WOUND RESPONSE TO INFECTION: ROLE OF LPS-BINDING PROTEIN

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION: 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.