Mesenchymal stem cells and inflammatory lung diseases
PANMINERVA MED 2009;51:5-16 ol. 51 – No. 1
S. S. IYER 1, 2, 3, C. CO 1, M. ROJAS 1, 2, 4
Inflammation, defined by Celsus around AD40 as “rubor, calor, dolor, tumor” (redness, heat, pain, nd swelling), is a highly evolved process that can rise in any tissue in response to pathogens, trauma, oxins, or autoimmune injury.1 Deficiencies in celluar and humoral components of the inflammatory response lead to an increased risk of infection and death.2 Thus, the ability to mount an inflammatory response is life-preserving. However, excessive inflammation can injure the lungs.
In patients with gram negative sepsis; a disregulated inflammatory response to bacterial endotoxin increases the risk for acute lung injury (ALI), which can lead to severe respiratory failure termed the acute respiratory distress syndrome (ARDS).3 ALI and ARDS are associated with significant morbidity, and mortality rates of greater than 30%.3 Because disregulated inflammation causes lung injury, strategies to attenuate the inflammatory response in ALI and ARDS are of considerable therapeutic interest.
Since the description of the immunomodulatory effects of BMDMSCs in vitro to their current applications in inflammatory lung diseases; BMDMSCs truly represent a bench to bedside paradigm. Indeed, considerable opportunity exists to extend the in vivo findings to the clinic to test whether MSC-based interventions are beneficial in patients with ALI, PH, and asthma.
At the same time, however, studies are needed to fill gaps in our understanding of the mechanistic role and the potential efficacy of BMDMSCs in inflam- matory lung diseases. It must be noted that in most of the in vivo studies of ALI, BMDMSCs have been administered either before or immediately after the inflammatory challenge. Care should be taken to design experiments to test the efficacy of BMDMSCs when administered during the progression of lung injury/inflammation so that clinical outcomes can be readily envisioned.
Similarly, differences in outcomes between intra- pulmonary versus intra-venous routes must be addressed. Because ALI is a heterogenous clinical entity that can result from pulmonary insults such as aspiration of gastric contents and extra-pulmonary insults such as sepsis and pancreatitis, the efficacy of BMDMSCs must be tested in various models of ALI.
It is possible that the effects of BMDMSCs may vary depending on the underlying cause of ALI, and also on the route of administration. Finally, studies investi- gating the effects of BMDMSCs in models of live bac- teria-induced ALI are paramount, to ensure that the anti-inflammatory effects of BMDMSCs does not compromise bacterial clearance. The way forward likely lies in identifying points of control in the inflam- matory response that are modulated by BMDMSCs and apply that knowledge to design complementary therapies in ALI. If the immense therapeutic poten- tial of BMDMSCs can be realized in the clinic, it will represent a breakthrough in the treatment of inflam- matory lung diseases.