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1.  Future Directions in Idiopathic Pulmonary Fibrosis Research. An NHLBI Workshop Report 
The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.
doi:10.1164/rccm.201306-1141WS
PMCID: PMC3983890  PMID: 24160862
idiopathic pulmonary fibrosis; alveolar epithelial cells; extracellular matrix; interstitial lung disease; inflammation
2.  Sarcoidosis-related Mortality in the United States from 1988 to 2007 
Rationale: It has been nearly 20 years since sarcoidosis mortality was examined at the population level in the United States.
Objectives: To examine mortality rates and underlying causes of death among United States decedents with sarcoidosis from 1988–2007.
Methods: We used data from the National Center for Health Statistics to (1) calculate age-adjusted sarcoidosis-associated mortality rates; (2) examine how those rates differ by age, sex, and race and ethnicity; and (3) determine underlying causes of death among sarcoidosis decedents.
Measurements and Main Results: From 1988–2007, there were 46,450,489 deaths in the United States and 23,679 decedents with sarcoidosis mentioned on their death certificates. Over this time, the age-adjusted, sarcoidosis-related mortality rate increased 50.5% in women and 30.1% in men. The greatest absolute increase in death rates was among non-Hispanic black females. Regardless of sex or race, mortality rates climbed most in decedents 55 years or older. The most common cause of death was sarcoidosis itself. Younger sarcoidosis decedents with pulmonary fibrosis were more likely to be black than white, and younger sarcoidosis decedents were more likely than similarly aged decedents in the general population to have a cardiac cause contribute to death.
Conclusions: From 1988–2007, sarcoidosis-related mortality rates increased significantly, particularly in non-Hispanic black females aged 55 years or older. The underlying cause of death in most patients with sarcoidosis was the disease itself. Among young sarcoidosis decedents, those with pulmonary fibrosis or a cardiac cause contributing to death were more likely to be black than white.
doi:10.1164/rccm.201010-1679OC
PMCID: PMC3137141  PMID: 21330454
sarcoidosis; mortality; epidemiology
3.  Serum Inter–α-Trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury 
Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-α-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury.
Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury.
Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined.
Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC.
Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis.
Clinical trial registered with www.clinicaltrials.gov (NCT00016627).
doi:10.1164/rccm.200803-386OC
PMCID: PMC2577729  PMID: 18703791
inter–α-trypsin inhibitor; hyaluronan; angiogenesis; pulmonary fibrosis
4.  Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia 
Rationale: Idiopathic interstitial pneumonia (IIP) and its familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. Both the genetics and the histologic type of IIP play a role in the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown.
Objectives: To evaluate gene expression in the lung tissue of patients with usual interstitial pneumonia or nonspecific interstitial pneumonia that was either familial or nonfamilial in origin, and to compare it with gene expression in normal lung parenchyma.
Methods: We profiled RNA from the lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal control subjects on a whole human genome oligonucleotide microarray.
Results: Significant transcriptional differences exist in familial and sporadic IIPs. The genes distinguishing the genetic subtypes belong to the same functional categories as transcripts that distinguish IIP from normal samples. Relevant categories include chemokines and growth factors and their receptors, complement components, genes associated with cell proliferation and death, and genes in the Wnt pathway. The role of the chemokine CXCL12 in disease pathogenesis was confirmed in the murine bleomycin model of lung injury, with C57BL/6CXCR4+/− mice demonstrating significantly less collagen deposition than C57BL/6CXCR4+/+ mice. Whereas substantial differences exist between familial and sporadic IIPs, we identified only minor gene expression changes between usual interstitial pneumonia and nonspecific interstitial pneumonia.
Conclusions: Taken together, our findings indicate that differences in gene expression profiles between familial and sporadic IIPs may provide clues to the etiology and pathogenesis of IIP.
doi:10.1164/rccm.200601-062OC
PMCID: PMC1899261  PMID: 16998095
familial interstitial pneumonia; global transcription analysis; interstitial lung disease; lung fibrosis; microarrays
5.  Acute Exacerbations of Idiopathic Pulmonary Fibrosis 
The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
doi:10.1164/rccm.200703-463PP
PMCID: PMC2094133  PMID: 17585107
acute exacerbation; pulmonary fibrosis; diagnosis; definition
6.  Fibroblast Foci Are Not Discrete Sites of Lung Injury or Repair 
Background: Usual interstitial pneumonia (UIP), the pathologic correlate of idiopathic pulmonary fibrosis, contains characteristic discrete areas of fibroblasts, myofibroblasts, and newly formed collagen, termed “fibroblast foci.” These lesions are argued to represent isolated sites of recurrent acute lung injury and suggested to be the mechanism of disease progression. We hypothesized that, rather than isolated, these lesions are part of an organized neoplasm.
Methods: Morphometric analysis of pentachrome-stained histologic sections of UIP was performed. Using point-counting technique on serial sections, fibroblast foci, arteries, and macrophage clusters were identified and we determined their individual “connectiveness” by estimating the Euler number. Two-dimensional micrographs were collated into a three-dimensional array from which a visual three-dimensional reconstruction could be constructed. Clonality analysis was performed using human androgen receptor gene methylation assay.
Results: Blood vessels show significant connectivity with a Euler number of 2, whereas macrophage clusters exhibited no connectivity. The fibroblast foci showed a high level of interconnection with Euler numbers ranging from 19 to 39. The computer generated three-dimensional models provide a visual confirmation of this connectiveness. Human androgen receptor gene methylation assay analysis of the foci showed balanced methylation consistent with polyclonality.
Conclusions: The fibroblast foci of UIP are the leading edge of a complex reticulum that is highly interconnected and extends from the pleura into the underlying parenchyma. It is a reactive, rather than a malignant, process.
doi:10.1164/rccm.200602-205OC
PMCID: PMC2648056  PMID: 16799077
fibroblast foci; fibroblast reticulum; idiopathic pulmonary fibrosis; usual interstitial pneumonia
7.  The NHLBI Lymphangioleiomyomatosis Registry 
Rationale: Pulmonary lymphangioleiomyomatosis is a progressive cystic lung disease that is associated with infiltration of atypical smooth muscle–like cells. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients.
Objectives: To describe the clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis–related forms.
Methods: Over a 3-yr period, from 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded for the purposes of this report.
Measurements and Main Results: All 230 subjects were women, aged 18 to 76 yr (mean ± SE, 44.5 ± 0.65 yr). The average age at onset of symptoms was 38.9 ± 0.73 yr and at diagnosis was 41.0 ± 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis–related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form.
Conclusions: The age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry.
doi:10.1164/rccm.200409-1298OC
PMCID: PMC2662978  PMID: 16210669
lymphangioleiomyomatosis; registry; tuberous sclerosis
8.  Clinical and Pathologic Features of Familial Interstitial Pneumonia 
Rationale: Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis.
Objectives: We evaluated families with 2 or more cases of idiopathic interstitial pneumonia among first-degree family members (familial interstitial pneumonia, or FIP), and identified 111 families with FIP having 309 affected and 360 unaffected individuals.
Methods: The presence of probable or definite FIP was based on medical record review in 28 cases (9.1%); clinical history, diffusing capacity of carbon monoxide (DLCO), and chest X-ray in 16 cases (5.2%); clinical history, DLCO, and high-resolution computed tomography chest scan in 191 cases (61.8%); clinical history and surgical lung biopsy in 56 cases (18.1%); and clinical history and autopsy in 18 cases (5.8%).
Results: Older age (68.3 vs. 53.1; p < 0.0001), male sex (55.7 vs. 37.2%; p < 0.0001), and having ever smoked cigarettes (67.3 vs. 34.1%; p < 0.0001) were associated with the development of FIP. After controlling for age and sex, having ever smoked cigarettes remained strongly associated with the development of FIP (odds ratioadj, 3.6; 95% confidence interval, 1.3–9.8). Evidence of aggregation of disease was highly significant (p < 0.001) among sibling pairs, and 20 pedigrees demonstrated vertical transmission, consistent with autosomal dominant inheritance. Forty-five percent of pedigrees demonstrated phenotypic heterogeneity, with some pedigrees demonstrating several subtypes of idiopathic interstitial pneumonia occurring within the same families.
Conclusions: These findings suggest that FIP may be caused by an interaction between a specific environmental exposure and a gene (or genes) that predisposes to the development of several subtypes of idiopathic interstitial pneumonia.
doi:10.1164/rccm.200408-1104OC
PMCID: PMC2718398  PMID: 16109978
cigarette smoking; familial pulmonary fibrosis; genetics; pulmonary fibrosis
9.  Oligoclonal CD4+ T Cells in the Lungs of Patients with Severe Emphysema 
Rationale: Within the lungs of patients with severe emphysema, inflammation continues despite smoking cessation. Foci of T lymphocytes in the small airways of patients with emphysema have been associated with disease severity. Whether these T cells play an important role in this continued inflammatory response is unknown. Objective: The aim of this study was to determine if T cells recruited to the lungs of subjects with severe emphysema contain oligoclonal T-cell populations, suggesting their accumulation in response to antigenic stimuli. Methods: Lung T-cell receptor (TCR) Vβ repertoire from eight patients with severe emphysema and six control subjects was evaluated at the time of tissue procurement (ex vivo) and after 2 weeks of culture with interleukin 2 (in vitro). Junctional region nucleotide sequencing of expanded TCR-Vβ subsets was performed. Results: No significantly expanded TCR-Vβ subsets were identified in ex vivo samples. However, T cells grew from all emphysema (n = 8) but from only one of the control lung samples (n = 6) when exposed to interleukin 2 (p = 0.0013). Within the cultured cells, seven major CD4-expressing TCR-Vβ subset expansions were identified from five of the patients with emphysema. These expansions were composed of oligoclonal populations of T cells that had already been expanded in vivo. Conclusion: Severe emphysema is associated with inflammation involving T lymphocytes that are composed of oligoclonal CD4+ T cells. These T cells are accumulating in the lung secondary to conventional antigenic stimulation and are likely involved in the persistent pulmonary inflammation characteristic of severe emphysema.
doi:10.1164/rccm.200410-1332OC
PMCID: PMC2718531  PMID: 15937291
antigens; chronic obstructive pulmonary disease; lymphocytes

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