Interleukin-10 Gene Therapy-Mediated Amelioration of Bacterial Pneumonia

Abstract

Respiratory infection by Actinobacillus pleuropneumoniae causes a highly pathogenic necrotizing pleuropneumonia with severe edema, hemorrhage and fever. Acute infection is characterized by expression of inflammatory cytokines, including interleukin-1 (IL-1), IL-6 and IL-8. To determine if high level production of inflammatory cytokines contributed to disease pathogenesis, we investigated if inhibiting macrophage activation with adenovirus type 5-expressed IL-10 (Ad-5/IL-10) reduced the severity of acute disease. Porcine tracheal epithelial cells infected with Ad-5/IL-10 produced bioactive human IL-10. When pigs were intratracheally infected with A. pleuropneumoniae, pigs pretreated with Ad-5/IL-10 showed a significant reduction in the amount of lung damage when compared to adenovirus type 5-expressing ␤-galactosidase (Ad-5/␤-Gal)-treated and untreated pigs. In addition, serum zinc levels were unchanged, the lung weight/body weight ratio (an indicator of vascular leakage) was significantly reduced, and lung pathology scores were reduced. Myeloperoxidase activity in lung lavage fluid samples, an indicator of neutrophil invasion, was decreased to levels similar to that seen in pigs not infected with A. pleuropneumoniae. Reduction in inflammatory cytokine levels in lung lavage fluid samples correlated with the clinical observations in that pigs pretreated with Ad-5/IL-10 showed a corresponding reduction of IL-1 and tumor necrosis factor (TNF) compared with untreated and Ad-5/␤-Gal-treated pigs. IL-6 levels were unaffected by pretreatment with Ad-5/IL-10, consistent with observations that IL-6 was not derived from alveolar macrophages. Since inflammatory cytokines are expressed at high levels in acute bacterial pleuropneumonia, these results indicate that macrophage activation, involving overproduction of IL-1 and TNF, is a prime factor in infection-related cases of massive lung injury.

Inflammatory Cytokines, Pleuropneumonia Infection and the Effect of Dexamethasone

“…In contrast to the above studies, Morrison et al [45] demonstrated that injection of a genetic construct capable of producing IL-10 into swine reduced the extent of A. pleuropneumoniae-induced pneumonia. This reduction was attributed to a concomitantly observed reduction in TNF-· and IL-1ß levels in lung lavage fluid.…”

Lung Natural Killer Cells Play a Major Counter-Regulatory Role in Pulmonary Vascular Hyperpermeability After Myocardial Infarction

“…11 In a porcine model of acute bacterial pneumonia, local expression of IL-10 suppressed lung edema and neutrophil invasion, resulting in significantly reduced lung damage. 29 These findings suggested that the protective role of IL-10 on the alveolar-capillary barrier is universal. However, the impact of systemic IL-10 is determined by the timing of application and the underlying disease, whereby in states of sterile inflammation it may be beneficial but deleterious in infection.…”

Mechanisms Involved in the Enhancement of Allergic Airways Neutrophil Influx by Permanent C-Fiber Degeneration in Rats

“…Although the role of IL-6 in the lung pathophysiology is still controversial since it may present pro-and anti-inflammatory effects, the functions of IL-10 offering clinical protection and reduction of lung pathology is well established (Morrison et al, 2000). Interleukin-10 reduces the levels and expression of TNF-␣ by mononuclear cells and mast cells (Weber et al, 1995).…”