Human Tubal-Derived Mesenchymal Stromal Cells Associated with Low Level Laser Therapy Significantly Reduces Cigarette Smoke–Induced COPD in C57BL/6 mice

Abstract

Cigarette smoke-induced chronic obstructive pulmonary disease is a very debilitating disease, with a very high prevalence worldwide, which results in a expressive economic and social burden. Therefore, new therapeutic approaches to treat these patients are of unquestionable relevance. The use of mesenchymal stromal cells (MSCs) is an innovative and yet accessible approach for pulmonary acute and chronic diseases, mainly due to its important immunoregulatory, anti-fibrogenic, anti-apoptotic and pro-angiogenic. Besides, the use of adjuvant therapies, whose aim is to boost or synergize with their function should be tested. Low level laser (LLL) therapy is a relatively new and promising approach, with very low cost, no invasiveness and no side effects. Here, we aimed to study the effectiveness of human tube derived MSCs (htMSCs) cell therapy associated with a 30mW/3J—660 nm LLL irradiation in experimental cigarette smoke-induced chronic obstructive pulmonary disease. Thus, C57BL/6 mice were exposed to cigarette smoke for 75 days (twice a day) and all experiments were performed on day 76. Experimental groups receive htMSCS either intraperitoneally or intranasally and/or LLL irradiation either alone or in association. We show that co-therapy greatly reduces lung inflammation, lowering the cellular infiltrate and pro-inflammatory cytokine secretion (IL-1β, IL-6, TNF-α and KC), which were followed by decreased mucus production, collagen accumulation and tissue damage. These findings seemed to be secondary to the reduction of both NF-κB and NF-AT activation in lung tissues with a concomitant increase in IL-10. In summary, our data suggests that the concomitant use of MSCs + LLLT may be a promising therapeutic approach for lung inflammatory diseases as COPD.

Cell Therapy Decreases Inflammation and Improves the Morphology of the Lung Parenchyma in a Murine Model of Cigarette Smoke-Induced Emphysema

“…Periods of exposure to cigarette smoke vary widely between emphysema models (from 3 to 9 months) [4], [20]- [23]. In the present investigation, an efficient induction of emphysema in mice was observed after 3 months (90 days) of exposure to cigarette smoke.…”

“…Finally, it should be emphasized that the results in animal models are important for the advancement in knowledge of the mechanisms orchestrating lung regeneration processes after injury [9], [20], [35], [36]. These results added to the set of information obtained in pioneering clinical trials in human patients open new perspectives for the implementation of large multicenter clinical trials to allow the verification with greater consistency the efficacy of cell-based therapies in obstructive pulmonary diseases [4], [5], [32], [34], [37]- [40].…”

Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD

“…The first of these studies did not examine therapeutic efficacy but focused on tracking of MSC in an elastase model in vivo 42. The second study demonstrated efficacy of human tubal-derived MSC in combination with low level laser therapy in CS-induced COPD43. A third study demonstrated relatively modest protection mediated by two doses of human MSC in a CS-induced model44.…”

“…In contrast to the study carried out by Peron et al . showing a requirement for low level laser therapy in combination with human tubal derived MSC43, Antunes et al . observed a reduction in collagen fibre deposition mediated by mouse MSC30.…”

Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure

“…The laser power was monitored during laser irradiation by collecting laser light with a partial reflection (4%) mirror. The laser irradiation dose was set at 1.8 J for 1 min [ 4 , 7 , 17 ]. The laser irradiation was performed 1 and 5h post each FA or vehicle inhalation.…”