telomere, Senescence, Microbiome, Genomics, transcriptomics

INTRODUCTION

Idiopathic pulmonary fibrosis (IPF) is a chronic Interstitial Lung Disease (ILD) with an etiology that remains to be fully elucidated. The natural course of patients with IPF is variable, but survival is worse than many cancers and is usually 3–5 years from diagnosis[1]. The prevalence estimates in the USA vary between 1.25 and 63 cases per 100,000 population and its incidence is 0.22 −8.6 per 100.000 of population, making it the most common among idiopathic ILD[2]. Despite the approval of Pirfenidone and Nintedanib by the FDA, the only curative treatment is lung transplantation.

In the last decades, there has been significant progress understanding the molecular mechanisms of pulmonary fibrosis in animal models of disease, however understanding the exact molecular mechanism underlying the initiation and progression in humans are only now emerging. Traditionally, in the early decades of pulmonary fibrosis research, investigators formulated hypotheses based on experimental models, mostly the bleomycin model or on observations in other organ systems and then sought to validate them in humans, most frequently with low throughput protein profiling approaches in a limited number of samples. In the first decade of the 21st century, we observed a dramatic inversion of this process. The increased availability of well characterized human cells derived from tissues and the emergence of high throughput transcriptomic profiling technologies, led to novel hypotheses based on human observations that were followed by sophisticated molecular biology and mouse genetics techniques[3]. In the second decade of the 21st century, this trend expanded and matured, with a dramatic increase in the number of samples and application of high throughput molecular profiling technologies often referred to as “omics” technologies based on their common suffix. The lung genomics research consortium that provided parallel transcriptomic, epigenetic, genetic and microRNA profiles on hundreds of well characterized tissues[46], marked the start of this era. The discovery of IPF associated common genetic variants [7], the role of the microbiome [8], and the recent description of molecular and cellular phenotypes using single cell sequencing technologies [9] , are among the most recent and significant progress on the field (Figure 1). These studies provided a nearly chaotic molecular image of the lung with numerous molecular and cellular aberrations.

Figure 1.

Figure 1

Omics technologies and their effects in IPF research.

In this review, we describe what we have learned about pulmonary fibrosis from the application of omics technologies to human tissues, focusing mainly on the lung, but also mentioning other compartments reflective of the disease. We discuss how these findings fit and contribute to our perception of the central role of aging hallmarks in IPF, with a specific focus on telomere attrition and mitochondrial dysfunction.

Insights from OMICS analyses of human fibrotic lungs

Genomics

The tremendous progress in understanding the genetics of familial pulmonary fibrosis and sporadic idiopathic pulmonary fibrosis has been recently described [10]. Here we focus on the impact that those genetic findings have had on our understanding of the mechanisms of human pulmonary fibrosis.

Genetic studies of familial pulmonary fibrosis have been important in the identification of rare DNA sequence variants in coding and non-coding regions with significant mechanistic implications. They have identified variants in two broad categories: surfactant protein processing (SFTPA2, SFTPC, ABCA3 [11, 12]) and telomere maintenance and homeostasis machinery (TERT, TERC, TINF2, RTEL1, PARN, DKC1 [1318]) gene mutations. These studies highlighted the central roles of endoplasmic reticulum (ER) stress and telomerase dysfunction in human pulmonary fibrosis. Elegant follow-up studies in genetically modified mice established the specific role of these mutations, as well as the general roles of ER stress [19, 20], and telomere attrition and telomerase dysfunction [21] as drivers of pulmonary fibrosis

Similarly, the application of genome wide association studies (GWAS), led to identification of common variants in both familiar pulmonary fibrosis and idiopathic pulmonary fibrosis with unprecedented reproducibility. The rs35705950 SNP in the promoter of MUC5B, a mucin expressed in airway epithelial cells, was associated with familial pulmonary fibrosis and IPF in multiple cohorts [2229] and three large GWAS studies [7, 30, 31], accounting for ~30% of the risk for developing IPF by some estimates[10] . GWAS studies identified additional variants, including TOLLIP [31] and AKAP13 [30]. A retrospective analysis suggested that patients carrying the SNPs for TOLLIP, benefitted preferentially from treatment with N-Acetylcysteine in the PANTHER-IPF clinical trial [32] opening the door for future genetic variant driven clinical trials. Telomerase pathway variants were also associated with disease in these cohorts[7, 30, 31]. Thus, in pulmonary fibrosis, GWAS results led to identification of the role of bronchial epithelial cells, innate immunity and supported the role of the telomerase pathway.

Transcriptomics

The application of genome wide transcript profiling to human tissues in pulmonary fibrosis has had numerous impacts on IPF research. Conceptually, the unbiased transcriptomic analysis of human lungs shifted pulmonary fibrosis researchers from basing their hypotheses on model systems or biological plausibility-based hypotheses, to human lung based generated hypotheses, and led to identification of novel pathways and molecular targets. Traditionally, transcriptomic data can be classified as generating reductionist and mechanistic hypotheses, previously described as “cherry picking”, or generating global “systems level” conceptual observations[33].

Among the global discoveries that have been gleaned from transcriptomic data are: the discovery that matrix metalloproteases (MMPs) are active participants in pulmonary fibrosis [3, 3436], the observation that developmental pathways are aberrantly activated in the IPF lungs [37], the observation that different classes of disease could be identified by gene expression patterns, allowing the recognition of distinct patient phenotypes [6, 3840], the discovery of mitochondrial abnormalities in IPF and their implications [41, 42], and the extent of microRNA expression changes [43].

There have been numerous reductionist studies where investigators identified a gene differentially expressed in IPF lungs and utilized this information to develop a mechanistic insight. Sometimes investigators interested in a pathway, used publicly available datasets to support their hypotheses. Among the molecules identified as potential novel regulators of fibrosis are: MMP7 [3], OPN [44], IGBP3 and 5 [45, 46], WISP1 [47] , FKBP10 [48], PINK1 [41], RXFP1 [49], PTPN11 [50]. In most of these studies, combination of cell culture, genetically modified mice and other methods were included to make a plausible cause for their role in pulmonary fibrosis. The fact that these genes were indeed differentially expressed in human tissues, highlights the complexity of the regulatory networks in humans. Of particular interest in this context are microRNAs, small non-coding RNA molecules that regulate gene expression. It has been estimated that close to 10% of the microRNAs are changed in the IPF lung. Numerus microRNAs have been mechanistically related to pulmonary fibrosis in recent years. The most studied are: miR-21, let-7 and miR-29 family of microRNAs [43, 5153].

Transcriptomics studies have also been utilized to prioritize biomarkers found in the blood stream, and to determine whether they were indicative of changes in the lung [5456]. Direct analysis of peripheral blood mononuclear cells (PBMC), led to identification of a 52-gene expression signature that predicted more severe prognosis in patients with IPF [57], a finding later replicated in six independent cohorts [58].

The majority of these findings have been obtained from experiments utilizing microarrays and performed on bulk tissue. Studies using RNA-sequencing either in bulk [5], or at the single cell level [9] are emerging and will have a significant influence on the field.

Epigenomics

Changes in epigenetic regulation of specific genes have been reported in IPF [5961, 62, 63], but several groups reported extensive methylation changes in IPF lungs [64, 65]. Comparison of IPF methylation patterns to lung cancer or control samples, revealed that IPF lungs displayed an intermediate methylation profile between lung cancer and control with 402 differentially methylated CpG islands overlapping between IPF and cancer. A later study [66] identified DNA methylation changes in IPF using comprehensive high-throughput arrays for relative methylation arrays (CHARM). This study focused on correlation of methylation and gene expression. Out of 2130 differentially methylated regions, 738 were associated with significant changes in gene expression and enriched for opposite changes between methylation and expression, suggesting a role for epigenetic regulation of gene expression in IPF.

To some extent, epigenomic studies did not lead to a wave of follow up studies. Critical questions regarding the cellular source of epigenetic changes, their relationship to patients’ fibrosis phenotypes and disease pathogenesis have not been answered. It is hoped that with the increased interest in aging related mechanisms in pulmonary fibrosis and the availability of advanced methodologies including single cell epigenomic analysis, a renewed interest will emerge [67, 68].

Microbiome

There has been a significant increase in information about the microbiome changes in IPF using state of the art next generation sequencing of bacterial 16r-rRNA Operational Taxonomic Units (OTU) clustering [69]. These new methods, more sensitive than the regular culture-dependent techniques, allow high-throughput analyses of numerous species. The majority of studies focused on the fibrotic lung microbiome in bronchoalveolar lavage (BAL) – a technique in which the content of the alveolar space is sampled by instilling fluid and suctioning it through a fiberoptic bronchoscope. Despite initial concerns about potential contaminations, the results have been reproducible and widely accepted[70, 71]. Two large studies identified correlations of changes in the microbiome with presence and progression of IPF [72, 73], as well connection with changes in peripheral blood gene expression[74, 75]. Changes in microbiome where observed in acute exacerbations [76] but not in patients treated with inhaled Interferon-γ [77]. While these associations do not necessarily imply causality, they do suggest a link between shifts in alveolar bacterial burden and IPF. Studies that directly assessed the microbiome of lung tissue, as opposed to BAL did not detect bacterial DNA in tissue samples obtained from patients with IPF competed to control lungs, questioning the true role of microbiome shifts in the lung[78].

At this stage, it is too early to determine whether the changes to the lung microbiome reported in BAL of IPF studies reflect basic pathogenetic mechanism, or are reflective of airway changes secondary to the remodeling. Experiments seeking to affect the lung microbiome in humans, and potentially studies assessing changes in fibrotic predisposition in gnotobiotic animals, will be required to resolve some of these questions.

Proteomics

Studies that applied targeted or global proteomic approaches to identify biomarkers or disease modifiers had a limited impact compared to transcriptomic, genomic or microbiome studies. Targeted proteomic approaches identified a peripheral blood protein signature that included MMP7 and MMP1 that distinguished patients with IPF from controls or other chronic lung diseases[54]. Later, applying a similar approach, the same group identified a peripheral blood protein signature that predicted outcome in IPF[79]. In both cases the investigators ended up with proteins that were increased in the human IPF lung, a comparison not performed in a later study that utilized a wider screening technique[80].

Comparison of IPF tissues with other interstitial lung disease revealed significant changes in proteins related to unfolded protein response, oxidative stress and DNA damage [81, 82] highlighting the extent of the aberrant expression of these proteins. While others revealed relatively predictable changes in proteins such as vimentin[83], a recent deep proteomic approach of fibrotic lung and skin led to the unexpected discovery of high levels of MZB1-positive plasma B cells in lung and skin fibrosis[84]. While the implications of this finding are not clear, they highlight the discovery potential of proteomic analysis of the lung, as well as the limitations of bulk analysis, as the major finding was a marker of infiltrating cells.

Metabolomics

Metabolomics analyses were, so far, rarely applied to the human fibrotic lung. A key study applied nuclear magnetic resonance spectroscopy to assess cellular metabolites in IPF and revealed elevations of Lactic acid and lactate dehydrogenase-5 (LDH5) in fibroblasts from IPF lungs[85]. Additional studies revealed alterations in glycolysis, glutathione biosynthesis, adenosine triphosphate degradation and ornithine aminotransferase pathways [86, 87]. Together with the evidence for metabolic reprogramming [88], mitochondrial dysfunction and extensive protein degradation in the IPF lung [35], these studies encourage a much wider, extensive and detailed studies of metabolomics in IPF.

Current insights into the pathogenesis of pulmonary fibrosis

The history of paradigm shifts in IPF can be described as a move from simple linear models of disease progression, highly influenced by tightly controlled animal models of disease, to more complex models based on information gleaned from the human lung. The initial inflammation driven fibrosis hypothesis that was mainly based on the bleomycin model of fibrosis, has been replaced by an epithelial primary injury paradigm. In this model, a primary chronic injury to epithelial cells, and a failure to repopulate them, leads to ongoing activation of fibroblasts, change in the phenotype of epithelial cells, and a self-perpetuating cycle of aberrant remodeling.

Two key human observations cemented this epithelial injury paradigm as probably the one that explains most features of IPF: First, the primary role of epithelial cells in IPF was solidified by the observation that the rs35705950 SNP, mostly associated with both familial pulmonary fibrosis and sporadic IPF in numerous cohorts [7, 2231], is in the promoter of MUC5B, a gene encoding a mucin expressed in airway epithelial cells. Second, the complex and not necessarily all evil role of inflammation in IPF, was highlighted by the revelation that an immunosuppressive regimen recommended for patients with IPF was detrimental and associated with increased hospitalizations and mortality in a prospective randomized controlled study [89]. Previous smaller studies have repeatedly shown lack of an effect of use of steroids or other immunosuppressive medications in IPF [90, 91], and pulmonary fibrosis seems to develop independently of inflammation in animal models of fibrosis [9295].

While these observations solidified the primary role of epithelial cells in IPF, they did not explain all of the molecular features of the human disease, this only happened when the hallmarks of aging were introduced to the IPF paradigm as described below.

Aging, the new wrinkle in IPF pathogenesis

To some extent, the connection of aging with IPF was in plain view of clinicians for at least three decades. Increased incidence and prevalence of IPF was consistently observed over the age of 65 and the disease is extremely rare below the age of 50[9698]. However, only in the last decade this concept obtained molecular and genetic support. As mentioned, the IPF lung is dramatically altered at its cellular and molecular composition. Type I epithelial cells are lost and type II epithelial cells are stressed, exhibit senescence markers, shorter telomeres [99] and increased expression of senescence associated microRNAs such as mir-34 [100]. Airway basal cells infiltrate the lung. The extracellular matrix composition is changed and its stiffness increased. Fibroblasts exhibit myofibroblast characteristics, but also exhibit a senescent phenotype with metabolic reprogramming. Macrophages and other inflammatory cells are activated or changed. IPF lungs exhibit extensive molecular changes including local TGFB1 activation [101103], WNT [104], SHH [105] pathways, the unfolded protein response [106], oxidative injury [107], epithelial injury and apoptosis[108], abnormal matrix deposition and stiffness [109, 110], fibroblast metabolic reprogramming [88, 111] and senescence [112], myofibroblast transdifferentiation [113, 114], metalloprotease activation and signaling [35, 115], changes in patterns of mRNA and microRNA expressions [6, 43] and epigenetic marks [116] . This nearly chaotic portrait of aberrant cell behavior in the IPF lungs became clearer when we consider that many of the hallmarks of aging [117] including telomere attrition, genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence, and altered intercellular communication are a present in the human IPF. Thus, aging, added to a genetic susceptibility and an environmental exposure, explains many of the molecular and cellular aberrations observed in the IPF lung. The majority of these attributes have been reviewed extensively recently [118], but to better explain the role of aging in IPF we will briefly describe the evidence for the role of telomeres and mitochondria in IPF.

Telomeres in IPF

Telomeres, the DNA repeats that protect the ends of linear chromosomes and, whose length is a measure of cellular age, emerged in IPF with the initial description of telomerase mutations in familial pulmonary fibrosis [14]. Since then, numerous mutations and variants in telomerase related proteins (TERT, TERC, TINF2, RTEL1, PARN, DKC1) have been identified in patients with familial and sporadic pulmonary fibrosis [13, 1518, 119]. Shortened telomeres are found in the blood of patients with IPF as [13] and are predictive of worst outcome [120] before and after transplantation [121]. Short telomeres are also observed in the lungs of patients with IPF, in particular in type II alveolar epithelial cells [122]. Mice genetically engineered to have short telomeres or severe telomere dysfunction, develop pulmonary fibrosis [21, 99, 123]. This effect is evident only when telomerase dysfunction is induced in alveolar type II cells and not in collagen expressing cells [99], consistent with the centrality of epithelial cells in human IPF. In humans, telomere shortening is observed independently of the presence of telomerase mutations, in both sporadic IPF and familial pulmonary fibrosis [124], highlighting the potential universal importance of telomere shortening and dysfunction in fibrosis.

Mitochondrial Dysfunction

Multitude of circumstantial evidence point towards a potential role for mitochondrial dysfunction in IPF. Those include excessive epithelial cell apoptosis, fibroblast metabolic derangements and impaired autophagy and immune dysfunction (reviewed at [125]). However, direct evidence to mitochondrial dysfunction in human IPF lungs has been demonstrated only recently [41].

In IPF lungs, human alveolar type II epithelial cells exhibit accumulation of dysmorphic and swollen mitochondria. These findings are associated with decreased expression of PINK1, a regulator of mitochondrial homeostasis and mitophagy. PINK1-deficient mice exhibit predisposition to fibrosis and mimic the human mitochondrial phenotype [41]. We have recently demonstrated that delivery of thyroid hormone or sobetirome, small molecule thyroid hormone agonist devoid of cardiac or musculoskeletal side effects blunted fibrosis in mouse models of pulmonary fibrosis [126]. These effects were dependent on the presence of PARGC1A and PINK1, regulators of mitogenesis and mitophagy, suggesting that the antifibrotic effect of thyroid hormone was mediated through restoration of mitochondrial homeostasis. Thyroid hormone reversed mitochondrial injury induced by bleomycin both in-vivo in mice, and in-vitro in mouse and human primary cells [126].

Another intriguing piece of the puzzle emerges from analysis of free circuiting mitochondrial DNA (mtDNA) in patients with IPF [127]. Briefly, mtDNA concentrations are increased in BAL or plasma obtained from patients with IPF. Increased plasma mtDNA is associated with disease progression and decreased survival. In vitro, mtDNA release increased in response to conditions that mimic the lung environment in IPF (TGF-β1 or stiff matrix) and exposure of fibroblasts to mtDNA augmented their transdifferentiation to myofibroblasts. Taken together, these findings suggest a central role for mitochondrial dysfunction in the pathogenesis of pulmonary fibrosis.

Putting it all together: an integrated model of pulmonary fibrosis

As previously mentioned, the introduction of the hallmarks of aging into the pulmonary fibrosis paradigm explains many of the features of the IPF lung. Telomere attrition and mitochondrial dysfunction become unifying themes that allow a cohesive model of the emergence, presence and progression of IPF (Figure 2). Basically, this model assumes a possible baseline genetic predisposition to injury, one that is not extremely detrimental to cells, otherwise it would not wait to be exhibited at the old age. Similarly, the model assumes a mild environmental injury, one that does not elicit an overwhelming inflammatory response, and thus, more often goes unnoticed clinically. The combination of the mild repeated injury, and the mild genetic predisposition lead to prolonged strain on the alveolar unit. In the alveolus, the cell that is more prone to this strain is the alveolar type II cell. This cell has been known to carry multiple functions critical to the integrity and function of the alveolar unit [128], including the metabolically intensive tasks of producing surfactant, serving as a progenitor for type I cells, and maintenance of fluid homeostasis. Indeed, type II cells are highly enriched with mitochondria [129, 130]. Thus, conditions that require enhanced replication because of loss of type I cells, or production of more surfactant (changes in microbiome, impaired mucus clearance), put a disproportionate metabolic and replicative stress on alveolar type II cells. The presence of relatively short telomeres or impaired telomerase function to begin with, could enhance this stress, because as cells proliferate, telomere attrition and uncapping leads to DNA damage response, downstream mitochondrial dysfunction, followed by release of ROS, mtDNA, DAMPs [131], and downstream activation of adjacent fibroblasts and macrophages creating a profibrotic microenvironment (Figure 2). If the fibroblasts also have relatively short telomeres, their response would potentially be abnormal and instead of proliferating normally and participating in a self-limited wound healing response, fibroblasts may develop a Senescence Associated Secretory Phenotype (SASP), characterized by growth arrest and secretion of extracellular matrix proteins such as fibronectin, proteases such as MMP-1, MMP-3 and MMP-10, PAI-1, IGFBPs [132], cytokines and chemokines [133], all known to be increased in IPF. SASP fibroblasts also exhibit metabolic derangements similar to what has been described in IPF and produce more ROS [134]. Macrophages will also be activated by the increase of DAMPs, cytokines and chemokines. It is also possible that in the presence of a systemic predisposition to aging, such as short telomeres or telomerase dysfunction, senescence will also emerge in macrophages and other lung inflammatory cells [135], a finding consistent with previous results in IPF patients [57, 136138]. Therefore, instead of a self-resolving response to injury, the lung enters a vicious cycle, with increased matrix stiffness, enhanced local injury, accumulation of senescent fibroblasts and epithelial cells, a failure to resolve injury that leads to propagation of the disease to adjacent alveoli. While, many of the details of this model need to be worked out, the appeal of the model is that it allows integration of all the seemingly unrelated pieces of information gleaned from the application of OMICS technologies to the human lung.

Figure 2.

Figure 2

An updated paradigm of the Pulmonary Fibrosis Vicious Cycle – Prolonged injury from environmental exposure in the presence of genetic predisposition and abnormal aging lead to DNA damage response, downstream mitochondrial dysfunction, release of ROS, mtDNA, DAMPs, that activate both fibroblasts and macrophages, release of cytokines and growth factors, enhancement of injury which lead to sustained and self-propagating fibrosis.

Final remarks

In this review, we aimed to highlight the significant impacts that the application of omics technologies has had in our understanding of human pulmonary fibrosis. While never in isolation, the results led to novel hypotheses and sometimes provided the data to support and develop coherent conceptual models of disease. Publicly available datasets have allowed investigators to seek human correlates of their mechanistic findings. While we could not describe all of the findings, we chose to focus on the insights that supported a modified paradigm of pulmonary fibrosis: a disease driven by recurrent epithelial injury in the context of genetic predisposition and activated aging mechanisms. Understanding the central role of epithelial cells, telomere attrition and mitochondrial dysfunction, have been facilitated by collecting tissue and blood samples and carefully phenotype cohorts of patients with familial and sporadic IPF. In 2014, we published a call for an open access biorepository for IPF research [139]. While there has been a significant increase in the number of patients with IPF involved in research, with increased availability of DNA, RNA and peripheral blood samples, efforts to generate central repository of human lung tissues and cells from patients with IPF have not been renewed. We see this as a significant threat, because with the critical mass of genetic and genomic insights, the discovery, development and validation of novel therapies and biomarkers depends on us continuing to study human lungs and cells using novel approaches such as single cell profiling. Because if there is one lesson that we learned from our first two decades of applying Omics technologies to the human lung, is that we need to keep analyzing the human lung - this is where we will learn how to understand, diagnose and treat human pulmonary fibrosis.

Highlights.

  • Idiopathic Pulmonary Fibrosis (IPF) is a progressive, lethal and incurable disease

  • Genetic studies highlight ER stress, telomerase dysfunction, and epithelial injury.

  • Transcriptomics identified role of microRNAs and outcome predictive biomarkers in IPF

  • The lung microbiome, metabolome and proteome are substantially altered in IPF

  • The hallmarks of aging explain many of the omics findings in IPF lungs

Acknowledgments

The work was in part supported by US National Institute of Health (NIH) grants R01HL095397, R01HL127349 (N.K.), Pulmonary Fibrosis Foundation (PPF) Albert Rose Established Investigator Award 415245 (G.Y.)

Footnotes

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Competing financial interests

G.Y., and N.K., are inventors on a pending patent on use of thyroid hormone as an antifibrotic agent entitled: “Novel Methods of Treating or Preventing Fibrotic Lung Diseases” -OCR 6368 - 047162-7029P1 (00219). N.K. consulted Biogen Idec, Boehringer Ingelheim, Numedii, MMI, Pliant, Third Rock, Samumed and has an ongoing collaboration with MiRagen, all outside the submitted work.

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