Mapping Chemical and Microbiological Heterogeneity Throughout Explanted Cystic Fibrosis Lung Specimens

  • STATUS
    Recruiting
  • End date
    Jul 18, 2022
  • participants needed
    20
  • sponsor
    University of Minnesota
Updated on 18 September 2021
fibrosis
lung transplant
respiratory disease
epithelial cells

Summary

There is plenty of evidence to suggest that the lung is not uniform. The internal surface area is 30 times that of skin, and the different bronchioles/bronchi/alveoli differ greatly in blood perfusion, temperature, oxygen tension, and pH. Also, particularly in the context of respiratory disease, notable differences are present in the structure of epithelial cells, cilia, production of mucus, and inflammatory/immune responses. All of these factors are known to impact the physiology of bacteria, yet, there is very little understanding of how they impact a) the presence/absence of particular bacterial species throughout the respiratory tract, or b) the metabolic processes used by these bacteria within the human host environment. A greater understanding of the relationships between environmental (chemical) gradients in the lungs of diseased patients (particularly those with cystic fibrosis) and the microbial communities that are present may lead to novel hypotheses about manipulation of the respiratory environment for therapeutic benefit. To investigate this further, the investigators propose to use explanted lung specimens from cystic fibrosis patients to test the following hypothesis:

Hypothesis: In patients with cystic fibrosis, bacterial community composition, metabolism and environmental chemistry will vary depending on their spatial location within the airways.

Description

To study this in greater detail, the investigators propose to study explanted tissue of CF patients that are scheduled to undergo single or double lung transplant surgery as a late-stage disease therapeutic strategy. This population will be limited to the Adult CF clinic, as pediatric subjects are rarely candidates for lung transplantation. The Adult CF Clinic performs upwards of 20 surgeries per year, and tissue that is explanted is typically discarded. Using this tissue, the investigators propose the following objectives:

  1. Use 16S culture-independent sequencing to characterize the spatial distribution of bacterial pathogens throughout the lungs of cystic fibrosis patients. Lungs will be dissected into 5 separate lobes, and mucus material will be collected, homogenized, and processed for bacterial species identification.
  2. Perform detailed analysis of specific gene expression throughout the respiratory tract that will serve as a proxy of environmental conditions found there. Using the same approach in Aim 1, bacterial mRNA will be extracted using established procedures. A subset of environmentally-specific genes will be detected to provide a readout of bacterial metabolism in use within the CF lung environment.
  3. Use in situ hybridization imaging to visualize the spatial distribution of specific bacteria and their gene expression profiles (informed by data generated in objectives 1 and 2). The bacteria and gene candidates identified/studied in Aims 1 and Aims 2 will then be subject to analysis using in situ hybridization imaging. Tissue will be processed using microtomy and fluorescent probes will be applied to image the spatial distribution of specific bacterial species and their metabolisms throughout the respiratory tract.

Information collected in these three objectives will then be paired with patient data (age, genotype, prior medical treatments, clinical microbiology data) to generate better working models of late-stage disease in CF patients.

Details
Condition Cystic Fibrosis, Lung Disease, Pulmonary Disease, Pancreatic Disorders, Pancreatic disorder
Clinical Study IdentifierNCT02128711
SponsorUniversity of Minnesota
Last Modified on18 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

diagnosis of cystic fibrosis
eligible for lung transplantation
exhausted other available therapies without success
informed consent

Exclusion Criteria

there are no exclusion criteria
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