Soft TCPTP Agonism—Novel Target to Rescue Airway Epithelial Integrity by Exogenous Spermidine

Abstract

A reparative approach of disrupted epithelium in obstructive airway diseases, namely asthma and chronic obstructive pulmonary disease (COPD), may afford protection and long-lasting results compared to conventional therapies, e.g., corticosteroids or immunosuppressant drugs. Here, we propose the polyamine spermidine as a novel therapeutic agent in airways diseases, based on a recently identified mode of action: T-cell protein tyrosine phosphatase (TCPTP) agonism. It may include and surpass single-inhibitors of stress and secondary growth factor pathway signaling, i.e., the new medicinal chemistry in lung diseases. Enhanced polyamine biosynthesis has been charged with aggravating prognosis by competing for L-arginine at detriment of nitric oxide (NO) synthesis with bronchoconstrictive effects. Although excess spermine, a higher polyamine, is harmful to airways physiology, spermidine can pivot the cell homeostasis during stress conditions by the activation of TCPTP. In fact, the dephosphorylating activity of TCPTP inhibits the signaling cascade that leads to the expression of genes involved in detachment and epithelial-to-mesenchymal transition (EMT), and increases the expression of adhesion and tight junction proteins, thereby enhancing the barrier functionality in inflammation-prone tissues. Moreover, a further beneficial effect of spermidine may derive from its ability to promote autophagy, possibly in a TCPTP-dependent way. Since doses of spermidine in the micromolar range are sufficient to activate TCPTP, low amounts of spermidine administered in sustained release modality may provide an optimal pharmacologic profile for the treatment of obstructive airway diseases.

Spermidine rescues the deregulated autophagic response to oxidative stress of osteoarthritic chondrocytes

“…After 24 h starvation, the cells were pretreated with SPD (Sigma S2501, spermidine trihydrochloride), 100 nM, 24 h. The starvation step was useful to reduce the endogenous polyamine pool so to better highlight the effect of 100 nM exogenous SPD pre-treatment. This subμmolar dose was selected on the basis of previous literature hints that indicate a narrow useful dosage window in which addition of exogenous SPD may support cell homeostatic activities by increasing the unbound pool without exerting inflammation or apoptosis promoting effects [32]. Previous work from our group showed that 1-10 μmolar doses instead promote chondrocyte terminal differentiation [33], in keeping with previous observations of high SPD levels in the extracellular matrix of the ossifying cartilage [34].…”

Polyamine supplementation reduces DNA damage in adipose stem cells cultured in 3-D

“…Spermine compacts DNA more actively than spermidine 52 . Furthermore, inside the cells spermidine is primarily complexed to anionic molecules and macromolecules (phospholipids of the cell membrane, ATP, RNA, DNA wrapped with histones) and only a fraction of the intracellular content represents the “free pool” 53 . Slight variation of this pool is achieved by treatment of the cells with low- µmolar/sub-µmolar amounts of spermidine, that have been shown to promote anti-inflammatory effects via triggering of T-cell protein tyrosine phosphatase (TCPTP) 54 or autophagy 55 .…”

“…Slight variation of this pool is achieved by treatment of the cells with low- µmolar/sub-µmolar amounts of spermidine, that have been shown to promote anti-inflammatory effects via triggering of T-cell protein tyrosine phosphatase (TCPTP) 54 or autophagy 55 . TCPTP is a phosphatase that exerts an anti-inflammatory role being able to down-regulate multiple signaling transduction pathways in the cells, acting at multiple levels 53 . An in vitro high throughput assay identified spermidine (at the same concentration used in the present work) and other 5 small molecules among 64280 potential candidates screened to tease out the best selective TCPTP agonists 56 .…”

<p>Smokers with COPD Show a Shift in Energy and Nitrogen Metabolism at Rest and During Exercise</p>

“…36 We saw higher levels of spermidine, a product of ORN that plays a role in the regulation of cell proliferation and nucleic acid synthesis. 37,38 Previous studies report higher levels of ARG in muscles of COPD patients, but not in arterial blood. 12,13 In stable patients with moderate-to-severe COPD, endogenous ARG and CIT production is upregulated but no difference in whole body NO production was detectable (ARG-to-CIT flux).…”