ABSTRACT Adenosine-5'-triphosphate (ATP) is the single most important molecule in life. It is the universal energy currency of all living things. The energy from ATP is used in the synthesis of RNA/DNA, proteins, and lipids. The energy is used in signal transduction, ion pumping, intracellular and extracellular movement, and heat production. To meet the metabolic demand for ATP, cells utilize oxygen to extract maximal energy from substrates. The dependence on oxygen over the course of evolution allowed cells to grow in size and complexity, but at the same time cells became dependent upon oxygen for cell function and survival. During periods of ischemia or hypoxia, ATP produced by oxidative phosphorylation decreases, cells compensate by increasing glycolytic and substrate level phosphorylation, as well as prioritizing ATP consuming processes. If ischemia or hypoxia continues, extracellular ATP levels increase due to leakage and cell death, and ATP becomes an endogenous ligand that activates purinergic receptors located on cells throughout the body. ATP induces a purinergic response that can vary from cell death to cell proliferation, depending on the concentration of extracellular ATP. The coupling of the energetic and purinergic roles of ATP in ischemia or hypoxia is well illustrated in the leading causes of death in humans in the United States. Intracellular ATP depletion leads to cellular dysfunction and extracellular ATP leads to purinergic mediated responses that attempt to rectify the ischemia or hypoxia issue. Understanding the connections between the energetic and purinergic roles of ATP could be useful in future therapies.

Ehringer WD, Smith KH. Coupling of the energetic and purinergic activities of ATP in ischemic and hypoxic disease states. Biosystems. 2025 Sep;255:105544. doi: 10.1016/j.biosystems.2025.105544. Epub 2025 Jul 23. PMID: 40712820.

ABSTRACT We have reported a new phenomenon in acute wound healing following the use of intracellular ATP delivery-extremely rapid tissue regeneration, which starts less than 24 h after surgery, and is accompanied by massive macrophage trafficking, in situ proliferation, and direct collagen production. This unusual process bypasses the formation of the traditional provisional extracellular matrix and significantly shortens the wound healing process. Although macrophages/monocytes are known to play a critical role in the initiation and progression of wound healing, their in situ proliferation and direct collagen production in wound healing have never been reported previously. We have explored these two very specific pathways during wound healing, while excluding confounding factors in the in vivo environment by analyzing wound samples and performing in vitro studies. The use of immunohistochemical studies enabled the detection of in situ macrophage proliferation in ATP-vesicle treated wounds. Primary human macrophages and Raw 264.7 cells were used for an in vitro study involving treatment with ATP vesicles, free Mg-ATP alone, lipid vesicles alone, Regranex, or culture medium. Collagen type 1α 1, MCP-1, IL-6, and IL-10 levels were determined by ELISA of the culture supernatant. The intracellular collagen type 1α1 localization was determined with immunocytochemistry. ATP-vesicle treated wounds showed high immunoreactivity towards BrdU and PCNA antigens, indicating in situ proliferation. Most of the cultured macrophages treated with ATP-vesicles maintained their classic phenotype and expressed high levels of collagen type 1α1 for a longer duration than was observed with cells treated with Regranex. These studies provide the first clear evidence of in situ macrophage proliferation and direct collagen production during wound healing. These findings provide part of the explanation for the extremely rapid tissue regeneration, and this treatment may hold promise for acute and chronic wound care.

Sarojini H, Billeter AT, Eichenberger S, Druen D, Barnett R, Gardner SA, Galbraith NJ, Polk HC Jr, Chien S. Rapid tissue regeneration induced by intracellular ATP delivery-A preliminary mechanistic study. PLoS One. 2017 Apr 5;12(4):e0174899. doi: 10.1371/journal.pone.0174899. PMID: 28380006; PMCID: PMC5381896.

ABSTRACT

BACKGROUND: Small unilamellar lipid vesicles were used to encapsulate adenosine triphosphate (ATP-vesicles) for intracellular energy delivery and were tested for diabetic skin wounds in rabbits.

METHODS: Diabetes was induced by alloxan. The mean peak blood glucose concentration was 505 mg/dL. One ear was made ischemic and 80 full-thickness wounds were created in 10 animals. ATP-vesicles or saline was used and healing was compared.

RESULTS: On the non-ischemic ears, mean closure time for ATP-vesicles-treated wounds was 13.7 days versus 16.4 days for saline-treated wounds (P < .05). On the ischemic ears, mean closure time for ATP-vesicles-treated wounds was 15.3 days versus 19.3 days for saline-treated wounds (P < .01). Histological study indicated better healing and re-epithelialization in the ATP-vesicles-treated wounds.

CONCLUSIONS: Intracellular delivery of ATP accelerated the healing process of diabetic skin wounds on ischemic and non-ischemic rabbit ears. The mechanisms deserve further study but may be related to improved cellular energy supplies.

Wang J, Wan R, Mo Y, Li M, Zhang Q, Chien S. Intracellular delivery of adenosine triphosphate enhanced healing process in full-thickness skin wounds in diabetic rabbits. Am J Surg. 2010 Jun;199(6):823-32. doi: 10.1016/j.amjsurg.2009.05.040. PMID: 20609726; PMCID: PMC2901881.