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Rationale: A well-known clinical paradox is that severe bacterial infections persist in the lungs of patients with cystic fibrosis (CF) despite the abundance of polymorphonuclear neutrophils (PMN) and the presence of a high concentration of human neutrophil peptides (HNP), both of which are expected to kill the bacteria but fail to do so. The mechanisms remain unknown. Objectives: This study examined several possible mechanisms to understand this paradox. Methods: PMN were isolated from sputum and blood of subjects with and without CF or non-CF bronchiectasis for phagocytic assays. HNP isolated from patients with CF were used to stimulate healthy PMN followed by phagocytic tests. Measurements and Main Results: PMN isolated from the sputum of the bronchiectatic patients display defective phagocytosis that correlated with high concentrations of HNP in the lung. When healthy PMN were incubated with HNP, decreased phagocytic capacity was observed in association with depressed surface Fcg RIII, actin-filament remodeling, enhanced intracellular Ca 21 , and degranulation. Treatment of PMN with an intracellular Ca 21 blocker or a1-proteinase inhibitor to attenuate the activity of HNP largely prevented the HNP-induced phagocytic deficiency. Intratracheal instillation of HNP in Pallid mice (genetically deficient in a1-proteinase inhibitor) resulted in a greater PMN lung infiltration and phagocytic deficiency compared with wild-type mice. Conclusions: HNP or PMN alone exert antimicrobial ability, which was lost as a result of their interaction. These effects of HNP may help explain the clinical paradox seen in patients with inflammatory lung diseases, suggesting HNP as a novel target for clinical therapy.

We conclude that resuscitation with albumin may have utility in reducing ventilator-induced lung injury after hemorrhagic shock, but not after endotoxic shock. These findings suggest that the mechanisms leading to ventilator-induced lung injury after hemorrhage differ from those after endotoxemia.

Human neutrophil peptides (HNP) exert immune-modulating effects. We hypothesized that HNP link innate and adaptive immunity through activation of costimulatory molecules. Human lung epithelial cells and CD4+ lymphocytes were treated with HNP separately or in coculture. Stimulation with HNP induced an increase in cell surface expression of CD54 (ICAM-1), CD80, and CD86 on lung epithelial cells and the corresponding major ligands, CD11a (LFA-1), CD152 (CTLA-4), and CD28 on CD4+ lymphocytes. There was an increased nuclear expression of the transcription factor p53 in human alveolar A549 cells and an elevated NF-kappaB (p50) and a degradation of I-kappaB protein in CD4+ lymphocytes following HNP stimulation. HNP enhanced the interaction between A549 cells and CD4+ lymphocytes by increasing cell adhesion and release of IFN-gamma, IL-2, and IL-8. This was attenuated by using an alpha1-proteinase inhibitor to neutralize HNP. We conclude that HNP play an important role in linking innate to acquired immunity by activation of costimulatory molecules in lung epithelial cells and CD4+ lymphocytes.

The mechanisms by which parenchymal cells interact with immune cells, particularly after removal of LPS, remain unknown. Lung explants from rats, mice deficient in the TNF gene, or human lung epithelial A549 cells were treated with LPS and washed, before naive alveolar macrophages, bone marrow monocytes, or PBMC, respectively, were added to the cultures. When the immune cells were cocultured with LPS-challenged explants or A549 cells, TNF production was greatly enhanced. This was not affected by neutralization of LPS with polymyxin B. The LPS-induced increase in the expression of ICAM-1 on A549 cells correlated with TNF production by PBMC. The cellular cross talk leading to the TNF response was blunted by an anti-ICAM-1 Ab and an ICAM-1 antisense oligonucleotide. In A549 cells, a persistent decrease in the concentration of intracellular cAMP was associated with colocalization of LPS into Toll-like receptor 4 and the Golgi apparatus, resulting in increased ICAM-1 expression. Inhibition of LPS internalization by cytochalasin D or treatment with dibutyryl cAMP attenuated ICAM-1 expression and TNF production by PBMC. In conclusion, lung epithelial cells are not bystanders, but possess memory of LPS through the expression of ICAM-1 that interacts with and activates leukocytes. This may provide an explanation for the failure of anti-LPS therapies in sepsis trials.

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IL-22 is a potent pro-inflammatory cytokine upregulated in psoriasis and in other inflammatory diseases. The function of IL-22 is regulated by the soluble scavenging receptor, IL-22 binding protein (IL-22BP or IL-22RA2). However, the role and regulation of IL-22BP itself in the pathogenesis of inflammatory disease remain unclear. We used the TLR7 agonist Imiquimod (IMQ) to induce a psoriasis-like skin disease in mice and found a strong downregulation of IL-22BP in the affected skin as well as in the lymph nodes of animals treated with IMQ. We also analysed psoriatic skin of patients and compared this to skin of healthy donors. Interestingly, IL-22BP expression was similarly downregulated in skin biopsies of psoriasis patients compared to the skin of healthy donors. Since IL-22BP is expressed foremost in dendritic cells, we characterized its expression in monocyte-derived dendritic cells (MoDC) during maturation. In this way, we found Prostaglandin E2 (PGE2) to be a potent suppressor of IL-22BP expression in vitro. We conclude that regulation of IL-22BP by inflammatory mediators is an important step for the progression of inflammation in the skin and possibly also in other autoimmune diseases.