NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease

Abstract

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.

Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD

“…No significant differences are found in VIP mRNA levels in surgically obtained lung tissue between patients with mild/moderate stable COPD (n=8, mean age 66 years), patients with severe stable COPD (n=7, mean age 54 years), smokers with normal lung function (n=15, mean age 71 years) and patients with IPF (n=10, mean age 50 years). However, lung tissue mRNA VIP levels are negatively correlated with FEV 1 /FVC ratio in all four groups [428].…”

VIP reduction in the pancreas of F508del homozygous CF mice and early signs of Cystic Fibrosis Related Diabetes (CFRD)

“…The role of VIP in human diseases such as CF, asthma, chronic obstructive pulmonary disease and diabetes is a matter of investigation [10,[42][43][44] . A study by Alcolado et al who used a VIP-KO mouse model that developed a CF-like phenotype, demonstrated that treatment with VIP corrected the lymphocyte aggregation, increased airway secretion, alveolar thickening and edema in the lung, as well as the goblet cell hyperplasia and tissue alterations in the duodenum found in the absence of VIP, with the post-treatment phenotype being similar to those of WT mice.…”

Pulmonary hypertension: Molecular aspects of current therapeutic intervention and future direction

“…The experimental and clinical study demonstrated the therapeutic perspective of vasoactive intestinal peptide (VIP) for the treatment of PH. VIP can also upregulate the synthesis of tetrahydrobiopterin (Szema et al, ) which is a critical cofactor in endothelial nitric oxide production (Goyal et al, ). Thus, chronic right ventricular hypertrophy and pulmonary vascular remodeling have observed in VIP knock out (VIP‐/‐) mice (Hu et al, ; Szema et al, ).…”

“…VIP can also upregulate the synthesis of tetrahydrobiopterin (Szema et al, ) which is a critical cofactor in endothelial nitric oxide production (Goyal et al, ). Thus, chronic right ventricular hypertrophy and pulmonary vascular remodeling have observed in VIP knock out (VIP‐/‐) mice (Hu et al, ; Szema et al, ). Furthermore, the treatment with inhaled Aviptadil (VIP agonist) was remarked to exhibit pulmonary vasodilating effect and improved oxygenation in patients with PH (Hu et al, ; Szema et al, ).…”