Treatment of autoimmune disorders of the lungs
Idiopathic pulmonary fibrosis is a chronic, inflammatory, progressive and fibrosing disease, limited to the lungs. The disease is characterized by pulmonary interstitial fibrosis, with a radiological and/or histological pattern of usual interstitial pneumonia, with poor prognosis (206). Idiopathic pulmonary fibrosis is triggered by an alveolar lesion that leads to the activation of TGF-β and disruption of the basal alveolar membrane. In the presence of persistent lesion pathways or altered repair mechanisms, activated TGF-β may lead to alveolar apoptosis and transformation of the epithelial-mesenchymal transition, with fibroblasts and fibrocytes differentiating into apoptosis-resistant myofibroblasts (207). The resulting excessive collagen and fibronectin deposition results in a chronic fibrosing process leading to idiopathic pulmonary fibrosis. In two studies (119, 120), hMSCs were used for the treatment of autoimmune disease-associated lung fibrosis. Both studies used the mice as the experimental model and, while the adipose tissue was chosen as the source of hMSCs in one study (120), in the other study (119), hMSCs were isolated from the bone marrow and umbilical cord. The cumulative survival rate, the lung weight, the hydroxyproline levels in the lungs and the Ashcroft's modified score for lung fibrosis were the outcomes used by most studies selected in this systematic review to assess the potential of hMSCs administration for the treatment of autoimmune disease-associated lung fibrosis. Because there were no human clinical trials among the studies selected, it was not possible to identify primary endpoints commonly used to evaluate the effectiveness of hMSCs administration for the treatment of autoimmune disease-associated lung fibrosis in humans. There is not a consensus regarding what constitutes the best primary endpoint that should be used in idiopathic pulmonary fibrosis clinical trials. Therefore, we propose that multiple endpoints such as the forced vital capacity, the single breath diffusing capacity for carbon monoxide, the 6-min walk test, and the cumulative survival rate should be used in conjunction. Exploratory endpoints such as the serum levels of inflammatory cytokines and profibrotic mediators can also be used as they provide important information about the ability of hMSCs to influences the pathological course of the disease. In both studies, an increase in the survival rates and a reduction in the severity of the disease was observed in conjunction with a decrease in the lung pathology. Regarding the mechanisms proposed for the action of hMSCs, Reddy et al. (120) described that the administration of hMSCs down-regulated the expression of both pro-inflammatory cytokines such as IL-2, IL-1β, TNF-α, and TGF-β and pro-fibrotic mediators such as bFGF, CTGF, COL3a1, and CoL1a1, leading to a reduction in inflammation and pulmonary fibrosis. In this study, it was also observed a downregulation in the expression of both matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP), resulting in the maintenance in the MMP-TIMP balance and preventing the restructuring of the matrix following the lung injury. In addition, in a study conducted by Liu et al. (119), lower levels of pro-inflammatory cytokines IL-6, IL-8, CCL2, IFN-γ, TNF-α and higher levels of TGF-β1 and CXCL10 were found to be associated with the presence of hMSCs. Specifically, Liu et al. (119) showed that hMSCs is able toblock α-SMA activation through a TGF-β1-mediated mechanism. This study also demonstrated that hMSCs promoted CD4+CD25+CD127(low/−)/foxp3+Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis and inhibitedCD3+CD8+cytotoxic T cells and CD3+CD56+ NKT cells proliferation in an experimental cell model. Table 6 summarizes the methodology employed and the results obtained in the studies selected in this systematic review regarding the effects of the administration of hMSCs for the treatment of autoimmune disorders of the lungs.
Table 6  List of in vivo studies in which the therapeutic potential of the administration of hMSCs for the treatment of autoimmune disorders of the lungs was evaluated.
References   Autoimmune disease   Source of hMSC   Variables   Experimental model   Clinical and laboratory effects   Mechanism proposed
(119)  Idiopathic pulmonary fibrosis  Bone marrow Umbilical cord  None  Mice  ↑Survival rates↓Pulmonary inflammation and fibrosis Effectiveness bone marrow-derived MSCs > effectiveness umbilical cord-derived MSCs  ↓CD3+CD56+ NKT cells↓CD3+CD8+ T cell induction↑CD3+CD4+ T cells↑CD4+CD25+CD127(low/−)/foxp3+ Tregs↓IFN-γ↓TNF-α↓IL-6↓IL-8↓CCL2↓α-SMA activation↑TGF-β1↑CXCL10
(120)  Idiopathic pulmonary fibrosis  Adipose tissue  None  Mice  ↑Survival rates↓Ashcroft's modified score for lung fibrosis↓Lung weight↓Lung pathology↓Collagen deposition in the lungs  ↓IL-2↓IL-1β↓TNF-α↓TGF-β↓bFGF↓CTGF↓COL3a1↓CoL1a1↓Matrix metalloproteinases↓Tissue inhibitor of metalloproteinases
Both the methodology employed and the results obtained by each article are represented in this table. α-SMA, alpha-smooth muscle actin; IL-8, interleukin 8; CTGF, connective tissue growth factor; COL3a1, collagen alpha-1(III) chain; CoL1a1, collagen, type I, alpha 1.