Extrinsic and intrinsic mechanisms are responsible for tendon healing, and a pathway is mediated via the vincular blood system and tenocytes
10. The extrinsic pathway is initiated by inflammatory cells and fibroblasts that migrate from the soft tissue around the injured tissue
11. This pathway is important in restoring tendon persistency and strength, but fibrosis and scarring may cause adhesion formation by disrupting the normal shear function of the tendon within the synovial sheath
12. After an appropriate tendon repair surgery, 20% of patients still have clinically limiting adhesions, and 10% of them will undergo a second surgical procedure
13,14.
Ample studies have focused on the effectiveness of physical barriers made from various biological origin/synthetic materials to prevent tendon adhesion formation 15,16. These barrier structures limit the formation of peritendinous adhesions by preventing the fibrotic tissue from reaching the tendon. In addition, previous studies have investigated the efficacy of various drugs such as NSAIDs, steroids, TGF-β neutralizers, 5-fluorouracil and plant flavonoids 4.These drugs were expected to prevent adhesion formation by changing cellular and molecular activities in tendon periphery inflammation and tendon healing 17. Although experimental results with these treatment methods have been successful, none of them have been widely accepted and/or used in clinical practice as a treatment 18.
In general, various complications, such as tendon adhesion, tissue trauma, ischemia, foreign body reaction, infection and hemorrhage, are due to an excessive phase of inflammation during the extrinsic healing period as well as due to the accumulation of excessive inflammatory cells in the subsynovial tissue around the tendon. These inflammatory cells secrete a large amount of cytokines and growth factors such as TGF-β, which have been shown to promote the synthesis of type 1 collagen and other extracellular matrix proteins by stimulating dermal fibroblasts with autocrine and paracrine signaling 7. TGF-β1 is involved in the generation of multiple connective tissue pathologies such as keloid and hypertrophic scars and Dupuytren contracture 19 and is the primary responsible cytokine for adhesion formation in mesothelial tissues, as tendon, synovium and peritoneum 20. Adhesion formation reduces with the inhibition of TGF-β with neutralizing antibody at the early stage of wound healing 10. Because TGF-β1 is a key factor in the formation of skin fibrosis and tendon adhesion, treatment approaches through TGF-β1 are thought to reduce tendon adhesion formation 20.
ACEIs inhibits the conversion of angiotensin I to its active form, angiotensin II 7. Angiotensin II plays an important role in wound healing by stimulating collagen production and fibrosis 21. Overactivity of angiotensin II has been associated with pathological fibrosis in organs such as heart, aorta, kidney and lung 7. Tang et al. reported that angiotensin II increases TGF-β expression. Thus, angiotensin II-related collagen synthesis could be blocked by inhibiting the conversion of angiotensin I to angiotensin II using ACEI 22. Additionally, it has been shown that enapril reduces hypertrophic scar formation by reducing TGF-β and angiotensin II levels 7; hence, it was used as a candidate drug to inhibate TGF-β in this study.
Previous studies have shown that oral treatment of enapril significantly reduced the formation of skin fibrosis around the tendon injury during wound healing in rats; however, no significant effect was observed on tendon adhesion formation.
TGF-β secretion after tendon injuries increases in the first 3 days, reaches maximum on day 3 and decreases to normal levels on day 7 10. In our study, enapril treatment was initiated after tendon injuries, and it was determined that the first 72 h did not reach the dose that would affect the tendon, and fibrosis was reduced in wound healing but not tendon adhesion formation.
Studies have reported that combination therapy with ibuprofen, an NSAID, and PELA [a di-block copolymer of poly (L-lactic acid)-polyethylene glycol] inhibits tendon adhesion formation with local application after tendon injury, but does not prevent adhesion formation with oral administration 22. Similarly, the systemic administration of TGF-β antibodies, such as TGF-β inhibitors, does not prevent tendon adhesion 23, but local administration has been shown to reduce adhesion formation 10,24. Overall, the results of our study and previous studies suggest that systemic treatment does not reach the optimal concentration to reduce tendon adhesion formation.
Although the systemic administration of antibodies against TGF-β and NSAIDs does not affect local application, previous studies on reducing tendon adhesions with local applications have revealed that enapril inhibits tendon adhesion formation with a combination of a local barrier that allows for its controlled release. Further studies are needed to test this proposition.