Abstract
Murine papain-induced emphysema is a model that reproduces many of the features found in patients. Bone marrow-derived mononuclear cells (BMMC) have already been used to repair the alveolar epithelium in respiratory diseases, but not in the papain model. Thus, we hypothesized that BMMC could prevent the pathophysiological processes in papain-induced experimental emphysema. Female BALB/c mice received intratracheal instillation of 50 μL of saline (S groups) or papain (P groups, 10 IU/50 μl of saline) on days 1 and 7 of the experimental protocol. On the 14th day, 2 × 106 BMMC of male BALB/c mice (SC21 and PC21) or saline (SS21 and PS21) were injected by the jugular vein. Analyses were done on days 14 (S14 and P14) and 21 (SS21, PS21, SC21, and PC21) of the protocol. qPCR evaluated the presence of the Y chromosome in the lungs of BMMC recipient animals. Functional residual capacity (FRC), alveolar diameter, cellularity, elastic fiber content, concentrations of TNF-α, IL-1β, IL-6, MIP-2, KC, IFN-γ, apoptosis, mRNA expression of the dual oxidase (DUOX1 and DUOX2), production of H2O2 and DUOX activity were evaluated in lung tissue. We did not detect the Y chromosome in recipients' lungs. FRC, alveolar diameter, polymorphonuclear cells (PMN) and levels of KC, MIP-2, and IFN-γ increased in P14 and PS21 groups; the changes in the latter were reverted by BMMC. TNF-α, IL-1β e IL-6 were similar in all groups. The amount of elastic fibers was smaller in P14 and PS21 than in other groups, and BMMC did not increase it in PC21 mice. PS21 animals showed increased DUOX activity and mRNA expression for DUOX1 and 2. Cell therapy reverted the activity of DUOX and mRNA expression of DUOX1. BMMC reduced mRNA expression of DUOX2. Apoptosis index was elevated in PS21 mice, which was reduced by cell therapy in PC21. Static compliance, viscoelastic component of elastance and pressure to overcome viscoelasticity were increased in P14 and PS21 groups. These changes and the high resistive pressure found on day 21 were reverted by BMMC. In conclusion, BMMC showed potent anti-inflammatory, antiapoptotic, antioxidant, and restorative roles in papain-triggered pulmonary emphysema.
Highlights
The pathophysiology of pulmonary emphysema is complex (Gold-Global Initiative for Chronic Obstructive Lung Disease, 2017)
The present study showed that the intravenous use of Bone marrow-derived mononuclear cells (BMMC) in an experimental model of papain-induced pulmonary emphysema resulted in a plethora of morpho-functional improvements in the pulmonary parenchyma
All these outcomes might be attributed to the BMMC cells because there was no male donor mice cells (Y chromosome) in the lung tissue of the female recipient mice
Summary
The pathophysiology of pulmonary emphysema is complex (Gold-Global Initiative for Chronic Obstructive Lung Disease, 2017). Five main mechanisms account for the pathogenesis of pulmonary emphysema: (1) imbalance in the proteolytic/anti-proteolytic system; (2) alterations of the tissue injury/repair mechanism; (3) inflammation; (4) oxidative stress; and, (5) apoptosis of lung cells (Barnes, 2006, 2014; Yoshida and Tuder, 2007; Bagdonas et al, 2015; Gold-Global Initiative for Chronic Obstructive Lung Disease, 2017). Elastase elicits a chain of inflammatory response with involvement of alveolar macrophages and neutrophil influx into the pulmonary parenchyma that leads to an important release of proteases, overcoming the antiproteolytic defenses of the lower respiratory tract, often resulting in destruction of the pulmonary parenchyma (Gross et al, 1965; Roth, 2008; Laurell and Eriksson, 2013; Bagdonas et al, 2015). Some mechanisms attempt to explain this “pulmonary maintenance/repair failure,” such as: increased cellular apoptosis (Imai et al, 2001; Majo et al, 2001; Tuder et al, 2003; Yokohori et al, 2004), reduction of cell proliferation and cellular chemotaxis (Carnevali et al, 1998; Rennard et al, 2006), among others
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