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Background Management of patients with interstitial lung disease (ILD) requires subspecialized, comprehensive, multidisciplinary care. The Pulmonary Fibrosis Foundation established the Care Center Network (CCN) in 2013 with identified criteria to become a designated CCN site. Despite these criteria, the essential components of an ILD clinic remain unknown. Research Questions How are ILD clinics within the CCN structured? What are the essential components of an ILD clinic according to ILD physician experts, patients, and caregivers? Study Design and Methods This study had three components. First, all 68 CCN sites were surveyed to determine the characteristics of their current ILD clinics. Second, an online, three-round modified Delphi survey was conducted between October and December 2019 with 48 ILD experts participating in total. Items for round 1 were generated using expert interviews. During rounds 1 and 2, experts rated the importance of each item on a 5-point Likert scale. The a priori threshold for consensus was more than 75% of experts rating an item as important or very important. In round 3, experts graded items that met consensus and ranked items deemed essential for an ILD clinic. Third, ILD patient and caregiver focus groups were conducted and analyzed for content to determine their perspectives of an ideal ILD clinic. Results Forty items across four categories (members, infrastructure, resources, and multidisciplinary conference) achieved consensus as essential to an ILD clinic. Patient and caregiver focus groups identified three major themes: comprehensive, patient-centered medical care; expanded access to care; and comprehensive support for living and coping with ILD. Interpretation The essential components of an ILD clinic are well-aligned between physician experts and patients. Future research can use these findings to evaluate the impact of these components on patient outcomes and to inform best practices for ILD clinics throughout the world.

Scleroderma-related interstitial lung disease (SSc-ILD) is a pulmonary fibrosing disorder characterized by systemic inflammation and progressive scarring of the lungs that leads to respiratory failure. Although certain immunosuppressive therapies may slow disease progression, current treatment strategies are not curative; consequently, SSc-ILD continues to be a major cause of morbidity and mortality. We present four cases of SSc-ILD that emphasize the importance of early screening and detection, close follow-up, and aggressive management. We also highlight the need for well-conducted clinical trials designed to identify new and effective treatments.

Interstitial lung diseases comprise a family of progressive pulmonary disorders that are often idiopathic or associated with various systemic diseases and that is characterized by bilateral lung involvement with inflammation and tissue remodeling or fibrosis. The impact of sex, including the anatomic and physiologic traits that one is born with, on the development and progression of interstitial lung diseases is not entirely clear. Variances between men and women are driven by differences in male and female biology and sex hormones, among other differences, but their role remains uncertain. In this review, we summarize sex-related differences in the epidemiology and progression of certain interstitial lung diseases with a focus on the connective tissue related interstitial lung diseases, idiopathic pulmonary fibrosis, and sarcoidosis. We also discuss cellular and pre-clinical studies that might shed light on the potential mechanisms responsible for these differences in the hope of unveiling potential targets for intervention and stimulating research in this needed field of investigation.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disorder characterized by progressive dyspnea, exercise intolerance and, ultimately, respiratory failure and death. The incidence of IPF seems to be increasing, whereas its etiology remains unelucidated. Agents capable of modulating inflammation, kinase pathways, vascular tone, coagulation and fibrosis have been tested in clinical studies although not always in large, randomized, placebo-controlled prospective trials. Despite this effort, a therapy capable of improving survival remains elusive. Consequently, the management of IPF focuses on the early identification of subjects for lung transplantation and on the treatment of comorbidities such as hypoxemia, cough and deconditioning. Until effective therapies are identified, patients and referring physicians are urged to consider participation in well-designed clinical trials.

Background: Abnormalities of lung coagulation and fibrinolysis in sarcoidosis are thought to play a role in the pathogenesis of this disease. Objective: We previously showed that bronchoalveolar lavage fluid (BALF) D dimer directly correlated with various measures of severity in sarcoidosis. Here, we analyze our observation that BALF D dimer was more frequently found at higher levels in African-American patients with pulmonary sarcoidosis. Methods: BALF D dimer was measured in 55 subjects with pulmonary sarcoidosis and 31 healthy volunteers by enzyme immunoassay. The healthy group established a normal range of BALF D dimer with 71 ng/ml as the highest measured level. This was the cut point for comparisons among the patients with sarcoidosis. Results: High BALF D dimer levels (>71 ng/ml) were found in younger patients with sarcoidosis and were associated with a significantly lower percent predicted forced expiratory volume in 1 s and greater numbers of BAL lymphocytes. Black patients with sarcoidosis had higher BALF D dimer levels (median 131, range 0–2,040 ng/ml) than white patients (median 18, range 0–605 ng/ml; p = 0.011). Higher than normal BALF D dimer levels were found in 61% of the black subjects with sarcoidosis, but in only 20% of the white individuals (χ2 = 5.539, p = 0.019). BALF D dimer was the only disease measure that discriminated black from white individuals with sarcoidosis. Conclusion: BALF D dimer is an indicator of lung fibrin formation and degradation in sarcoidosis. The relationship of high D dimer levels with greater BAL lymphocytosis and worse lung function may be a marker of active sarcoidosis, especially in African-Americans who tend to suffer a more serious form of the disease.

The Department of Veterans Affairs (VA) Health Care System is the largest integrated single payer system in the United States. Its primary mission is to provide primary care, specialized care, and related medical and social support services to veterans. Much time and resources are expended on chronic obstructive pulmonary disease, known as COPD, at VA hospitals and clinics, thereby justifying the development of multifaceted strategies to address this problem. This article discusses the special problems of COPD in veterans who use VA facilities. The article also highlights the contributions of the VA to the research, training, and development of clinical practice guidelines for the management of this pervasive disease and presents the challenges that threaten its role in this area.

Trehalose-6,6'-dimycolate (TDM), or cord factor, is a mycobacterial cell wall component that induces granuloma formation and proinflammatory cytokine production in vivo and in vitro. The purpose of this work was to better understand the mechanisms by which TDM promotes lung granuloma formation. This was accomplished by characterizing cytokine mRNA expression during TDM-induced alveolitis culminating in cohesive granuloma development. A single intravenous injection of TDM given to C57BL/6 mice produced lung granulomas that peaked in number 5 days after challenge and were nearly resolved by 14 days. mRNA in whole lung preparations was quantitated by bioluminescent RT-PCR. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 were significantly elevated during granuloma development and decreased during granuloma resolution. There were no detectable changes in mRNA for interferon-y (IFN-y), IL-2, IL-4, IL-5, IL-10, and IL-12(p40). The level of TNF-alpha protein extracted from lung minces highly correlated with morphologic indices of granulomatous inflammation, indicating that it may be an important modulator of the inflammatory intensity induced by TDM. TDM may interact specifically with macrophages in vivo, as evidenced by induction of TNF-alpha, IL-1beta, and IL-6, but not IFN-gamma, protein in bone marrow-derived macrophages from C57BL/6 mice. TDM may therefore play an important role early in macrophage activation during the host granulomatous response to mycobacteria.

Extracellular matrices (ECMs) can stimulate human monocytic cells to express interleukin-1β (IL-1β), a proinflammatory cytokine implicated in the regulation of tissue inflammation. In this study, we explored the intracellular mechanisms responsible for ECM induction of IL-1β using human promonocytic U937 cells transfected with the full-length human IL-1β gene promoter connected to a reporter gene. Using this system, we demonstrated that the ECM molecules fibronectin (FN), type I collagen (Coll), fibrin (Fb) and laminin (Lm) induced transcription of the IL-1β gene (which was associated with a modest increase in IL-1β protein secretion) in suspended cells, when used in their soluble monomeric form. This effect was mimicked or blocked by anti-integrin monoclonal antibodies (mAbs) and was dependent on the activation of protein kinase C (PKC). Three of the ECMs tested (FN, Coll and Fb) induced the activation of mitogen-activated protein kinases (MAPKs), whereas Lm had no effect. FN, Coll and Fb (but not Lm) also induced DNA binding of the transcription factor activator protein-1 (AP-1), but not that of nuclear factor-κB. Co-transfection of U937 cells with a competing AP-1 oligomer blocked the IL-1β response induced by FN, but not that induced by the other ECMs. By inhibiting AP-1 translocation, glucocorticoids also blocked the FN-induced response, but not that of the other ECMs. These studies suggest that the signalling pathways which mediate ECM induction of IL-1β expression in human monocytic cells converge at the level of PKC activation. However, they diverge in other aspects, as demonstrated by the differential activation of MAPKs and the need for diverse transcription factors.

Purpose: The aim of this survey was to gather data about the incidence of various sleep disorders particularly sleep apnea, in subjects with IPF who participated in a regional patient-oriented seminar on this condition. We hypothesized that the frequency of Obstructive Sleep Apnea (OSA) and psychiatric sleep disorders would be disproportionately high in the IPF population. Methods: The project was a one-time survey administered to stable patients with IPF and their family members from the South eastern USA who participated in the “Living with IPF” public seminar at the Emory University campus. The survey used a validated questionnaire, i.e., Sleep Disorders Questionnaire (SDQ), to detect presence of Sleep Apnea (SA) and selected sleep disorders - Restless Legs Syndrome (RLS), Psychiatric Sleep Disorders (PSY) and narcolepsy (NAR). The questionnaire was administered to all participants (with and without IPF), in a confidential manner. The findings were used to determine if there were differences in the incidence of SA and other sleep disorders between individuals with IPF and those without the disease. Results: A total of 52 people agreed to participate in the study. One subject was excluded due to unclear IPF status. The median SDQ raw scores in IPF patients for SA, RLS, PSY and NAR were 28.7, 27.1, 26.2 and 26.5, respectively; overall, they were not statistically different in IPF patients versus control subjects. However, as validated in other studies, patients with history of OSA had significantly higher SDQ-SA scores. Conclusions: The present study aimed to investigate cross-sectionally the incidence of self-reported sleep conditions in patients with IPF versus healthy family member controls. Overall, we did not find a disproportionately higher incidence of sleep disorders in the

Idiopathic pulmonary fibrosis is characterized by progressive fibrosis of the lung and poor prognosis. This is the case report of a patient with idiopathic pulmonary fibrosis that highlights many of the controversies inherent in the diagnosis and treatment of this disease.

The hypothesis of this study was that D dimer, a specific degradation product of cross-linked fibrin, would be increased in the bronchoalveolar lavage (BAL) fluids of patients with sarcoidosis and that it would be related to other BAL parameters of disease activity. Eight of 10 sarcoidosis patients but none of 18 healthy volunteers had detectable BAL D dimer by enzyme immunoassay. Autoradiography revealed the presence of fibrinogen and D dimer in the BAL fluids from sarcoidosis patients. Bronchoalveolar lavage D dimer levels in sarcoidosis patients correlated with total BAL cells per milliliter, lymphocytes per milliliter, and total protein level, but not macrophages per milliliter. The D dimer in the BAL fluids from sarcoidosis patients did not correlate with D dimer in the blood. Our findings indicate that BAL D dimer parallels directly the lymphocytic alveolitis that characterizes pulmonary sarcoidosis.

The interstitial lung diseases (ILD) are a diverse group of lung disorders that involve primarily the parenchyma of the lung. Whether idiopathic or secondary to systemic disorders, inhaling exposures, or drugs, they inflame and scar the interstitium of the lungs and obliterate alveoli and capillary units. The scarring or fibrosis produces restrictive lung impairment while destruction of the alveoli, interstitium, and capillaries results in severe gas exchange abnormalities. Clinically, the ILD present subtly with progressive dyspnea on exertion and a dry cough. Rales or crackles on examination prompt chest radiography that may reveal bilateral infiltrates. These infiltrates are often treated as atypical pneumonias that fail to respond to antimicrobial therapy over weeks to months. Because of this and their infrequent presentation in the primary care setting, the diagnosis of ILD is commonly delayed. This paper highlights the natural history of the ILD in general, gives a broad overview of the pathophysiology in these diseases, and encourages greater awareness for the detection of ILD in primary care.

Granulomatous inflammation of the lung is characterized by the recruitment and organization of activated macrophages and lymphocytes in discrete lesions laced in a network of matrix proteins. These lesions, termed granulomas, represent an important defense mechanism against infectious organisms such as fungi and mycobacteria, but also can be elicited by noninfectious agents. Occasionally, this inflammatory reaction can develop for unknown reasons, causing a systemic illness termed sarcoidosis. The mechanisms involved in granuloma formation in the lung have not been elucidated entirely. However, studies performed in animal models of granuloma formation and in humans suggest important roles for specific soluble mediators (eg, cytokines, chemokines) produced by monocytic cells. If uncontrolled, granulomatous inflammation leads to excessive tissue remodeling, causing fibrosis and/or cavitation as seen in tuberculosis. This review summarizes our current understanding of the factors involved in granuloma formation in the lung with particular attention to their role in sarcoidosis and tuberculosis.

The incidence and severity of the acute respiratory distress syndrome (ARDS) is increased in critically ill patients with a prior history of chronic alcohol abuse; however, the specific mechanisms responsible for this association are unknown. Recently, we determined that chronic ethanol ingestion in rats decreased the alveolar epithelial lining fluid (ELF) concentration of the antioxidant glutathione (GSH), which is a characteristic finding in patients with ARDS. However, the effects of chronic alcohol abuse on the human alveolar epithelium are essentially unknown. Therefore, as a first step we asked if chronic alcohol abuse, independent of other comorbid conditions, decreases the concentration of GSH in the human lung. We determined that otherwise healthy chronic alcoholics had significantly decreased ELF concentrations of GSH compared with nonalcoholic control subjects (79 micromol [48 to 118 micromol] versus 576 micromol [493 to 728 mmol], p0.001). Furthermore, the percentage of GSH in the oxidized form was higher in the chronic alcoholics (9.8% [2.2 to 14.8%] versus 2.8% [0.4 to 4.0%] p = 0.05), indicative of increased utilization of GSH. This is the first report that chronic alcohol abuse alters GSH homeostasis in the human lung, and suggests a potential mechanism by which chronic alcohol abuse predisposes susceptible patients to develop ARDS.

Fibrinogen, with or without its conversion to fibrin, in the extravascular spaces of injured and inflamed lung tissues is thought to promote inflammatory responses that can eventually lead to pulmonary fibrosis. One of these responses likely involves the elaboration of the proinflammatory cytokine interleukin (IL)- 1beta. We reported that both fibrinogen and fibrin stimulated production of IL-1beta message and protein by binding to CD18 integrin receptors on normal human monocytes (J. Immunol., 1995;154:1879-1887). The purpose of the current work was to extend our previous observations by characterizing the transcriptional regulation of fibrinogen-induced IL-1beta expression. Our model was the human monocytic cell line U937 transfected with the human IL-1beta promoter connected to reporter genes. We found that fibrinogen induced the IL-1beta promoter and that induction could be blocked by anti-CD18 antibody. Transfection with deletion constructs of the promoter and DNA electrophoresis mobility gel shift assays suggested that sequences containing activator protein (AP)-1, cyclic adenosine monophosphate response element (CRE), and nuclear factor (NF)-kappaB cis-acting motifs regulate IL-1beta gene expression by fibrinogen. In combination with competitive cotransfection studies using consensus oligonucleotides mimicking these motifs, we conclude that transactivation of an NF-kappaB-like sequence is necessary for induction of the IL-1beta gene, that activation of CRE may repress induction of the gene, and that AP-1 potentially modulates induction and repression of the gene induced by fibrinogen. This study begins to define the molecular mechanisms by which fibrin(ogen) promotes and regulates expression of the IL-1beta gene and further substantiates a role for fibrin(ogen) in tissue injury and inflammation.

Aberrant deposition of extracellular matrices (ECMs) may affect lung inflammation by influencing cell adhesion, migration, and activation. Little is known about the expression of ECMs in lungs with granulomatous inflammation. Therefore the authors investigated the distribution of ECMs, matrix receptors of the integrin family, and transforming growth factor-beta 1 (TGF-beta 1) in lungs from patients with pulmonary sarcoidosis and animals with experimental granulomatosis. Immunohistochemistry revealed increased deposition of type I collagen and fibronectin in human lung granulomas when compared with healthy human lungs. Procollagen type I and cellular fibronectin also were increased, suggesting local synthesis of ECM in sarcoid granulomas. These findings were accompanied by increased staining for fibronectin (alpha 5 beta 1) and collagen (alpha 2 beta 1) integrin receptors. The matrix-inducing cytokine TGF-beta 1 was co-distributed with the aforementioned molecules in the granulomas, whereas no significant staining for TGF-beta 1 was found in healthy lungs. Similar to sarcoid lungs, analysis of lung sections obtained from a murine model of granuloma formation revealed increased expression of fibronectin, collagen, integrin receptors, and TGF-beta 1 within granulomas. Based on these observations, there is increased expression of ECM and matrix receptors in both human and experimental lung granulomas. Such alterations may influence the recruitment and activation of inflammatory cells and fibroblasts, promoting granuloma formation and remodeling of tissue by fibrosis. Activation of mononuclear cells resulting in production of TGF-beta 1 is likely to contribute to the changes described.

Diffuse pulmonary inflammation in interstitial lung diseases is associated with increased coagulation in the extravascular spaces of the lung. We hypothesized that conditions favoring coagulation over fibrinolysis in the lung are related to inflammation. Pulmonary coagulation and fibrinolysis were studied in two strains of mice susceptible or resistant to the development of lung inflammation in response to the mycobacterial cell wall glycolipid trehalose-6,6'-dimycolate (TDM). Susceptible animals treated with TDM intravenously develop well-organized collections of mononuclear cells in the lung parenchyma referred to as granulomas in this report. More granulomas were found in the susceptible ICR mice than in the resistant A/J mice after intravenous administration of TDM (7 +/- 1 granulomas/mm2 versus 1 +/- 0.3 granulomas/mm2, p = 0.005). Granuloma formation was associated with increased lung procoagulant activity (PCA) measured in bronchoalveolar lavage (BAL) cell lysates from susceptible mice. In contrast, TDM-resistant A/J mice challenged with TDM did not have a significant BAL cell PCA response, but expressed several-fold greater levels of lung BAL fluid plasminogen activator activity (PAA) than ICR mice. To examine the role of coagulation in the TDM pulmonary inflammatory response, susceptible C57Bl/10SnJ mice were anticoagulated by oral administration of warfarin prior to challenge of TDM; these mice developed fewer pulmonary granulomas than TDM-treated mice without warfarin treatment (2.6 +/- 0.5 granulomas/mm2 versus 6.5 +/- 0.8 granulomas/mm2, p < 0.001) but had similar BAL cell PCA and lung inflammatory changes as measured by lung weights and BAL cellularity.(ABSTRACT TRUNCATED AT 250 WORDS)

A high pressure liquid chromatographic (HPLC) method is described for the simultaneous determination of folpet, piperonyl butoxide, and pyrethrins in aerosol pesticide formulations. The aerosol propellants are removed from the can and the remaining components are determined by HPLC, using an U1-trasphere 5 μm ODS reverse phase column and a UV detector at 254 nm. Recoveries for the 3 components are greater than 98%.