Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?

Cystic fibrosis-related diabetes (CFRD) is the most frequent complication of cystic fibrosis (CF) and associated with increased mortality. Why patients have an accelerated loss of lung function before the diagnosis of CFRD remains poorly understood. We reported that patients with or without CFRD had increased glucose excursions when compared to healthy peers. Studies have demonstrated that patients with CF have increased glucose fluctuations and hyperglycemia and that this may affect the clinical course of CF and lead to lymphocyte dysfunction. T-helper 17 (Th17) lymphocytes produce and secrete the pro-inflammatory cytokine IL-17. The Th17 pathway is involved in CF lung inflammation, ß-cell destruction in type 1 diabetes (T1D) and Th17 cells of patients with type 2 diabetes have increased production of IL-17 when compared to healthy peers. Also, regulatory T-cells (Tregs) have been shown to be dysfunctional and produce IL-17 in T1D. Furthermore, vitamin D can affect inflammation in CF, diabetes and the differentiation of lymphocytes. In this review, we discuss the potential roles of hyperglycemia on Th17 cells, Tregs and IL-17 as a potential cause for accelerated lung function decline before CFRD and how this could be modulated by vitamin D or by directly intervening in the IL-17A pathway.

Agreement of bioelectric impedance analysis and dual-energy X-ray absorptiometry for body composition evaluation in adults with cystic fibrosis.

Malnutrition in cystic fibrosis (CF) is associated with increased mortality and can lead to fat-free (FFM) and fat mass (FM) loss. Dual-energy X-ray absorptiometry (DXA) is used and validated to measure FFM and FM. DXA's high cost has led to the utilization of less costly techniques such as bioelectrical impedance analysis (BIA). The aim of this study was to determine the agreement of FFM, FM and %FM measurements taken with DXA and BIA in adults with CF. We measured FFM, FM and %FM in 34 adults with CF with a leg-to-leg BIA and an iDXA and determined agreement using Bland-Altman analysis. While DXA and BIA measurements were well correlated (r > 0.8), mean biases between both methods were between 8 and 11%. BIA underestimated FM and %FM and overestimated FFM. In a clinical research setting where these measurements are used to phenotype patients, BIA cannot replace DXA.

Cigarette smoke-induced proteostasis imbalance in obstructive lung diseases.

The airway and alveolar surface is exposed daily to 8,000 L of air containing oxygen, particles, bacteria, allergens and pollutants, all of which have the potential to induce oxidative stress within cells. If one is also a cigarette smoker, then the exposure to reactive oxidants increases exponentially. More than any other tissue, the lung is at risk of undergoing oxidative changes in protein expression, structure and function. The oxidant burden of chronic cigarette smoke exposure can overwhelm the lung cells' capacity to maintain proteostasis, a process of regulated protein synthesis, folding and turnover. Somewhat surprisingly, most chronic cigarette smokers do not develop chronic obstructive pulmonary disease (COPD), likely because cells initiate a highly effective unfolded protein response (UPR) in the presence of oxidant-derived endoplasmic reticulum (ER) stress that allows cells to survive. The UPR initiates several signaling pathways that decrease protein translation, limit cell cycle progression, increase protein degradation and chaperone-mediated protein folding, and activate the transcription factor Nrf2 that induces antioxidant gene expression. Each of these actions decreases ER stress in a process of "healthy proteostasis". If these responses are insufficient, apoptosis ensues. In this article, we review the mechanisms of healthy and dysfunctional proteostasis related to cigarette smoke exposure and COPD.