lactoferrin and Wounds-and-Injuries

Agennix is developing recombinant human (rh) lactoferrin, a glycoprotein with antibiotic, anti-inflammatory and immunomodulatory activity, for the potential treatment of cancers, asthma and chronic wounds. rh Lactoferrin is currently undergoing phase II clinical trials.

Topics: Aspergillus; Asthma; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Lactoferrin; Neoplasms; Recombinant Proteins; Wound Healing; Wounds and Injuries

Lactoferrin (LF) is a pleiotropic glycoprotein that is found in bodily secretions and is postulated to enhance the gastrointestinal barrier and promote mucosal immunity. Thus, the ability of talactoferrin, an oral recombinant form of human LF, to limit gut injury and the production of biologically active gut-derived products was tested using a rat model of trauma-hemorrhagic shock (T/HS).. Male rats were orally dosed with vehicle or talactoferrin (1000 mg/kg, every day) for 5 d before being subjected to T/HS or trauma-sham shock (T/SS). Subsequently, rats were subjected to a laparotomy (trauma) and hemorrhagic shock (mean arterial pressure, 30-35 mm Hg × 90 min) or to T/SS, followed by resuscitation with their shed blood. Before inducing shock, the mesenteric lymphatic duct was catheterized for collection of mesenteric lymph. Four hours after the end of the shock or sham-shock period, rats were sacrificed, a segment of the distal ileum was collected for morphologic analysis, and lymph samples were processed and frozen. Subsequently, lymph samples were tested in several pharmacodynamic assays, including endothelial cell permeability, neutrophil respiratory burst activity, and red blood cell (RBC) deformability. Total white blood cell counts in lymph samples were also quantified.. Pretreatment with talactoferrin reduced the incidence of T/HS-induced morphologic injury of ileum to T/SS levels. Post-T/HS lymph from vehicle-treated rats increased endothelial monolayer permeability and neutrophil priming for an augmented respiratory burst, and induced loss of RBC deformability, compared with T/SS groups. Talactoferrin pretreatment significantly reduced the biological activity of T/HS lymph on respiratory burst activity and RBC deformability, but had no effect on the lymph cell count or endothelial cell permeability.. These results provide a proof of principle that prophylactic dosing of oral talactoferrin can potentially protect the gut in a T/HS model and limit the production of biologically active factors in rat gastrointestinal tissue subjected to ischemia-reperfusion-type injuries.

Topics: Administration, Oral; Animals; Ileum; Lactoferrin; Laparotomy; Lymph; Lymphatic System; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Respiratory Burst; Shock, Hemorrhagic; Wounds and Injuries

The secretory leukocyte protease inhibitor (SLPI) re-establishes homeostasis at sites of infection by virtue of its ability to exert antimicrobial activity, to suppress LPS-induced cellular immune responses, and to reduce tissue damage through inhibition of serine proteases released by polymorphonuclear neutrophil granulocytes (PMNs). Microarray analysis of bone marrow (BM) populations highly enriched in promyelocytes, myelocytes/metamyelocytes (MYs), and BM neutrophils demonstrates a transient, high mRNA expression of SLPI and genuine secondary granule proteins (GPs) in MYs. Consistent with this finding, immunostaining of BM cells showed SLPI and the secondary GP lactoferrin (LF) to be present in cells from the myelocyte stage and throughout neutrophil differentiation. Subcellular fractionation studies demonstrated the colocalization of SLPI and LF in subcellular fractions highly enriched in secondary granules. Finally, exocytosis studies demonstrated a corelease of SLPI and LF within minutes of activation. Collectively, these findings strongly indicate that SLPI is localized in secondary granules of PMNs. However, the amount of SLPI detected in PMNs is low compared with primary keratinocytes stimulated by growth factors involved in wound healing. This implicates that neutrophil-derived SLPI might not contribute essentially to re-establishment of homeostasis at sites of infection but rather, exert physiologically relevant intracellular activities. These might include the protection of secondary GPs against proteolytic activation and/or degradation by proteases, which might be dislocated to secondary granules at minute amounts as a consequence of spillover.

Topics: Bone Marrow Cells; Cell Culture Techniques; DNA Primers; Exocytosis; Humans; Immunohistochemistry; Keratinocytes; Lactoferrin; Neutrophils; Reverse Transcriptase Polymerase Chain Reaction; Secretory Leukocyte Peptidase Inhibitor; Skin; Transcription, Genetic; Wounds and Injuries

Circulating levels of lactoferrin, a specific granule protein of neutrophilic leukocytes, and eosinophil cationic protein (ECP), a specific granule protein of eosinophilic leukocytes, were serially measured in 19 patients at risk for adult respiratory distress syndrome (ARDS). Those patients who developed ARDS had significantly higher concentrations of both proteins than the patients without signs of ARDS. High ECP levels were observed in spite of peripheral eosinopenia. The lactoferrin levels were also increased in relation to circulating numbers of neutrophils. These findings are consistent with an enhanced turnover and/or activity of eosinophils and neutrophils in ARDS and thereby support other clinical and experimental observations suggesting a central pathophysiologic role for granulocytes in ARDS. No relation was found between ARDS or serum concentrations of lactoferrin or ECP and degree of complement consumption, suggesting that other mechanisms besides complement activation may underlie granulocyte activation in ARDS.

Topics: Adolescent; Adult; Aged; Blood Proteins; Complement Activation; Critical Care; Eosinophil Granule Proteins; Female; Humans; Lactoferrin; Male; Middle Aged; Neutrophils; Prospective Studies; Respiratory Distress Syndrome; Ribonucleases; Shock, Septic; Wounds and Injuries