Secretory phenomena in the non-lactating human mammary gland.

The normal non-lactating premenopausal human mammary gland has been shown by immunohistochemistry and transmission electron microscopy to secrete a number of antimicrobial peptides such as beta-defensins, the cathelicidin LL37, lactoferrin and adrenomedullin. In addition, the non-lactating gland elaborates a prominent glycocalyx at the apical membrane of the glandular epithelial cells, parts of which are shed into the lumen of endpieces and ducts. This glycocalyx includes the mucins MUC 1 and MUC 4, a strongly Alcian Blue positive palyanionic component and sulfated material stained with Aldehyde Fuchsin. MUC 1 and the Alcian Blue positive material are considered to play an antimicrobial role, too. Lactalbumin and lipid droplets also occur in the non-lactating gland. At the EM-level secretory phenomena operating by exocytosis and by means of the apocrine mechanism have been observed. Cytoskeletal components presumably play a role in apocrine secretion. Apart from secretion at the cellular apex, secretion at the cellular basis also occurs regularly, which may represent the production of para- or endocrine factors.

Antimicrobial peptides are present in immune and host defense cells of the human respiratory and gastrointestinal tracts.

Previous studies have implicated antimicrobial peptides in the host defense of the mammalian intestinal and respiratory tract. The aim of the present study has been to characterize further the expression of these molecules in non-epithelial cells of the human pulmonary and digestive systems by detailed immunohistochemical analysis of the small and large bowel and of the large airways and lung parenchyma. Additionally, cells obtained from bronchoalveolar lavage were analyzed by fluorescent activated cell sorting and immunostaining of cytospin preparations. hBD-1, hBD-2, and LL-37 were detected in lymphocytes and macrophages in the large airways, lung parenchyma, duodenum, and colon. Lymphocytes positive for the peptides revealed a staining pattern and distribution that largely matched that of CD3-positive and CD8-positive T-cells. Macrophages with positive staining for the antimicrobial peptides also stained positively for CD68 and CD74. In view of the morphology of the LL-37-positive and hBD-2-positive mucosal lymphocytes, they are probably also B-cells. Thus, antimicrobial peptides of the defensin and cathelicidin families are present in a variety of non-epithelial cells of mucosal organs. These findings confirm that antimicrobial peptides have multiple functions in the biology of the mucosa of these organs.

An angiogenic role for the human peptide antibiotic LL-37/hCAP-18.

Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor-like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.

Adrenomedullin in mammalian and human skin glands including the mammary gland.

Adrenomedullin is a peptide that has been ascribed numerous functions. In the present paper, adrenomedullin has been localized immunhistochemically in a variety of skin glands of humans, elephants and impalas: apocrine scent glands, eccrine sweat glands, holocrine glands and mammary glands. In the apocrine glands expression of adrenomedullin varied with respect to staining intensity and intracellular localization. In general, glands which appeared to be actively secreting were more strongly stained than quiescent glands. However, within a single glandular tubule, individual cells differed considerably in the staining intensity of adrenomedullin. Adrenomedullin was present in both non-lactating and lactating mammary secretory epithelia, both ducts and alveoli reacted positively. In human mammary glands displaying apocrine metaplasia, the apical protrusions were strongly positive. Furthermore, positive immunostaining was found in endothelium and often in smooth muscle cells of small arteries and veins and in mast cells as well. Many of the adrenomedullin-positive epithelial cells were most strongly stained in the area of the Golgi apparatus, the cellular apex and particularly close to the basal side of the cell membrane. This pattern suggests packaging of adrenomedullin into secretory granules and secretion both at the apex of cells and at their basis. The first form of secretion suggests exocrine secretion, the latter form endocrine secretion of adrenomedullin. A possible hormonal function is in line with basally located electron dense small secretory granules, which have been found by electron microscopy in the glandular epithelia studied.