Biomedical subjects

Laura L Koth

Publications and source records attributed to Laura L Koth.

7 recordsLinked to original sources

PubMed2026

Pilot study identifying distinct circulating proteomic profiles associated with longitudinal CT-defined fibrotic and inflammatory sarcoidosis.

INTRODUCTION: Pulmonary sarcoidosis exhibits heterogeneous clinical trajectories ranging from self-limited disease resolution to chronic progressive fibrosis, yet reliable biomarkers capable of distinguishing these disease patterns remain lacking. Whether longitudinal CT-defined sarcoidosis phenotypes are associated with distinct circulating molecular signatures remains unknown. METHODS: We performed high-throughput plasma proteomics (SomaScan 11K) in participants with pulmonary sarcoidosis classified into longitudinal chest CT-defined progressive fibrosis, progressive nodular inflammatory disease, or resolving disease trajectories, along with healthy controls. CT phenotypes were assigned based on predefined longitudinal changes in reticulation, traction bronchiectasis, nodular involvement, and mediastinal lymphadenopathy across serial CT scans. One plasma sample per participant was selected from the study visit corresponding to the CT time point at which criteria for the assigned longitudinal phenotype were met. Principal component analysis, hierarchical clustering, pathway enrichment, and correlation-based analyses linking protein expression to quantitative CT features were used to evaluate whether distinct longitudinal CT phenotypes were associated with divergent proteomic signatures. RESULTS: Principal component analysis and hierarchical clustering suggested partial segregation by CT-defined phenotype. Longitudinal CT phenotypes were associated with distinct pathway-level proteomic signatures, with progressive fibrosis enriched for epithelial-mesenchymal transition signaling, and progressive nodular inflammatory disease enriched for mTORC1, MYC, oxidative phosphorylation, adipogenesis, and fatty acid metabolism pathways. Correlation analyses showed coordinated protein-expression patterns associated with fibrotic CT features and mediastinal lymph node enlargement. DISCUSSION: These findings suggest that longitudinal CT-defined fibrotic and inflammatory sarcoidosis phenotypes are associated with distinct pathway-level proteomic signatures. This pilot study provides preliminary proof-of-concept evidence that integrating longitudinal CT imaging phenotypes with plasma proteomics may serve as a framework for future mechanistic studies and biomarker discovery in pulmonary sarcoidosis.

Humans↗

PubMed2005

A distinctive alveolar macrophage activation state induced by cigarette smoking.

RATIONALE: Macrophages are believed to play a central role in emphysema based largely on data from mouse models. However, the relevance of these models to smoking-related lung disease in humans is uncertain. OBJECTIVES: We sought to comprehensively characterize the effects of smoking on gene expression in human alveolar macrophages and to compare these with effects seen in transgenic mouse models of emphysema. METHODS: We used DNA microarrays with genomewide coverage to analyze alveolar macrophages from 15 smokers, 15 nonsmokers, and 15 subjects with asthma (disease control). Selected gene expression changes were validated by polymerase chain reaction and ELISA. Expression changes were compared with those identified by microarray analysis of interleukin-13-overexpressing and integrin-beta6-deficient mice, which both develop emphysema. MEASUREMENTS AND MAIN RESULTS: All 15 smokers shared a common pattern of macrophage gene expression that distinguished them from nonsmokers, a finding not observed in subjects with asthma. We identified 110 genes as differentially expressed in smokers despite using conservative statistical methods. Matrix metalloproteinase 12, a proteinase that plays a critical role in mouse models, was the third most highly induced gene in smokers (ninefold, p < 0.0001). However, most changes in smokers were not reflected in mouse models. One such finding was increased osteopontin expression in smokers (fourfold, p = 0.006), which was confirmed at the protein level and correlated with the degree of airway obstruction. CONCLUSIONS: Smoking induces a remarkably consistent and distinctive pattern of alveolar macrophage activation. These studies identify aspects of mouse models that are directly relevant to human smokers and also reveal novel potential mediators of smoking-related diseases.

Adult↗

PubMed2005

Hypersensitivity pneumonitis reaction to Mycobacterium avium in household water.

BACKGROUND: Hypersensitivity pneumonitis has been described with exposure to aerosolized Mycobacterium avium complex (MAC) in indoor hot tubs (hot tub lung). OBJECTIVES: To describe a case of MAC-associated hypersensitivity pneumonitis-like reaction possibly from showering and review previous hot tub lung reports. METHODS: For the case report, we investigated a patient with histologically diagnosed hypersensitivity pneumonitis and MAC-positive sputum culture findings. Mycobacterial cultures were obtained from his home and workplace. Isolates were typed using pulsed-field gel electrophoresis. For the review, MEDLINE and EMBASE were searched for hot tub lung reports, which were reviewed and summarized. RESULTS: A 50-year-old man had progressive dyspnea and episodic fever and myalgias. Pulmonary function testing results revealed obstruction and impaired diffusion; a chest CT scan found diffuse, centrilobular, ground-glass nodules, and air trapping, and a lymphocytic alveolitis with an elevated CD4/CD8 ratio. Transbronchial biopsy showed multiple well-formed nonnecrotizing granulomas. Multiple respiratory samples and shower and bathtub specimens grew MAC, with matching pulsed-field gel electrophoresis patterns. The patient changed from showering to tub bathing. Prednisone and antimycobacterial drugs were administered for approximately 1 year. His symptoms, pulmonary function abnormalities, and CT scan findings resolved. The literature review yielded 36 cases of hot tub lung. Clinical features included dyspnea (97%), cough (78%), and fever (58%). Pulmonary function testing showed obstruction (67%), restriction (55%), and impaired diffusion (75%). A chest CT scan showed ground-glass opacification (95%) and nodules (67%). Granulomas were well-formed in 95%. Treatments included discontinuation of hot tub use and prednisone, antimycobacterial drugs, or both. Outcomes were favorable. CONCLUSIONS: A hypersensitivity pneumonitis-like reaction to mycobacteria can occur from exposures other than hot tubs. There are key differences between classic hypersensitivity pneumonitis and MAC-associated hypersensitivity pneumonitis. Antimycobacterial therapy may be required. The possibility of MAC hypersensitivity pneumonitis from showering raises potential implications in the investigation of patients with hypersensitivity pneumonitis.

Alveolitis, Extrinsic Allergic↗

PubMed2004

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2.

BACKGROUND: Asthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. METHODS: To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. RESULTS: We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. CONCLUSION: We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2.

Animals↗

PubMed2003

Spotted long oligonucleotide arrays for human gene expression analysis.

DNA microarrays produced by deposition (or 'spotting')of a single long oligonucleotide probe for each gene may be an attractive alternative to other types of arrays. We produced spotted oligonucleotide arrays using two large collections of approximately 70-mer probes, and used these arrays to analyze gene expression in two dissimilar human RNA samples. These samples were also analyzed using arrays produced by in situ synthesis of sets of multiple short (25-mer) oligonucleotides for each gene (Affymetrix GeneChips). We compared expression measurements for 7344 genes that were represented in both long oligonucleotide probe collections and the in situ-synthesized 25-mer arrays. We found strong correlations (r = 0.8-0.9) between relative gene expression measurements made with spotted long oligonucleotide probes and in situ-synthesized 25-mer probe sets. Spotted long oligonucleotide arrays were suitable for use with both unamplified cDNA and amplified RNA targets, and are a cost-effective alternative for many functional genomics applications. Most previously reported evaluations of microarray technologies have focused on expression measurements made on a relatively small number of genes. The approach described here involves far more gene expression measurements and provides a useful method for comparing existing and emerging techniques for genome-scale expression analysis.

Cell Line↗

PubMed2002

Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma.

Asthma is an increasingly common disease that remains poorly understood and difficult to manage. This disease is characterized by airway hyperreactivity (AHR, defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction and chronic eosinophilic inflammation. AHR and mucus overproduction are consistently linked to asthma symptoms and morbidity. Asthma is mediated by Th2 lymphocytes, which produce a limited repertoire of cytokines, including interleukin-4 (IL-4), IL-5, IL-9 and IL-13. Although each of these cytokines has been implicated in asthma, IL-13 is now thought to be especially critical. In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia. Furthermore, IL-13 delivery to the airway causes all of these effects. IL-13 is thus both necessary and sufficient for experimental models of asthma. However, the IL-13-responsive cells causing these effects have not been identified. Here we show that mice lacking signal transducer and activator of transcription 6 (STAT6) were protected from all pulmonary effects of IL-13. Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology. These results demonstrate the importance of direct effects of IL-13 on epithelial cells in causing two central features of asthma.

Animals↗

PubMed2002

Hard metal interstitial lung disease: high-resolution computed tomography appearance.

Hard metal interstitial lung disease (HM-ILD) is a rare form of interstitial lung disease caused by aerosolized particulates containing cobalt inhaled during the manufacture or grinding of hard metal. The high-resolution computed tomography (HRCT) appearance of HM-ILD includes reticulation, traction bronchiectasis, and large peripheral cystic spaces in a mid and upper lung distribution. This appearance, along with a consistent occupational exposure, should specifically suggest the diagnosis of HM-ILD.

Adult↗