Overexpression of IL-1 Receptor Antagonist Attenuates Obliterative Bronchiolitis in Murine Tracheal Transplant Model

Obliterative bronchiolitis (OB) remains an impediment to long-term survival after lung transplantation. IL-1 beta (IL-1β) has been studied as proinflammatory and profibrotic factor in allograft chronic lung tissue rejection. IL-1 receptor antagonist (IL-1rn) is competitive inhibitor to IL-1β and mediates the anti-inflammatory and antifibrotic effects of mesenchymal stem cells during lung injury. We hypothesized that IL-1rn overexpression prevents the progression of OB in an established heterotopic tracheal transplantation model. Tracheas from BALB/c mice were implanted and wrapped in the omentum of BALB/c (isografts), C57BL/6 (allografts), IL-1rn overexpression (IL-1rn+/+), IL-1rn knock out (IL-1rn-/-) mice. The tracheas explanted after 21 days were evaluated histologically, and real time-PCR for IL-1rn, IL-1β, IL-1 alpha (IL-1α) mRNA levels. Cytokine quantification for these proteins in plasma samples was done by ELISA 21 days after surgery. IL-1rn overexpression mice showed significant reduction of the tracheal luminal occlusion compared to control allograft animals (p<0.0001). The gene expression of IL-1rn in tracheal tissue explanted from IL-1rn overexpression animals was increased (50-150 fold) as compared to tissue from control isograft, allograft and IL-1rn knock out animals (p<0.0001). [figure 1] There was also significant increase in plasma IL-1rn levels in the IL-1rn +/+ animals as compared to other groups (p<0.0001). The results suggest that IL-1rn overexpression protects against experimental OB. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new strategy for the treatment of OB

Overexpression of IL-1 Receptor Antagonist Attenuates Obliterative Bronchiolitis in Murine Tracheal Transplant Model

Obliterative bronchiolitis (OB) remains an impediment to long-term survival after lung transplantation. IL-1 beta (IL-1β) has been studied as proinflammatory and profibrotic factor in allograft chronic lung tissue rejection. IL-1 receptor antagonist (IL-1rn) is competitive inhibitor to IL-1β and mediates the anti-inflammatory and antifibrotic effects of mesenchymal stem cells during lung injury. We hypothesized that IL-1rn overexpression prevents the progression of OB in an established heterotopic tracheal transplantation model. Tracheas from BALB/c mice were implanted and wrapped in the omentum of BALB/c (isografts), C57BL/6 (allografts), IL-1rn overexpression (IL-1rn+/+), IL-1rn knock out (IL-1rn-/-) mice. The tracheas explanted after 21 days were evaluated histologically, and real time-PCR for IL-1rn, IL-1β, IL-1 alpha (IL-1α) mRNA levels. Cytokine quantification for these proteins in plasma samples was done by ELISA 21 days after surgery. IL-1rn overexpression mice showed significant reduction of the tracheal luminal occlusion compared to control allograft animals (p<0.0001). The gene expression of IL-1rn in tracheal tissue explanted from IL-1rn overexpression animals was increased (50-150 fold) as compared to tissue from control isograft, allograft and IL-1rn knock out animals (p<0.0001). [figure 1] There was also significant increase in plasma IL-1rn levels in the IL-1rn +/+ animals as compared to other groups (p<0.0001). The results suggest that IL-1rn overexpression protects against experimental OB. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new strategy for the treatment of OB