Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally-occurring peptides which can combat infections through their direct microbicidal properties and/or by influencing the host's immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been employed to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies. This has led to the adoption of the current name for this family of peptides, Cationic Host Defence Peptides, which encompasses the wide range of described functions. Over the last three decades there has been substantial interest in therapeutically harnessing CHDP, with more than 5000 papers published in this area of research since 2017 alone. These include the examination of potential clinical uses for CHDP ranging from infections including multidrug-resistant bacteria 16-19 , to chronic inflammatory diseases such as arthritis 20 , asthma 21 and colitis 22 , as well as some cancers 23. Peptide-based therapeutics currently in clinical trials are primarily for the treatment of infections such as respiratory, oral and catheter-related infections, and for wound healing (see http://dramp.cpu-bioinfor.org/browse/ClinicalTrialsData.php). This review will provide an overview of current understanding of the scope of functions of CHDP, primarily from eukaryotes. Emerging therapeutic applications of these peptides, current clinical trials and the associated clinical developmental challenges will be discussed. Although there is increasing interest in the development of non-peptide mimics of CHDP for therapeutic application, such as peptoid analogs (reviewed in 24), a comprehensive discussion of these approaches is beyond the scope of this review. [H1] Naturally occurring CHDP The antimicrobial peptide database has catalogued more than 2600 natural antimicrobial peptides, including those annotated as immunomodulatory 25. The major families of CHDP from eukaryotes that are of interest from a drug discovery perspective are summarized below. [H2] Vertebrate CHDP CHDP from vertebrates have an essential role in the first line of defense against microbial pathogens. Upon infection, CHDP can kill pathogens through diverse mechanisms 26-31 (discussed below), acting rapidly and directly on the pathogen when present in high local concentrations, or indirectly to modify components of host defense. These peptides exhibit immunomodulatory activities that can be either pro-or anti-inflammatory depending on the phase of the infection (see below) 12-14,29. CHDP from vertebrates are amphipathic peptides containing amino acids with hydrophilic and hydrophobic side chains at opposite sides of the molec...

Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene 1 . Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain 2 – 6 . We asked what abnormalities impair eradication when a bacterium lands on the pristine surface of a newborn CF airway? To investigate these defects, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease 7 , 8 . At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria 8 . Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria in vivo , when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO 3 − transport 9 – 13 . Without CFTR, airway epithelial HCO 3 − secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying bacterial killing could report on the benefit of therapeutic interventions.

The effects of surfactant, surfactant lipids, and surfactant protein A (SP-A) on the surface phagocytosis of [3H]thymidine-labeled Staphylococcus aureus (SAE) by rat alveolar macrophages were studied. Alveolar macrophages only ingest SAE when the bacteria are opsonized with rat serum prior to incubation with alveolar macrophages. Preincubation or "opsonization" of the bacteria with surfactant did not result in phagocytosis by the macrophages. However, preincubation of the macrophages with surfactant increased the phagocytosis of rat serum-opsonized bacteria by approximately 70% when compared to the control macrophages. The factor present in surfactant causing the stimulation of the phagocytosis is probably SP-A. Preincubation of macrophages with human SP-A enhanced the phagocytosis to the same extent as whole surfactant, whereas preincubation with surfactant lipids had no effect on the phagocytosis. The SP-A-induced enhancement of the phagocytosis is time, temperature, and concentration dependent. Phagocytosis of opsonized SAE by alveolar macrophages was maximal after 15 min of incubation and at an SP-A concentration of 1 micrograms/ml. No phagocytosis occurred at 0 degrees C. In addition, whole surfactant and SP-A induce a lucigenin-dependent chemiluminescence response in alveolar macrophages. The chemiluminescence response is initiated after 15 min of incubation and reaches a maximum after 30 min. The concentration of SP-A needed for an optimal response is in the same order of magnitude as the concentration needed for maximal enhancement of the phagocytosis of SAE by alveolar macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Two lineage segregation events in mammalian development form the trophectoderm, primitive endoderm, and pluripotent primitive ectoderm. In mouse embryos, Oct4, Cdx2, Nanog, and Gata6 govern these events, but it is unknown whether this is conserved between mammals. Here, the expression patterns of these genes and their products were determined in porcine oocytes and embryos and in bovine embryos. CDX2 and GATA6 expression in porcine and bovine blastocysts resembled that of mouse, indicating conserved functions. However, NANOG expression was undetectable in porcine oocytes and embryos. Some inner cell mass cells in bovine blastocysts expressed NANOG protein. OCT4 protein was undetectable in porcine morulae, but present in both the trophectoderm and the inner cell mass of blastocysts, suggesting that downregulation of OCT4 in the trophectoderm does not precede trophectoderm formation. Combined, the results indicate differences in lineage segregation between mammals. Developmental Dynamics 237: 918 -927, 2008.

Abstract. This article starts with a brief account of the history of research on pulmonary surfactant. We will then discuss the morphological aspects and composition of the pulmonary surfactant system. We describe the hydrophilic surfactant proteins A and D and the hydrophobic surfactant proteins B and C, with focus on the crucial roles of these proteins in the dynamics, metabolism, and functions of pulmonary surfactant. Next we discuss the major disorders of the surfactant system. The final part of the review will be focused on the potentials and complications of surfactant therapy in the treatment of some of these disorders. It is our belief that increased knowledge of the surfactant system and its functions will lead to a more optimal composition of the exogenous surfactants and, perhaps, widen their applicability to treatment of surfactant disorders other than neonatal respiratory distress syndrome.Key words: Surfactant protein-Pulmonary surfactant-Respiratory distress syndrome. HistoryResearch on surfactant goes back to 1929 when von Neergaard published the first paper about the difference in pressure needed to inflate lungs with air or with liquid [333]. He found that the pressure necessary for filling the lungs with air was higher than when the lungs were filled with liquid. To explain this result he stated that the alveoli were stabilized by lowering the naturally high surface tension of the air/water interface. In 1946 Thannhauser and co-workers reported that lung tissue has a remarkably high content of the lipid dipalmityl lecithin (current name, dipalmitoylphosphatidylcholine)Offprint requests to: Henk P. Haagsman.