This original work investigated the longitudinal systemic impact of urogynecologic surgery with or without mesh implantation using a rat model. 
         Hypothesis/aims of study: The lifetime risk of undergoing a single operation for urinary incontinence or pelvic organ prolapse in a woman by age 80 is estimated at ~11.1%. As an acute stressor, surgery can lead to noninfectious tissue damage, causing post-surgical systemic inflammatory response (PSIR). The PSIR may obscure other inflammatory conditions such as infections, and trigger organ dysfunction in vulnerable populations. It is thus crucial to define the natural progression of PSIR after urogynecologic surgeries to ensure appropriate postoperative management. To date, scarce data has been collected in the regard. 
Urogynecologic meshes have been used to overcome the high failure rates of native tissue repair. The impact of mesh implantation on the process of PSIR remains unclear. Robust evidence shows that mesh evokes rapid foreign body response in tissue following implantation and induces long-lasting inflammation restrained at mesh-tissue interface [1]. Thus, we hypothesized that uncomplicated mesh-induced inflammation contributes to the PSIR in the early stage but may not have systemic effect in the long term due to mesh encapsulation. 
        We aimed to define the longitudinal impact of benign urogynecologic surgeries with or without mesh implantation on systemic inflammation using a rat model. As secondary outcomes, the impact of age and body weight on these immune mediators was also examined.

All animal studies were approved by the University Institutional Animal Care and Use Committee. Based on a power analysis using published data comparing serum cytokines between subjects with and without surgery [2], at least 4 animals in each group were needed to achieve 80% power to detect meaningful differences with p<0.05. Sixty six middle-aged (6 – 9 months, 260 – 350 grams) female Wistar rats were randomly grouped into 1) no-surgery (n=12), 2) surgery without mesh (n=20), and 3) surgery with mesh (n=34). In the surgical groups, 42 animals undergoing bilateral ovariectomy (OVX) were further divided into groups evaluated at 3- (very early, n=12), 7- (early, n=14), and 42-day (late, n=16) post-surgery. To examine the effect of OVX, surgical groups without OVX were also evaluated at 42-days (n=12).  
         In surgical groups, transabdominal supracervical hysterectomy with or without OVX was performed. In groups with mesh implantation, a polypropylene mesh (Restorelle) was implanted on the anterior and posterior vagina via a modified sacrocolpopexy following supracervical hysterectomy. At different time points following surgery, plasma samples were collected. Proteins from proximal vaginal tissues were extracted with high-salt buffer.  Multiplex assays based on Luminex technology (ThermoFisher) were used to quantify 5 cytokines (G-CSF, IL-6, IL-12p70, IL-1β, TNFα) and 6 chemokines (eotaxin, MCP-1, MCP-3, IP-10, MIP-1α, GROα). Kruskal-Wallis with post-hoc tests, Spearman correlation coefficients (rho) and linear regression models were used for data analysis. Significance was set at p<0.05.

All animals survived the procedures without mesh exposure. Among the 11 analytes, 3 cytokines (G-CSF, IL-1β, TNFα) and 4 chemokines (eotaxin, MCP-1, MCP-3, IP-10 and MIF-1α) were detected in all or most samples. Relative to no-surgery controls, surgery without mesh implantation induced a temporary increase of circulating proinflammatory mediators at 3-day post-surgery (p<.001), with an increase of detectable TNFα, and IL-1β, as well as increase of IP-10, MCP-1 and MCP-3 by 117%, 132% and 29% (p=.007, .035, .002, <.001, and .003, respectively) (Figure 1). Their levels decreased at 7 days and returned to normal at 42 days (all p>.05). In groups with mesh implantation, we noted a comparable pattern of change in plasma cytokines and chemokines, showing a surge at 3-day post-surgery (p<.001, Figure 2). However, the magnitudes of these changes were slightly lower than those without mesh, particularly at 7-days (p=.014). Notably, eotaxin levels were significantly reduced with mesh implantation, as compared to those without mesh, by 62%, 42% and 37% at 3-, 7-, and 42-day post-surgery (p=.012, .014, and .001, respectively) (Figure 2). 
         Furthermore, comparable outcomes were observed between the OVX and non-OVX groups at 42 days post-surgery (all p>.05), demonstrating a similarly subsided systemic inflammatory response in the long-term, irrespective of OVX status. 
Correlations of immune mediators in the plasma and tissue were only observed at 3-day post-surgery. Specifically, a robust positive correlation between plasma and tissue levels of G-CSF (rho=0.630, p=.01) was found. In addition, age and body weight showed differential impact on the systemic inflammation, with older rats having higher level of plasma MCP-1 (p<.001), and rats with heavier body weight having higher levels of plasma MCP-3 (p=.002).

Our findings demonstrated that pelvic surgeries induced an increase of plasma proinflammatory cytokines and chemokines in the immediate post-surgical period, indicating a rapid PSIR. Importantly, mesh implantation did not escalate the overall systemic inflammatory status across the time course, suggesting that the impact of mesh is primarily local. The limited effect of mesh on systemic inflammation was further supported by our results showing a lack of direct correlations between vaginal tissue and circulating levels of immune mediators at later time points. 
        The rapid PSIR is likely a stress response to surgical tissue injury, as also shown in research investigating the systemic effect of surgeries in other fields. In additional to the documented increase of plasma TNFα, IL-1β, IP-10, and MCP-1 [2], here we showed that MCP-3 also contributes to the PSIR. Although the PSIR play a defensive role against pathogen invasion and possibly initiates tissue repair cascades by activating various immune cells, it may trigger organ dysfunctions under certain circumstances, e.g., deteriorating cognitive function in the elderly. Further study is needed to better understand the underlying mechanisms and develop evidence-based strategies to mitigate its adverse effects. 
        While our data showed that the mesh implantation has limited systemic effects, examining a more inclusive panel of inflammatory markers will be useful to verify the results. In addition, tests of various mesh products should be considered as implant-induced systemic reactions can be material-specific and vary due to different mechanical and textile properties. Interestingly, we observed that mesh implantation induced a persistent decrease of circulating level, but not tissue level of eotaxin (CCL11). As a potent recruiter of eosinophils, eotaxin plays key roles in allergic conditions. Since an increase of circulating eotaxin has been associated with age-related cognitive decline and other neurodegenerative disorders [3], it remains uncertain whether mesh implantation produces beneficial effects in the regard, which highlights the need for future mechanistic studies.
        In our secondary outcomes, we showed a positive responsiveness of circulating MCP-1 to aging and MCP-3 to heavier body weight, which corroborates results from studies showing that aging and obesity are chronic inflammatory status. 
        Limitations of this study include that the data obtained from rats may not be directly translatable and that specific animal models (aging and obesity) are needed to verify the effect of age and body weight on the plasma proinflammatory mediators.

Urogynecologic surgery evokes a rapid PSIR shortly after the procedures while mesh implantation has limited systemic effect except for a persistent decrease of circulating eotaxin.

Liang R, Fisk A, King G, Meyn L, Xiao X, Moalli P. Characterization of vaginal immune response to a polypropylene mesh: Diabetic vs. normoglycemic conditions. Acta Biomater. 2022 Apr 15;143:310-319.
Shih L, Guler N, Syed D, Hopkinson W, McComas KN, Walborn A, Hoppensteadt D, Fareed J, Rondina MT. Postoperative Changes in the Systemic Inflammatory Milieu in Older Surgical Patients. Clin Appl Thromb Hemost. 2018 May;24(4):583-588.
Ivanovska M, Abdi Z, Murdjeva M, Macedo D, Maes A, Maes M. CCL-11 or Eotaxin-1: An Immune Marker for Ageing and Accelerated Ageing in Neuro-Psychiatric Disorders. Pharmaceuticals (Basel). 2020 Sep 2;13(9):230. doi: 10.3390/ph13090230. PMID: 32887304; PMCID: PMC7558796.

Continence 7S1 (2023) 100767
DOI: 10.1016/j.cont.2023.100767