TABLE 4.
Recent relevant ex-vivo and in-vitro human studies reporting ocular surface disease manifestations of PLMs.
| Cell type | Agents used | Study description | Preservatives | Findings | |
|---|---|---|---|---|---|
| References | |||||
| Park et al. (2011) | Ex-vivo orbital fat | PGAs | Evaluate the adipocyte density in orbital fat after exposure to preserved PGAs | BAK, PQ | The mean adipocyte density was significantly increased in eyes exposed to preserved PGAs, suggesting adipocyte atrophy |
| Choi et al. (2012) | Orbital adipocytes | PGAs | Evaluate the effects of PF PGAs in orbital fat | None | LAT, TRV, BIM, and TAF inhibited intracellular lipid accumulation and preadipocyte differentiation |
| Seibold et al. (2013) | In vitro subcutaneous adipocytes | BBs and PGAs | Compare the short-term effects of PF-TIM, various PGAs, and BAK alone on adipocyte cytotoxicity and preadipocyte proliferation | BAK | PF-TIM and BAK alone yielded anti-proliferative effects on pre-adipocytes and cytotoxic effects on mature adipocytes compared with the minimal toxicity caused by PGAs |
| Lopilly Park et al. (2012) | Ex-vivo tears | PGAs and BBs | Proteomic analysis of tears from patients using TIM, or various preserved PGAs, including LAT, TRV, or BIM for >1 year | BAK | Increased levels of MMP-1, MMP-3, MMP-9, IL-1β, IL-6, and decreased levels of TIMP-1 and TIMP-2 in PGA treated eyes compared with TIM |
| Mohammed et al. (2020) | Ex-vivo tears | PGAs | Evaluate the profile of inflammatory cytokines among various preserved and PF PGAs | BAK, PQ | BAK-preserved PGAs induced significant mRNA and protein expression of IL-1β, IL-6, and IL-8 compared with PQ and PF-PGAs |
| Zhang et al. (2017) | In vitro | BBs and miotics | Evaluate the effects of PF TIM and PIL in MG epithelial cells | None | TIM and PIL resulted in dose-dependent atrophy and dropout of MG epithelial cells |
| MGs | |||||
| Han et al. (2018) | In vitro | AAs | Evaluate the effects of various AAs on the structure and function of MG epithelial cells | None | Brimonidine elicits a dose-dependent differentiation of MG epithelial cells, increasing neutral lipidsand lysosome levels |
| MGs | |||||
| Rath et al. (2019) | In vitro | PGAs | Evaluate the effects of various preserved and PF PGAs on MG epithelial cells | BAK, PQ | Cell viability was significantly reduced in BAK-containing PGAs and BAK alone compared with PF PGAs and TRV with PQ |
| MGs | |||||
| Ammar et al. (2010) | In vitro cornea and conjunctiva | PGAs | Percentage of living epithelial cells to different preserved PGAs | BAK, PQ, SZ | PQ and SZ resulted in higher percentages of living cells compared with BAK |
| Whitson and Petroll (2012) | In vitro cornea | PGAs | Evaluate the toxicity of preserved and PF PGAs in the corneal epithelium | BAK, PQ | BAK-containing formulations resulted in significantly greater toxicity and less cell viability |
| Paimela et al. (2012) | In vitro cornea | PGAs | Determine the cytotoxic and inflammatory effects of preserved LAT and TRV | BAK, PQ | PQ-containing TRV activated NF-κB and significantly increased IL-6 and IL-8 compared with BAK |
| Yuan et al. (2016) | In vitro cornea | Miotics | Evaluate the cytotoxic effects of pilocarpine in stromal cells | None | Pilocarpine can induce apoptosis of corneal stromal cells in a dose-dependent manner |
| Liang et al. (2022) | In vitro conjunctiva and cornea | PGAs | Effects of preserved and PF PGAs in a wound-healing epithelial cell model | BAK, PQ, SZ | BAK significantly delayed healing through decreased Ki-67-positive cell numbers and actin disorganization compared to PQ, SZ, and PF-PGAs |
| Hedengran et al. (2022) | In vitro conjunctiva | PGAs | Viability of goblet cells and secretion of cytokines and mucins after exposure to TRV | BAK, PQ | PQ-containing TRV resulted in no goblet cell loss. Both PQ and BAK showed no differences in mucin and IL-6 and IL-8 secretion |
| Hedengran et al. (2021) | In vitro conjunctiva | CAIs, AAs, and miotics | Evaluate the effects of BAK-containing PLMs in conjunctival GCs | BAK | BAK-preserved LAT, followed by DORZ, resulted in significantly less GC density. BRIM did not affect GC survival |
PLMs, pressure-lowering medications; PGAs, prostaglandin analogs; BAK, benzalkonium chloride; PQ, polyquad; PF, preservative-free; LAT, latanoprost; TRV, travoprost; BIM, bimatoprost; TAF, tafluprost; BBs, beta blockers; TIM, timolol; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; IL, interleukin; MGs; Meibomian glands; AAs, alpha agonists; SZ; Sofzia; NF-κB, nuclear factor kappa beta; GC, goblet cells.