Catherine A. Meldrum

Bio: Catherine A. Meldrum is an academic researcher from University of Michigan. The author has contributed to research in topics: COPD & Spirometry. The author has an hindex of 17, co-authored 33 publications receiving 1037 citations.

Increased Cytokine Response of Rhinovirus-infected Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease

Abstract: Rationale: Airway inflammation is a central feature of chronic obstructive pulmonary disease (COPD). COPD exacerbations are often triggered by rhinovirus (RV) infection.Objectives: We hypothesized that airway epithelial cells from patients with COPD maintain a proinflammatory phenotype compared with control subjects, leading to greater RV responses.Methods: Cells were isolated from tracheobronchial tissues of 12 patients with COPD and 10 transplant donors. Eight patients with COPD had severe emphysema, three had mild to moderate emphysema, and one had no emphysema. All had moderate to severe airflow obstruction, and six met criteria for chronic bronchitis or had at least one exacerbation the previous year. Cells were grown at air–liquid interface and infected with RV serotype 39. Cytokine and IFN expression was measured by ELISA. Selected genes involved in inflammation, oxidative stress, and proteolysis were assessed by focused gene array and real-time polymerase chain reaction.Measurements and Main Resul...

Lung Dendritic Cell Expression of Maturation Molecules Increases with Worsening Chronic Obstructive Pulmonary Disease

Abstract: Rationale: Dendritic cells (DCs) have not been well studied in chronic obstructive pulmonary disease (COPD), yet their integral role in activating and differentiating T cells makes them potential participants in COPD pathogenesis.Objectives: To determine the expression of maturation molecules by individual DC subsets in relationship to COPD stage and to expression of the acute activation marker CD69 by lung CD4+ T cells.Methods: We nonenzymatically released lung leukocytes from human surgical specimens (n = 42) and used flow cytometry to identify three DC subsets (mDC1, mDC2, and pDC) and to measure their expression of three costimulatory molecules (CD40, CD80 and CD86) and of CD83, the definitive marker of DC maturation. Spearman nonparametric correlation analysis was used to identify significant correlations between expression of DC maturation molecules and COPD severity.Measurements and Main Results: Expression of CD40 by mDC1 and mDC2 and of CD86 by mDC2 was high regardless of GOLD stage, but CD80 and...

A New Approach for Identifying Patients with Undiagnosed Chronic Obstructive Pulmonary Disease.

Abstract: Rationale: Chronic obstructive pulmonary disease (COPD) is often unrecognized and untreatedObjectives: To develop a method for identifying undiagnosed COPD requiring treatment with currently available therapies (FEV1 <60% predicted and/or exacerbation risk)Methods: We conducted a multisite, cross-sectional, case-control study in US pulmonary and primary care clinics that recruited subjects from primary care settings Cases were patients with COPD and at least one exacerbation in the past year or FEV1 less than 60% of predicted without exacerbation in the past year Control subjects were persons with no COPD or with mild COPD (FEV1 ≥60% predicted, no exacerbation in the past year) In random forests analyses, we identified the smallest set of questions plus peak expiratory flow (PEF) with optimal sensitivity (SN) and specificity (SP)Measurements and Main Results: PEF and spirometry were recorded in 186 cases and 160 control subjects The mean (SD) age of the sample population was 627 (101) years; 55

Cytotoxic Potential of Lung CD8+ T Cells Increases with Chronic Obstructive Pulmonary Disease Severity and with In Vitro Stimulation by IL-18 or IL-15

Abstract: Lung CD8(+) T cells might contribute to progression of chronic obstructive pulmonary disease (COPD) indirectly via IFN-gamma production or directly via cytolysis, but evidence for either mechanism is largely circumstantial. To gain insights into these potential mechanisms, we analyzed clinically indicated lung resections from three human cohorts, correlating findings with spirometrically defined disease severity. Expression by lung CD8(+) T cells of IL-18R and CD69 correlated with severity, as did mRNA transcripts for perforin and granzyme B, but not Fas ligand. These correlations persisted after correction for age, smoking history, presence of lung cancer, recent respiratory infection, or inhaled corticosteroid use. Analysis of transcripts for killer cell lectin-like receptor G1, IL-7R, and CD57 implied that lung CD8(+) T cells in COPD do not belong to the terminally differentiated effector populations associated with chronic infections or extreme age. In vitro stimulation of lung CD8(+) T cells with IL-18 plus IL-12 markedly increased production of IFN-gamma and TNF-alpha, whereas IL-15 stimulation induced increased intracellular perforin expression. Both IL-15 and IL-18 protein expression could be measured in whole lung tissue homogenates, but neither correlated in concentration with spirometric severity. Although lung CD8(+) T cell expression of mRNA for both T-box transcription factor expressed in T cells and GATA-binding protein 3 (but not retinoic acid receptor-related orphan receptor gamma or alpha) increased with spirometric severity, stimulation of lung CD8(+) T cells via CD3epsilon-induced secretion of IFN-gamma, TNF-alpha, and GM-CSF, but not IL-5, IL-13, and IL-17A. These findings suggest that the production of proinflammatory cytokines and cytotoxic molecules by lung-resident CD8(+) T cells contributes to COPD pathogenesis.

Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.

Abstract: Background: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, Eur...

Idiopathic Pulmonary Fibrosis.

Abstract: Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis appears to be increasing in incidence. It requires early recognition and intervention with supportive care and pharmacologic agents to forestall its progression. Lung transplantation may be curative, but the disease may recur in transplanted lungs.

Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

Abstract: Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.

Idiopathic pulmonary fibrosis

Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive lung scarring and the histological picture of usual interstitial pneumonia (UIP). It is associated with increasing cough and dyspnoea and impaired quality of life. IPF affects ∼3 million people worldwide, with incidence increasing dramatically with age. The diagnostic approach includes the exclusion of other interstitial lung diseases or overlapping conditions and depends on the identification of the UIP pattern, usually with high-resolution CT; lung biopsy might be required in some patients. The UIP pattern is predominantly bilateral, peripheral and with a basal distribution of reticular changes associated with traction bronchiectasis and clusters of subpleural cystic airspaces. The biological processes underlying IPF are thought to reflect an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible ageing individual, although many questions remain on how to define susceptibility. Substantial progress has been made in the understanding of the clinical management of IPF, with the availability of two pharmacotherapeutic agents, pirfenidone and nintedanib, that decrease physiological progression and likely improve progression-free survival. Current efforts are directed at identifying IPF early, potentially relying on combinations of biomarkers that include circulating factors, demographics and imaging data.