Vitamin A Deficiency and the Lung

Abstract

Vitamin A (all-trans-retinol) is a fat-soluble micronutrient which together with its natural derivatives and synthetic analogues constitutes the group of retinoids. They are involved in a wide range of physiological processes such as embryonic development, vision, immunity and cellular differentiation and proliferation. Retinoic acid (RA) is the main active form of vitamin A and multiple genes respond to RA signalling through transcriptional and non-transcriptional mechanisms. Vitamin A deficiency (VAD) is a remarkable public health problem. An adequate vitamin A intake is required in early lung development, alveolar formation, tissue maintenance and regeneration. In fact, chronic VAD has been associated with histopathological changes in the pulmonary epithelial lining that disrupt the normal lung physiology predisposing to severe tissue dysfunction and respiratory diseases. In addition, there are important alterations of the structure and composition of extracellular matrix with thickening of the alveolar basement membrane and ectopic deposition of collagen I. In this review, we show our recent findings on the modification of cell-junction proteins in VAD lungs, summarize up-to-date information related to the effects of chronic VAD in the impairment of lung physiology and pulmonary disease which represent a major global health problem and provide an overview of possible pathways involved.

Keywords: E-cadherin; N-cadherin; Vitamin A deficiency; collagen; epithelial–mesenchymal transition; extracellular matrix; lung; pulmonary disease; retinoic acid; retinol.

Figure 1

Intracellular signalling pathways of vitamin A. (A) Nuclear receptor signalling pathway. In blood, hydrophobic retinol (ROH) is bound by retinol-binding protein (RBP4) and transthyretin (TTR) and retinoic acid (RA) is bound to albumin. They enter the cell through membrane diffusion or ROH via the membrane transporter stimulated by RA (STRA6). Inside the cell, ROH is found in cytosol bound to cellular retinol binding protein (CRBP), metabolized into retinaldehyde (RAL), which is irreversibly converted into RA. Intracellular RA is transported by cellular retinoic acid binding proteins (CRABP) or fatty acid binding protein 5 (FABP5) and it can be degraded by CYP26 or translocated to the nucleus, where it binds and activates nuclear receptors. If transported by CRABP it binds nuclear retinoid acid receptors (RARs), whilst in association to FABP5 it binds peroxisome proliferation-activated receptor β/δ (PPARβ/δ), activating the transcription of specific target genes; (B) RA extranuclear effects. In response to RA, a subpopulation of RARα and RARγ present in membrane lipid rafts activates kinase cascades. In neuronal cells, extracellular signal-regulated kinase (ERK) phosphorylation is mediated through RARγ in association with sarcome (Src) kinase, whereas in other cellular subtypes RARα is the effector of the transduction cascade through p38 mitogen-activated protein kinase (p38MAPK) or ERK signalling. Activated p38MAPK and Erks translocate to the nucleus where they phosphorylate several targets, being mitogen- and stress-activated protein kinase (MSK1) a good candidate. Plasma ROH, bound to RBP4, binds to the cell receptor STRA6 which phosphorylates and activates Janus kinases2/signal transducers and activators of transcription 5 (JAK2/STAT5) signalling pathway. This phosphorylated STAT5 translocates into the nucleus where it regulates gene expression of target genes.

Figure 2

Retinoids are involved in epithelial-mesenchymal transition: (A) Markers of epithelial-mesenchymal transition (EMT) are observed in vitamin A-deficient (VAD) lungs. Lung protein extracts from control and chronic VAD rats were analysed by western blot to characterize EMT in this animal model. A decrease in E-cadherin and β-catenin protein levels was observed in VAD lungs, together with increased levels of N-cadherin, all of them hallmarks of EMT. A representative experiment is shown (n = 3). MW, molecular weight; (B) Epithelial-mesenchymal transition (EMT) in vitamin A-deficient (VAD) lung. VAD induces the activation of transforming growth factor β (TGF-β) which, in turn, drives the progression of the EMT observed. Basement membrane (BM) thickens and extracellular matrix (ECM) changes its composition in VAD lungs. Concomitant with these results, epithelial cells loss cell junctions and express mesenchymal markers, favouring the disassembly of the epithelial barrier and the migration of these newly formed mesenchymal cells.