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Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial m...

BackgroundMatrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF.MethodsThe IPF cohort (n = 300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Controls (n = 100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls.ResultsAll the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted.ConclusionsCirculating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.

Idiopathic pulmonary fibrosis (IPF) is a progressive, inflammatory lung disease that is monitored clinically by measures of lung function, without effective molecular markers of disease activity or therapeutic efficacy. Lung immune cells active in the pro-fibrotic process include inflammatory monocyte and interstitial macrophages that express the C-C motif chemokine receptor 2 (CCR2). CCR2+ monocyte lung influx is essential for disease phenotypes in models of fibrosis and identified in lungs from subjects with IPF. Here, we show that our peptide-based radiotracer 64Cu-DOTA-ECL1i identifies CCR2+ inflammatory monocytes and interstitial macrophages in multiple preclinical mouse models of lung fibrosis, using positron emission tomography (PET) imaging. Mice with bleomycin-induced fibrosis treated with blocking antibodies to interleukin-1β, a mediator of fibrosis associated with CCR2+ cell inflammation, or with pirfenidone, an approved anti-fibrotic agent, demonstrated decreased CCR2-dependent interstitial macrophage accumulation and reduced 64Cu-DOTA-ECL1i PET uptake, compared to controls. Lung tissues from patients with fibrotic lung disease demonstrated abundant CCR2+ cells surrounding regions of fibrosis, and an ex vivo tissue-binding assay showed correlation between radiotracer localization and CCR2+ cells. In a phase 0/1 clinical study of 64Cu-DOTA-ECL1i PET, healthy volunteers showed little lung uptake, while subjects with pulmonary fibrosis exhibited increased uptake, notably in zones of subpleural fibrosis, reflecting the distribution of CCR2+ cells in the profibrotic niche. These findings support a pathologic role of inflammatory lung monocytes/macrophages in fibrotic lung disease and the translational use of 64Cu-DOTA-ECL1i PET to track CCR2-specific inflammation for image-guided therapy.One Sentence SummaryPET imaging of CCR2+ cells in lung fibrosis identifies a therapeutic response in mouse models and displays a perifibrotic signal in subjects with IPF.

Making the diagnosis of idiopathic pulmonary fibrosis (IPF) can be challenging. However, with the recent Food and Drug Administration (FDA) approval of anti-fibrotic therapies for IPF, distinguishing IPF from other interstitial lung diseases (ILDs) has become increasingly necessary, as this distinction appreciably modifies patient management. Furthermore, the clinical course of patients with IPF is particularly variable. Currently, clinicians make use of clinical, radiological, and physiologic testing to diagnose IPF, define disease severity, and predict disease progression. Biomarkers are quantifiable biological indicators that can be objectively measured in an accurate and reproducible manner. In diseases such as IPF biomarkers provide the potential for diagnosing disease, predicting and evaluating responses to disease-specific therapies, and accurately estimating disease prognosis. The use of biomarkers in IPF is still in its infancy. In this chapter we review the current IPF biomarker literature and comment on current biomarker strengths and limitations.

Sleep disordered breathing is made up of a group of conditions that include obstructive sleep apnea, central sleep apnea, complex sleep apnea, and sleep-related hypoventilation. Continuous positive airway pressure (CPAP) is the first-line therapy for obstructive sleep apnea. The other forms of sleep disordered breathing require different types of positive airway pressure (PAP). Adherence to PAP can be challenging and affected by multiple factors. Educating the patient regarding the consequences of untreated sleep disordered breathing and the benefits of PAP is the first step in improving adherence. Attention to social, psychological, and demographic factors that may contribute to difficulty complying is important. Addressing side effects such as nasal symptoms and equipment usability issues is also beneficial. Compliance can be monitored by the data download cards present in PAP machines, but clinicians must be aware of the limitations of the data obtained. The challenges of improving adherence occur along with the increasing need to demonstrate to payers a patient's adherence to and benefit from PAP therapy.

Sleep-disordered breathing, especially obstructive sleep apnea (OSA), has a high prevalence among the elderly, where it may present with atypical symptoms. Untreated OSA can reduce quality of life and have adverse health consequences. Effective treatment is available, so all physicians treating the elderly should be aware of the clinical presentation, diagnostic methods, and treatment options for OSA.

A 43-year-old man with antisynthetase syndrome was seen in our pulmonary clinic for worsening dyspnea. He was recently diagnosed with antisynthetase syndrome because he had nonspecific interstitial pneumonitis on a surgical lung biopsy and polymyositis associated with anti-Jo-1 and anti-SSA-52 autoantibodies. Along with his worsening dyspnea, he also had a dry cough, lower extremity edema, and abdominal distension. He had gained 11 kg over 1 month. He had been taking prednisone 40 mg daily 2 months prior, which had been recently weaned to 20 mg daily. He had also been on mycophenolate mofetil but had recently discontinued it on his own.

Bronchiolitis obliterans syndrome is the leading cause of chronic lung allograft dysfunction. We have demonstrated that respiratory viral infection is a bronchiolitis obliterans syndrome risk factor and virus-dependent injury induces expression of innate airway epithelial genes belonging to the interleukin (IL)-12 family. Thus, we hypothesized that epithelial cell IL-12 family members could mediate lung allograft dysfunction.We used mouse and human allograft specimens to evaluate the role of epithelial cell IL-12 family members in allograft dysfunction associated with and without viral infection.Murine and human IL-12 family members were characterized and manipulated in allografts and then correlated with epithelial cell injury, immune cell accumulation, and collagen deposition.In a mouse model of lung transplantation, concurrent viral infection and allogeneic transplantation increased epithelial injury and this was followed by exaggerated accumulation of macrophages and collagen deposition. This virus-driven allograft dysfunction was associated with an epithelial innate response manifested by a synergistic increase in the production of the macrophage chemoattractant IL-12 p80 (p80), but not IL-12 or IL-23. Blockade or overexpression of donor epithelial p80 resulted in a corresponding abrogation or enhancement of macrophage accumulation and allograft dysfunction. We extended these findings to human recipients with viral infection and transplant bronchitis and again observed excessive epithelial p80 expression that correlated with increased macrophage accumulation.These experiments support a role for an enhanced epithelial innate response as a central process in allograft dysfunction and identify the macrophage chemoattractant p80 as an innate epithelial effector of disease progression.

Background Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes. Objective To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server. Methods We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency

Leukocyte recruitment to the airway lumen is a central feature of inflammatory conditions such as asthma and respiratory viral infection. Characterization of mediators that regulate leukocyte recruitment in these conditions revealed increased IL-12 p40 homodimer (p80) levels were associated with enhanced airway macrophage accumulation. To examine this association, we used in vivo and in vitro assays to demonstrate p80, but not IL-12 or p40, provided a macrophage chemoattractant signal. Macrophages from genetically deficient mice indicated p80-dependent chemotaxis was independent of IL-12 and required IL-12Rβ1 (Rβ1) expression. Furthermore, analysis of murine cell lines and primary culture macrophages revealed Rβ1 expression, with an intact cytoplasmic tail, was necessary and sufficient to mediate p80-dependent chemotaxis. To examine the role for Rβ1 in mediating macrophage accumulation in vivo, we contrasted Sendai virus-driven airway inflammation in wild-type and Rβ1-deficient mice. Despite similar viral burden and production of the macrophage chemoattractant p80, the Rβ1-deficient mice displayed a selective decrease in airway macrophage accumulation and resistance to viral-dependent mortality. Thus, Rβ1 mediates p80-dependent macrophage chemotaxis and inhibition of the p80-Rβ1 interaction may provide a novel anti-inflammatory strategy to manipulate the inflammation associated with asthma and respiratory viral infection.