**7. Integrative Vision on the Effects of Cannabinoids in Gut-Lung-Skin Epithelial Inflammation**

In summary, in a multitude of inflammatory models located in the epithelia of the gutlung-skin barrier, cannabinoids show similar and consistent effects. In vitro studies show that all types of cannabinoids have potent anti-inflammatory effects, mostly expressed as the ability to prevent a rise in cytokines when inflammation is produced in the cellular experimental model (Table 1). Consistently, both natural and artificial cannabinoids were able to regulate the induced increase in the expression of TNF-α, IFN-γ, Ils 1β, 6, 8 and 17A, as well as MCP-1 and 2, and various other cofactors of inflammation. Vascular and cellular proliferative factors were also suppressed, adding to the potential benefits in regulating inflammation, possibly including the processes in the tumoral microenvironment. While some controversial results were documented, there is a large number of studies supporting the positive effects of cannabinoids in inflammations of the gut-lung-skin axis, and some significant results are presented in Table 1.

The investigation of the effects of cannabinoids on animal models of various inflammatory conditions of the gut-lung-skin axis has validated the anticipated results. Cannabinoids are able to reproduce the same anti-inflammatory effects that were observed in vitro in advanced experimental in vivo models, which lead to the identification of further beneficial effects. Cannabinoids modulate cell signaling and regulate the accumulation of inflammatory cells at the site of the inflammation, while also decreasing the activity of some chemokines and the expression of pro-inflammatory proteins. All of these positive direct and indirect anti-inflammatory effects have been attributed to a wide variety of cannabinoids, and relevant studies that support these findings are listed in Table 2.

The encouraging results emerging from in vitro and animal studies have prompted the translation to human trials. However, this has been made difficult, at least in part, by legislation and the need to obtain authorization from institutions regulating the use of cannabinoids that need to enforce national, trans-national and international regulations [194]. However, multiple trials have explored the potential of cannabinoids in inflammatory diseases pertaining to the gut-lung-skin barrier. The status of these trials and the preliminary or definitive results are listed in Table 3.

Unfortunately, not all of the cannabinoids that have proven effective in in vitro conditions or on animal models have provided significant results in humans, and some even presented significant adverse effects. Nevertheless, perfecting some new artificial cannabinoids with optimal receptor affinities or associating other compounds that modulate the effects via antagonism or post-receptor regulation may lead to improved results. The higher patient acceptance of natural compounds or their derivatives may prove essential in obtaining better compliance and superior results when associating cannabinoids in inflammatory conditions, especially in a chronic setting which implies sustained treatment [195]. Further randomized placebo-controlled clinical trials are needed to support the already overwhelming evidence regarding the beneficial results of cannabinoids in inflammations of the gut-lung-skin epithelium. In Figure 1, we summarized the effects of natural or synthetic cannabinoids on several receptors implicated in decreasing the inflammation in the gut-lung-skin barrier.


**Table 1.** The roles of cannabinoids in inflammatory conditions of the gut-lung-skin barrier demonstrated in in vitro studies.

**Table 1.** *Cont.*


(↓) = decrease in expression and/or concentration; (↑) = increase in expression and/or concentration; BPC = β-Caryophyllene; OEA = oleoylethanolamide; TRPV = transient receptor potential channel; GPR = G-coupled protein receptor.

> **Table 2.** The roles of cannabinoids in inflammatory conditions of the gut-lung-skin barrier evidenced in in vivo studies.



**Table 2.***Cont.*


**Table**

**2.**

*Cont.*

\* Hypothesized, ye<sup>t</sup> to be demonstrated; (↓) = decrease in expression and/or concentration; (↑) = increase in expression and/or concentration; CLP = cecal ligation and puncture; DNBS = 2,4-dinitrobenzene sulphonic acid; DSS = dextran sulphate sodium; PLA2 = phospholipase A2; MDA = malondialdehyde; MPO = myeloperoxidase; mTOR = mammalian target of rapamycin; NFAT = nuclear factor of activated T cells; NPE = neurogenic pulmonary edema; TNBS = trinitrobenzene sulfonic acid; RSV = respiratory syncytial virus; SEB = taphylococcal enterotoxin B; SOD = superoxide dismutase.

> **Table 3.** Human trials evaluating the safety and efficacy of cannabinoids in inflammatory conditions of the gut-lung-skin barrier.



**Table 3.** *Cont.*

CDAI = Crohn's disease activity index; CRP = C-reactive protein; DAI = disease activity index; IgG = immunoglobulin G.

**Figure 1.** The summarization of the main effects of endocannabinoids, as well as natural and synthetic cannabinoids on several receptors promoting the decrease of inflammation in the gutlung-skin barrier. (↓) = decrease in expression and/or concentration; (↑) = increase in expression and/or concentration.

#### **8. Conclusions**

The epithelia of the gastrointestinal tract, the pulmonary system and the cutaneous membrane share common features in regard to physiology, molecular signaling, and cell activity in pathological conditions. Furthermore, recent data suggest that the gut-lungskin barrier exhibits cross-talk involving various cells and cytokines, and responds in a similar way to epithelial disruption and local inflammation. This unitary behavior is also evidenced in the response to cannabinoids, a large class of compounds with well-known anti-inflammatory properties. A large number of in vitro and in vivo animal studies have shown promising results in either reducing or preventing inflammation in experimental models involving the elements of the gut-lung-skin barrier. Human studies have shown mixed results, with some cannabinoids either being ineffective or not tolerable in the treatment of specific inflammatory conditions. The reasons for treatment failure or intolerance may be revealed by translating the observations regarding the effects of cannabinoids on inflammation between studies involving specific elements of the gut-lung-skin barrier. The success that some of the clinical trials have achieved is encouraging and warrants further studies that will undoubtedly clarify the definitive role of cannabinoids in epithelial inflammation.

**Author Contributions:** Conceptualization, C.S., C.C., A.C.; writing—original draft preparation, C.S., C.C., I.A.B., A.-E.S., A.O.D., D.C., A.C.; writing—review and editing, C.S., A.O.D., D.C., A.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by a grant of the Romanian Ministry of Research and Innovation, CCCDI-UEFISCDI [project number 61PCCDI/2018 PN-III-P1-1.2-PCCDI-2017-0341], within PNCDI-III.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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