Attenuation of the Acute-Phase Response in Thermally Injured Rats by Cholesterol-Containing Cationic Liposomes Used as a Delivery System for Gene Therapy

Abstract

Cholesterol-containing cationic liposomes alone modulate the acute-phase response and cytokine expression in thermally injured rats and are an effective delivery system for gene therapy in trauma. Setting: Laboratory. Intervention: Fifty-six adult male Sprague-Dawley rats with a full-thickness scald burn covering 60% of total body surface area were randomly divided into 2 groups to receive either intravenous injections of cholesterolcontaining cationic liposomes or saline (control). Main Outcome Measures: Body weights, muscle and liver dry-wet weights, serum levels of constitutive hepatic proteins, acute-phase protein levels, and cytokine levels were determined at 1, 2, 5, and 7 days after thermal injury. Results: Rats receiving cholesterol-containing cationic liposomes had less body weight loss, increased serum transferrin levels, and decreased serum ␣ 1-acid glycoprotein levels when compared with controls (PϽ.05). Serum interleukin 1␤ and tumor necrosis factor ␣ levels were decreased in rats receiving liposomes at 1 and 2 days after burn compared with controls (PϽ.05). Conclusions: These results suggest that cholesterolcontaining cationic liposomes alone may have a beneficial effect in modulating the hypermetabolic response after burn injury by decreasing type 1 acute-phase proteins and the expression of the proinflammatory cytokines interleukin 1␤ and tumor necrosis factor ␣. Therefore, cholesterol-containing cationic liposomes appear to be suitable as a delivery system for gene therapy in trauma.

The GH/IGF-1 system in critical illness

“…[15–18] IGF-1 gene transfer became an area of interest secondary to the ability of IGF-1 to ameliorate the inflammatory signaling cascade, as well as its association with the stimulation of wound healing. [16, 19] The use of this therapy would be most applicable in patient populations such as those with skin disorders and burns.…”

Effect of Multiple Gene Transfers of Insulinlike Growth Factor I Complementary DNA Gene Constructs in Rats After Thermal Injury

“…[18][19][20] Cationic liposomes are also useful in the treatment of many forms of trauma, exerting antiinflammatory activity by inhibiting nitric oxide, interleukin 1␤, and tumor necrosis factor ␣ synthesis, to attenuate the hypermetabolic response. [21][22][23][24] We have shown that a weekly subcutaneous injection of cholesterol-containing cationic liposomes encapsulating the cDNA coding for the IGF-I gene driven by a CMV promoter is an efficient and safe therapeutic approach to increase IGF-I protein skin concentrations with…”

Genomic analysis of insulin‐like growth factor‐I gene transfer in thermally injured rats

“…Even though IGF‐I gene transfer in burned rats has been shown to have no significant effects on circulating stress response proteins in plasma, 5,6 gene expression responses observed at 10 days in rat liver treated with local IGF‐I gene transfer were significant. The overall level of effects on mRNA transcription after burn trauma were attenuated in the IGF‐I gene transfer‐treated burned rats when compared to sham‐treated animals (Table 2).…”

“…While it is known that systemic IGF‐I injections are beneficial after burn, the associated systemic increases in IGF‐I have toxic side‐effects. Transient localized gene transfer has been shown to ameliorate inflammatory signaling due to burn and to stimulate wound healing 5–7 . To evaluate the effects of IGF‐I gene transfer on burns, we assessed its effect on gene expression using Affymetrix DNA microarray analyses.…”

“…Nonviral liposome‐mediated gene therapy has several advantages over viral gene therapy 9 . Nonviral delivery systems typically result in robust, prompt, and transient localized gene expression without triggering confounding immunological responses or tachyphylaxia 5,6,9–14 . We have determined the optimal liposome/DNA ratios, biodistribution, and feasibility of nonviral liposomal cDNA injections into the skin 5,15,16 .…”