Macular pigment and macular volume in eyes of patients with cystic fibrosis

Abstract

Background. Because patients with cystic fibrosis (CF) are living longer, chronic malabsorption of carotenoids associated with CF resulting in decreased macular pigment (MP) may affect macular long-term health in later-life pathology. This study compared the macular pigment optical density (MPOD) and corresponding central macular volume (MV) of adult CF subjects and age-matched normal controls subjects to determine whether chronic malabsorption associated with CF could adversely affect macular photoreceptor anatomy. Objective. Our aim was to compare MPOD with measurements of central MV in CF patients with age-matched controls. Design. In nine adult CF patients (ages: 29–46) without a history of carotenoid supplementation or known retinal or optic nerve disease MPOD and MV were measured by heterochromatic flicker photometry (HFP) and optical coherence tomography (OCT), respectively, and compared to results obtained from 14 age-matched controls. Results. MPOD was significantly reduced at 15’ and 30’ eccentricities in CF subjects compared to normal subjects (mean difference ?0.21 at 15’, ?0.25 at 30’, p < 0.005). No significant difference, in MV noted at any of the eccentricities tested between CF and normal subjects (CF: normal MV ratios ranged from 0.94 to 1.1 for all eccentricities with p > 0.1 at all eccentricities). Best corrected vision acuity and fundus examination were normal in all subjects. Conclusions. Unsupplemented CF patients have markedly lower levels of macular carotenoids (e.g., lutein and zeaxanthin), but well-maintained visual function and no significant reductions in central MV primarily composed of macular photoreceptors. Future studies are needed to determine whether the lifelong decrease in protective central retinal carotenoids predisposes CF patients to later-life retinal pathology.     

Targets for cystic fibrosis therapy: proteomic analysis and correction of mutant cystic fibrosis transmembrane conductance regulator

Proteomic analysis has proved to be an important tool for understanding the complex nature of genetic disorders, such as cystic fibrosis (CF), by defining the cellular protein environment (proteome) associated with wild-type and mutant proteins. Proteomic screens identified the proteome of CF transmembrane conductance regulator (CFTR), and provided fundamental information to studies designed for understanding the crucial components of physiological CFTR function. Simultaneously, high-throughput screens for small-molecular correctors of CFTR mutants provided promising candidates for therapy. The majority of CF cases are caused by nucleotide deletions (ΔF508 CFTR; >75%), resulting in CFTR misfolding, or insertion of premature termination codons (～10%), leading to unstable mRNA and reduced levels of truncated dysfunctional CFTR. In this article, we review recent results of proteomic screens, developments in identifying correctors for the most frequent CFTR mutants, and comment on how integration of the knowledge gained from these studies may aid in finding a cure for CF and a number of other genetic disorders.     

Proteomic biomarker discovery for the monogenic disease cystic fibrosis

Proteomics was initially viewed as a promising new scientific discipline to study complex disorders such as polygenic, infectious and environment-related diseases. However, the first attempts to understand a monogenic disease such as cystic fibrosis (CF) by proteomics-based approaches have proved quite rewarding. In CF, the impairment of a unique protein, the CF transmembrane conductance regulator, does not completely explain the complex and variable CF clinical phenotype. The great advances in our knowledge about the molecular and cellular consequences of such impairment have not been sufficient to be translated into effective treatments, and CF patients are still dying due to chronic progressive lung dysfunction. The progression of proteomics application in CF will certainly unravel new proteins that could be useful as biomarkers either to elucidate CF basic mechanisms and to better monitor the disease progression, or to promote the development of novel therapeutic strategies against CF. This review will summarize the recent technological advances in proteomics and the first results of its application to address the most important issues in the CF field.     

Sphingosine-1-phosphate: A Janus-faced mediator of fibrotic diseases

Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that acts either on G protein-coupled S1P receptors on the cell surface or via intracellular target sites. In addition to the well established effects of S1P in angiogenesis, carcinogenesis and immunity, evidence is now continuously accumulating which demonstrates that S1P is an important regulator of fibrosis. The contribution of S1P to fibrosis is of a Janus-faced nature as S1P exhibits both pro- and anti-fibrotic effects depending on its site of action. Extracellular S1P promotes fibrotic processes in a S1P receptor-dependent manner, whereas intracellular S1P has an opposite effect and dampens a fibrotic reaction by yet unidentified mechanisms. Fibrosis is a result of chronic irritation by various factors and is defined by an excess production of extracellular matrix leading to tissue scarring and organ dysfunction. In this review, we highlight the general effects of extracellular and intracellular S1P on the multistep cascade of pathological fibrogenesis including tissue injury, inflammation and the action of pro-fibrotic cytokines that stimulate ECM production and deposition. In a second part we summarize the current knowledge about the involvement of S1P signaling in the development of organ fibrosis of the lung, kidney, liver, heart and skin. Altogether, it is becoming clear that targeting the sphingosine kinase-1/S1P signaling pathway offers therapeutic potential in the treatment of various fibrotic processes. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

Lysoglycerophospholipids in chronic inflammatory disorders: The PLA2/LPC and ATX/LPA axes

Lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), the most prominent lysoglycerophospholipids, are emerging as a novel class of inflammatory lipids, joining thromboxanes, leukotrienes and prostaglandins with which they share metabolic pathways and regulatory mechanisms. Enzymes that participate in LPC and LPA metabolism, such as the phospholipase A₂ superfamily (PLA₂) and autotaxin (ATX, ENPP2), play central roles in regulating LPC and LPA levels and consequently their actions. LPC/LPA biosynthetic pathways will be briefly presented and LPC/LPA signaling properties and their possible functions in the regulation of the immune system and chronic inflammation will be reviewed. Furthermore, implications of exacerbated LPC and/or LPA signaling in the context of chronic inflammatory diseases, namely rheumatoid arthritis, multiple sclerosis, pulmonary fibrosis and hepatitis, will be discussed. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

A novel marker for assessment of liver matrix remodeling: An enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated type I collagen neo-epitope (C1M)

A competitive enzyme-linked immunosorbent assay (ELISA) for detection of a type I collagen fragment generated by matrix metalloproteinases (MMP) -2, -9 and -13, was developed (CO1-764 or C1M). The biomarker was evaluated in two preclinical rat models of liver fibrosis: bile duct ligation (BDL) and carbon tetra chloride (CCL4)-treated rats. The assay was further evaluated in a clinical study of prostate-, lung- and breast-cancer patients stratified according to skeletal metastases. A technically robust ELISA assay specific for a MMP-2, -9 and -13 neo-epitope was produced and seen to be statistically elevated in BDL rats compared to baseline levels as well as significantly elevated in CCL4 rats stratified according to the amount of total collagen in the livers. CO1-764 levels also correlated significantly with total liver collagen and type I collagen mRNA expression in the livers. Finally, the CO1-764 marker was not correlated with skeletal involvement or number of bone metastases. This ELISA has the potential to assess the degree of liver fibrosis in a non-invasive manner.     

Circulating microRNAs as potential biomarkers for smoking-related interstitial fibrosis

Numerous efforts have been made to indentify reliable and predictive biomarkers to detect the early signs of smoking-induced lung disease. Using 6-month cigarette smoking in mice, we have established smoking-related interstitial fibrosis (SRIF). Microarray analyses and cytokine/chemokine biomarker measurements were made to select circulating microRNAs (miRNAs) biomarkers. We have demonstrated that specific miRNAs species (miR-125b-5p, miR-128, miR-30e, and miR-20b) were significantly changed, both in the lung tissue and in plasma, and exhibited mainstream (MS) exposure duration-dependent pathological changes in the lung. These findings suggested a potential use of specific circulating miRNAs as sensitive and informative biomarkers for smoking-induced lung disease.     

Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist

Background

Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the airways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8, play an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule antagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2 antagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers.

Methods

Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study. AZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and induced sputum was collected 6 h later.

Results

Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79% reduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction in neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages (47%), leukotriene B₄ (39%) and CXCL8 (52%).

Conclusions

AZD8309 inhibited LPS-induced inflammation measured in induced sputum of normal volunteers, indicating that this treatment may be useful in the treatment of neutrophilic diseases of the airways, such as COPD, severe asthma and cystic fibrosis.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00860821","term_id":"NCT00860821"}}NCT00860821.