Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation.

Abstract

Acute lung injury is a frequent and treatment-limiting consequence of therapy with hyperoxic gas mixtures. To determine if IL-11 is protective in oxygen toxicity, we compared the effects of 100% O2 on transgenic mice that overexpress IL-11 in the lung and transgene (-) controls. IL-11 markedly enhanced survival in 100% O2 with 100% of transgene (-) animals dying within 72-96 h and > 90% of transgene (+) animals surviving for more than 10 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Significant differences in copper zinc superoxide dismutase and catalase activities were not noted and the levels of total, reduced and oxidized glutathione were similar in transgene (+) and (-) animals. Glutathione reductase, glutathione peroxidase, and manganese superoxide dismutase activities were slightly higher in transgene (+) as versus (-) mice after 100% O2 exposure, and IL-11 diminished hyperoxia-induced expression of IL-1 and TNF. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-11 markedly diminished this cell death response. These studies demonstrate that IL-11 markedly diminishes hyperoxic lung injury. They also demonstrate this protection is associated with small changes in lung antioxidants, diminished hyperoxia-induced IL-1 and TNF production, and markedly suppressed hyperoxia-induced DNA fragmentation.

Pulmonary Expression of Leukemia Inhibitory Factor Induces B Cell Hyperplasia and Confers Protection in Hyperoxia

“…The IL-6-type cytokines, LIF, IL-6, IL-11, oncostatin-M, ciliary neurotropic factor, and cardiotropin-1 are grouped together based on their shared use of gp130 as the ␤-subunit of their receptor complexes and the well documented overlap of their effector profiles (1,24,25). In accord with these commonalities, we expected to see structural similarities in comparisons of the phenotypes of the LIF transgenic mice and transgenic mice in which the CC10 promoter was used to drive the expression of IL-6 or IL-11 (26,27).…”

“…Exposure to 100% O 2 -Mice were exposed to 100% oxygen in a 50 ϫ 30 ϫ 30-cm airtight chamber as described previously (24,25). The fractional inspired O 2 concentration in the chamber was monitored with an in-line oxygen analyzer (Vascular Technology, Inc., Chelmsford, MA) and maintained with a constant flow of gas (ϳ3 liters/min).…”

“…Effect of LIF on IL-6 Production-Studies were next undertaken to determine whether LIF induced the production of IL-6 or IL-11 which are known to ameliorate HALI (24,25). IL-6 mRNA could not be detected in lungs from transgene (Ϫ) mice on normal water or dox water breathing room air or 100% O 2 for up to 72 h (Fig.…”

Use of the Tetracycline-controlled Transcriptional Silencer (tTS) to Eliminate Transgene Leak in Inducible Overexpression Transgenic Mice

“…In early studies, these promoters were used to directly drive the expression of transgenes in the lung. These studies provided impressive insights into the chronic respiratory effector functions of inflammatory mediators and the pathogenesis of asthma, adult respiratory distress syndrome, lung development, and pulmonary fibrosis (2)(3)(4)(5)(6)(7)(8)(9). In these systems, the transgene is activated in utero and expressed in a constitutive fashion thereafter.…”

Lysophosphatidic acid generation by pulmonary NKT cell ENPP-2/autotaxin exacerbates hyperoxic lung injury

“…Separate sets of animals were studied for different experimental outcome groups. Eight-to 10-week-old mice were placed in cages in a customized airtight plexiglass chamber, and exposure to 100 % inhaled oxygen was conducted for 72 h, as described [16].…”