Recent evidence suggests that mesenchymal stem cells may attenuate lung inflammation and fibrosis in acute lung injury. However, so far, no study has investigated the effects of mesenchymal stem cell therapy on the time course of the structural, mechanical, and remodeling properties in pulmonary or extrapulmonary acute lung injury.
Prospective randomized controlled experimental study.
University research laboratory.
One hundred forty-three females and 24 male C57BL/6 mice.
Control mice received saline solution intratracheally (0.05 mL, pulmonary control) or intraperitoneally (0.5 mL, extrapulmonary control). Acute lung injury mice received Escherichia coli lipopolysaccharide intratracheally (2 mg/kg in 0.05 mL of saline/mouse, pulmonary acute lung injury) or intraperitoneally (20 mg/kg in 0.5 mL of saline/mouse, extrapulmonary acute lung injury). Mesenchymal stem cells were intravenously injected (IV, 1 × 105 cells in 0.05 mL of saline/mouse) 1 day after lipopolysaccharide administration.
At days 1, 2, and 7, static lung elastance and the amount of alveolar collapse were similar in pulmonary and extrapulmonary acute lung injury groups. Inflammation was markedly increased at day 2 in both acute lung injury groups as evidenced by neutrophil infiltration and levels of cytokines in bronchoalveolar lavage fluid and lung tissue. Conversely, collagen deposition was only documented in pulmonary acute lung injury. Mesenchymal stem cell mitigated changes in elastance, alveolar collapse, and inflammation at days 2 and 7. Compared with extrapulmonary acute lung injury, mesenchymal stem cell decreased collagen deposition only in pulmonary acute lung injury. Furthermore, mesenchymal stem cell increased metalloproteinase-8 expression and decreased expression of tissue inhibitor of metalloproteinase-1 in pulmonary acute lung injury, suggesting that mesenchymal stem cells may have an effect on the remodeling process. This change may be related to a shift in macrophage phenotype from M1 (inflammatory and antimicrobial) to M2 (wound repair and inflammation resolution) phenotype.
Mesenchymal stem cell therapy improves lung function through modulation of the inflammatory and remodeling processes. In pulmonary acute lung injury, a reduction in collagen fiber content was observed associated with a balance between metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 expressions.
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1Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
2Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
3The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON, Canada.
4Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada.
5Laboratory of Cellular and Molecular Cardiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
6Laboratory of Inflammation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
7The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
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Dr. Dos Santos was supported by the Canadian Institutes of Health Research (MOP106545), the Ontario Thoracic Society (OTS2010/2011), and the Physicians Services Incorporate (PSI 09 - 21); Dr Rocco was supported by Centers of Excellence Program (PRONEX-FAPERJ-E26/110.575/2010), Brazilian Council for Scientific and Technological Development (CNPq-573555/2008-7 and 473274/2008-6), Rio de Janeiro State Research Supporting Foundation (FAPERJ–E-26/102.910/2008, E26/110.550/2009, E26/110.292/2010, and E-26/111.364/2010), Coordination for the Improvement of Higher Education Personnel (CAPES–Pós-Doc SUS 062/12/2009), and INCT-INOFAR (CNPq n° 573.564/2008–6). Dr. Maron-Gutierrez received grant support (PhD scholarship) from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). Dr. Mei consulted for Northern Therapeutics. Dr. Stewart is employed by Northern Therapeutics. The remaining authors have disclosed that they do not have any potential conflicts of interest.
Address requests for reprints to: Claudia C. dos Santos, MD, MSc, Department of Critical Care, St. Michael’s Hospital, 30 Bond Street, Room 4–011, Toronto, ON, M5B 1WB, Canada. E-mail: email@example.com. Patricia R. M. Rocco, MD, PhD, Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos ChagasFilho, s/n, Bloco G-014, Ilha do Fundão 21941-902, Rio de Janeiro, Brazil. E-mail: firstname.lastname@example.org