Skin is the first line of defense against the hostile environment. Skin is not only a mechanical barrier but also an immune organ capable of mounting a coordinated inflammatory response. Inflammatory responses serve to recruit immune cells to the wound and also to contain and kill invading organisms. Lipopolysaccharide binding protein (LBP) is a potent facilitator of these functions and the investigators have found high levels of LBP bioactivity within surgical wounds. LBP at low levels potentiates cytokine production in response to LPS; these cytokines are critical in immune cell recruitment and activation. LBP is also an opsonin and potentiates the bactericidal activity of bactericidal/permeability increasing protein (BPI). Wound infections are commonplace after thermal injuries and represent a major cause of morbidity and mortality. Although systemic immune responses may contribute to local wound responses against infection, the investigators postulate that local factors within the wound, particularly LBP, play the most critical role. They hypothesize that LBP within the wound decreases bacterial infection after thermal injury by increasing local inflammatory cytokine production and bactericidal activity. The investigators propose to test this hypothesis by investigating the relationship between LBP, inflammatory cytokines and leukocyte bacterial killing in a rat model of cutaneous thermal injury. LPS is invariably present in burn wounds; LPS is also one of the most potent inducers of cytokine production by leukocytes and this action is markedly amplified by LBP.
Aim 1 will determine the effect of wound LBP on local cytokine production after thermal injury. LBP functions as an opsonin for gram-negative bacteria and also reduces by 10,000-fold the concentration of neutrophil-derived BPI necessary to kill gram-negative bacteria. The investigators anticipate that increased LBP at the site of burn injury will increase wound bactericidal activity by potentiating neutrophil and macrophage recruitment, activation and bacterial killing.
Aim 2 will determine the effect of wound LBP on local bactericidal activity after thermal injury. LBP present in the burn wound after injury could arise from a number of sources, of which transudation from the serum and local production are the two most likely. Wound derived LBP would be ideally situated to regulate the local immune response and may play an increasing role once altered capillary permeability after injury has resolved.
Aim 3 will determine the source and regulation of wound LBP production after thermal injury.
| Taddonio, Michael A; Dolgachev, Vladislav; Bosmann, Markus et al. (2015) Influence of lipopolysaccharide-binding protein on pulmonary inflammation in gram-negative pneumonia. Shock 43:612-9 |
| Hemmila, Mark R; Kim, Jiyoun; Sun, Jian M et al. (2006) Gene therapy with lipopolysaccharide binding protein for gram-negative pneumonia: respiratory physiology. J Trauma 61:598-605; discussion 605-6 |
| Su, Grace L; Gong, Ke Qin; Fan, Ming Hui et al. (2005) Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice. Hepatology 41:187-95 |
| Su, Grace L; Wang, Stewart C; Aminlari, Alireza et al. (2004) Impaired hepatocyte regeneration in toll-like receptor 4 mutant mice. Dig Dis Sci 49:843-9 |
| Su, Grace L; Goyert, Sanna M; Fan, Ming-Hui et al. (2002) Activation of human and mouse Kupffer cells by lipopolysaccharide is mediated by CD14. Am J Physiol Gastrointest Liver Physiol 283:G640-5 |
| Steinstraesser, Lars; Tack, Brian F; Waring, Alan J et al. (2002) Activity of novispirin G10 against Pseudomonas aeruginosa in vitro and in infected burns. Antimicrob Agents Chemother 46:1837-44 |
| Su, Grace L (2002) Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256-65 |
