Distal airways are protected from goblet cell metaplasia by diminished expression of IL-13 signalling components.

BACKGROUND: Increased mucus production is a critical factor impairing lung function in patients suffering from bronchial asthma, the most common chronic inflammatory lung disease worldwide. OBJECTIVE: This study aimed at investigating whether goblet cell (GC) metaplasia and mucus production are differentially regulated in proximal and distal airways. METHODS: Female Balb/c mice were sensitized to ovalbumin (OVA) and challenged with an OVA-aerosol on two consecutive days for 1 week (acute) or 12 weeks (chronic). Real-time RT-PCR analysis was applied on microdissected airways. RESULTS: In acutely and chronically OVA-challenged mice, GC metaplasia and mucus production were observed in proximal but not in distal airways. In contrast, inflammation reflected by the infiltration of eosinophils and expression of the TH2-type cytokines IL-4 and IL-13 was increased in both proximal and distal airways. Abundance of IL-13Rα1 was lower in distal airways of healthy control mice. Under acute and chronic OVA-exposure, activation of IL-13Rα1-dependent signalling cascade, reflected by Spdef and Foxo3A transcription factors, was attenuated in distal compared to proximal airways. CONCLUSION AND CLINICAL RELEVANCE: These data indicate that distal airways might be less sensitive to IL-13-induced GC metaplasia and mucus production through lower expression of IL-13Rα1 and attenuated activation of downstream signalling. This might represent a protective strategy to prevent mucus plugging of distal airways and thus impaired ventilation of attached alveoli.

IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice.

BACKGROUND: Interleukin (IL) 37 has been described as a negative regulator of innate immunity, as it reduces the activation and cytokine production of different innate immune cells. Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma. METHODS: Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48 h (anti-CD3/anti-CD28 stimulation or unstimulated), and IL-37 concentrations in supernatants were determined. Wild-type, IL-18Rα-deficient ((-/-) ), and SIGIRR(-/-) C57BL/6 mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute experimental asthma, and IL-37 was applied intranasally prior to each OVA challenge. Airway hyper-responsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, and mucus production were determined. RESULTS: IL-37 production of human PBMCs was significantly lower in allergic asthmatics vs healthy children. In wild-type mice, intranasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished the hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18Rα or SIGIRR/IL-1R8. CONCLUSIONS: This study demonstrates that IL-37 is able to ablate a TH2 cell-directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Rα as well as the orphan receptor SIGIRR/IL-1R8.

Pulmonary haptoglobin and CD163 are functional immunoregulatory elements in the human lung.

BACKGROUND: The acute-phase protein haptoglobin (Hp) and its receptor CD163 serve as immunomodulators and possess anti-inflammatory besides antioxidant functions. OBJECTIVES: To further understand the role of the recently described pulmonary Hp (pHp) and its receptor CD163 in case of inflammation and infection, pHp and CD163 were investigated on mRNA and protein level to gain insight into the cellular events taking place upon stimulation with the inflammatory mediators LPS, Pam3, cytokine IL-6 and dexamethasone, and upon infection with respiratory pathogens (Haemophilus influenzae, Streptococcuspneumoniae and Chlamydia pneumoniae) by use of a human ex vivo tissue culture model and cell cultures of A549 and alveolar epithelial cells type II. In addition, pHp and CD163 expression in COPD and sarcoidosis was assessed. METHODS: We conducted experiments using 942 ex vivo cultured lung samples applying immunohistochemistry, immunocytochemistry, in situ hybridization, immunofluorescence, real-time PCR, RT-PCR, slot and Western immunoblot analyses with tissue lysates and culture supernatants as well as ELISA and cytometric bead array analyses. RESULTS: This study describes for the first time the expression, regulation and secretion of pHp and its receptor CD163 in the human lung. The release of soluble mediators from A549 cell line and human monocyte-derived macrophages was observed indicating that Hp differentially activates the release of soluble mediators and major chemoattractants. CONCLUSIONS: The findings indicate a native function of pHp and CD163 as functional pulmonary defense elements due to local expression, regulation and secretion during lung infection and as part of the inflammatory immune response of the respiratory system.

Transcriptom-based identification of a putative role for the human Acyl-CoA-Binding-Protein (ACBP) in vesicular trafficking.

In the present study we performed a transcriptom-based analysis of human Acyl-CoA-Binding-Protein (ACBP) target genes. By applying Genomatix BiblioSphere expert level based co-citation filter 4 (GFG level 4) ras homolog gene family member B (RhoB) and its interacting rhophilin-2 (Rhpn2) were refined from 64 ACBP sensitive genes. TaqMan-based qRT-PCR confirmed the accuracy of the array-derived expression data. Based on Gene Ontology (GO) classification RhoB and Rhnp2 were allocated to endosomal transport and signaling processes. Thus, we suggest RhoB and Rhnp2 as ACBP target genes contributing to the proposed and evolutionary conserved function of ACBP in vesicular transport processes.

[Reactions of the domestic pig to exhausting motor stress of middle intensity]. / Reaktionen des Hausschweines bei erschöpfenden motorischen Belastungen mittlerer Intensität.

The VO 2max value was established from twelve pigs, followed by checks of their responses to endurance stress (walk 0.7 m/sec, ambient temperatures between 22 degress C and 24 degrees C, relative humidities between 67 and 78 per cent). Also measured were the rectal temperature, heart rate, respiratory rate, haemoglobin level of the blood, haematocrit, mean corpuscular haemoglobin concentration, plasma volume, blood volume, total haemoglobin, plasma glucose concentration and plasma lactid acid concentration. A differentiation could be made between one group weighing between 53.3 +/- 2.47 kg and enduring 97 +/- 9 minutes and another weighing 60.0 +/- 1.38 kg and enduring 36 +/- 6 minutes. The two groups differed from one another for their plasma and blood volumes, their values being 42.6 +/- 3.8 ml/kg and 67.5 +/- 7.5 ml/kg or 33.5 +/- 3.4 ml/kg and 52.2 +/- 5.9 ml/kg. The groups produced quantitatively different responses to endurance stress. The demands implied in endurance were widely met by the circulatory system, while the energy transfer was characterised primarily by aerobic energy collection.