Characterising the Regional Immunity of Lung Disease

Abstract

Rebecca J Edge. PhD Medicine 4yr (IIRM). Characterising the Regional Immunity of Lung Disease. 2020. Background; Chronic lung diseases are a major cause of morbidity and premature mortality worldwide, and pose a significant public health concern. An aberrant inflammatory response plays a key role in respiratory diseases, however many of these diseases are severely heterogeneous. Although there is a recognised regional variation in underlying inflammatory processes, there is a fundamental lack of research into immunophenotyping of the lung as a whole, and as such, cellular immunity across the lungs is poorly understood. Hypothesis; There are fundamental differences in inflammation across the lungs of patients with end stage chronic lung disease that could be characterised by regional sampling of different lobes of the lungs. It was expected that fundamental discovery in the early phases would dictate the direction of later investigations. Methods; Wedge biopsy samples were obtained from the upper, middle and lower lobes of explanted lungs from transplant recipients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and cystic fibrosis. Leukocyte phenotyping, cytokine expression and immune checkpoint signaling were explored. Results; The results demonstrated a high degree of heterogeneity in inflammatory distribution across the lungs, as well as between patients, and led to several important observations. Firstly, female patients with emphysematous COPD have greater heterogeneity in leukocytes, compared to males. The number of leukocytes is significantly elevated in the left lungs of patients with ILD compared to the right lung, and there was an unprecedented increase in the frequency of intermediate monocytes in ILD, which coincided with areas of disease severity. The study is also the first of its kind to characterise immune checkpoint molecules in lung tissue without cancer, in two different chronic lung conditions, identifying significant differences in expression between the two cohorts. Conclusion; Is it clear from the evidently heterogenic inflammation described between patients, lungs and lobes, that we should not generalise inflammation in lung disease. Isolated sampling techniques can place exorbitant or insubstantial importance to a finding that may not be relevant to the lung or disease as a whole. The characterisation of regional heterogeneity in chronic lung disease provides an important first step to greater insight into end stage inflammation in lung disease, and could eventually overcome the barriers of lobar heterogeneity to accelerate the effectiveness of lung specific inflammation treatments.

Date of Award	31 Dec 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Rajamiyer Venkateswaran (Supervisor) & James Fildes (Supervisor)