C. Olgart Höglund

Nerve growth factor levels and localisation in human asthmatic bronchi.

Nerve growth factor (NGF) has recently been suggested to be an important mediator of inflammation. In support of this, serum levels of NGF have been shown to be enhanced in asthmatics. However, it has not yet been shown whether the levels of NGF are also altered locally in asthmatic airways, when compared with healthy subjects, and the localisation of potential sources of NGF in the human bronchus have not yet been described. The aim of the present study was to assess NGF levels in bronchoalveolar lavage fluid (BALF) from asthmatics and to compare them to those of control subjects. Furthermore, the authors wanted to localise potential sources of NGF in bronchial tissue, and to number NGF-immunopositive infiltrating cells in the bronchial submucosa. BALF and bronchial biopsies were obtained from seven control subjects and seven asthmatic patients by fibreoptic bronchoscopy. NGF protein levels were quantified by enzyme-linked immunosorbent assay in BALF. NGF localisation was examined by immunohistochemistry on bronchial biopsy sections. The asthmatics exhibited significantly enhanced NGF levels in BALF. Intense NGF-immunoreactivity was observed in bronchial epithelium, smooth muscle cells and infiltrating inflammatory cells in the submucosa, and to a lesser extent in the connective tissue. The asthmatics exhibited a higher number of NGF-immunoreactive infiltrating cells in the bronchial submucosa than control subjects. This study provides evidence that nerve growth factor is locally produced in the airways, and shows that this production is enhanced in asthmatics. These findings suggest that nerve growth factor is produced by both structural cells and infiltrating inflammatory cells in human bronchus in vivo, and the authors suggest that the increase in nerve growth factor protein in bronchoalveolar lavage fluid observed in asthmatic patients may originate both from structural cells, producing increased nerve growth factor levels in inflammatory conditons, and from the increase in nerve growth factor-immunopositive cells determined in the bronchial submucosa.

Changes in immune regulation in response to examination stress in atopic and healthy individuals

Background Stress can aggravate the allergic inflammation, but determinants of disturbed immune regulation are largely unknown.

Nerve growth factor is released by IL-1β and induces hyperresponsiveness of the human isolated bronchus

Nerve growth factor (NGF) is a neurotrophic factor essential for the development and survival of neurons, and is also an important mediator of inflammation. It is released by airway cells stimulated by interleukin (IL)-1β. As IL-1β induces airway hyperresponsiveness (AHR) to the tachykinin NK-1 receptor agonist [Sar9,Met(O2)11]-substance P in human isolated bronchi, the aim of this study was to determine whether IL-1β was able to induce NGF release from isolated bronchi, and whether NGF might participate into IL-1β-induced AHR. IL-1β (10 ng·mL−1; 21°C; 15 h) increased the release of NGF from human isolated bronchi in vitro, and, in organ bath studies, the response of human bronchi to [Sar9,Met(O2)11]-substance P (0.1 µm). A significant correlation was found between these responses. AHR induced by IL-1β was abolished by a blocking anti-human NGF antibody. Finally, NGF (1 ng·mL−1; 37°C; 0.5 h) by itself induced a significant increase in [Sar9,Met(O2)11]-substance P responsiveness. By contrast, it did not change the maximal contraction to acetylcholine. In conclusion, the present study clearly demonstrated that nerve growth factor may participate in the airway hyperresponsiveness induced by interleukin-1β, which supports the neuro-immune cross-talk that may be active in the development of hyperresponsiveness in the human airways, and suggests nerve growth factor is active in the airways in asthma.

Modality and sex differences in pain sensitivity during human endotoxemia

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (Ps>.70). Suprathreshold noxious pain was not affected by LPS in men (Ps⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that womens pain perception and modulation is more sensitive to immune activation than mens.

Why sickness hurts : A central mechanism for pain induced by peripheral inflammation

Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that womens pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.

Altered apoptosis in bronchoalveolar lavage lymphocytes after allergen exposure of atopic asthmatic subjects

The increased number of lymphocytes in airways during an asthmatic response is believed to be the result of increased recruitment of these cells. However, it is possible that a decreased apoptotic rate could also contribute to the increased number. The aim of the present study was to investigate whether allergen airway provocation influences the apoptotic phenotype of lung and peripheral blood lymphocytes (PBL) in subjects with atopic asthma. Bronchoalveolar lavage (BAL) lymphocytes and PBL from 12 asthmatic subjects previously challenged with allergen (n = 7) or saline (n = 5) were exposed to the apoptotic stimulus tributyltin (TBT) in vitro and assayed for apoptosis. Airway allergen provocation resulted in decreased sensitivity of BAL lymphocytes to TBT-induced apoptosis, with 42.2% (range 33.9–62.5%) apoptotic cells before challenge versus 23.5% (range 15.3–42.4%) after challenge, while PBL were unaffected. The increased apoptosis resistance correlated with higher numbers of Bcl-2-expressing lymphocytes. Interestingly, baseline caspase-3-like activity was significantly elevated in viable BAL lymphocytes compared with viable PBL, and was unaltered by allergen exposure. In conclusion, allergen inhalation renders bronchoalveolar lavage lymphocytes more resistant to apoptosis while peripheral blood lymphocytes were not influenced at all, indicating that the apoptotic phenotype of airway lymphocytes may play a role in asthmatic inflammation.

Increased levels of nerve growth factor in the airways of patients with sarcoidosis

Objectives.  Nerve growth factor (NGF) is a potent neuronal growth factor with inflammatory properties that recently has been proposed to be of importance in airway pathology. A role for NGF in the inflammatory granulomatous lung disease sarcoidosis is not well elucidated. The aims of this study were to investigate the secreted levels of NGF in bronchoalveolar lavage fluid (BALF) from sarcoidosis patients compared with patients with resolved disease, patients with another granulomatous disease – chronic beryllium disease (CBD) – and healthy subjects and also to investigate the relationship between NGF levels and markers of inflammation.

117. Self-rated health in response to experimental manipulations of inflammation is mediated by sickness behavior as assessed by the sickness questionnaire

Factors that influence subjective health ratings (e.g. pain, tiredness, lack of energy) resemble immune activated sickness behavior. Accordingly, previous research has shown a relation between inflammatory cytokines and poor self-rated health. However, neither the causality of the association, nor what mediates it, is clear. In this study we investigated if a transient immune activation would affect subjective health perception and, if so, if this effect is mediated by symptoms of sickness behavior. Using a between-subject design, 51 healthy subjects were injected with either endotoxin (LPS 0.6 ng/kg) or placebo. Stimulation resulted in a peak response in pro-inflammatory cytokines after 90–120 min. Ninety minutes after injection, both perceived health framed to represent current (“How is your health right now?”) and global health (“How would you rate your general state of health”?) was significantly lower in the endotoxin condition (p’s < .01). The effect of endotoxin on self-rated health was mediated by sickness behavior as assessed by a newly developed questionnaire, Sickness Questionnaire, to 91% for current and 68 % for global health. In conclusion, it is demonstrated that a transient inflammatory activation, likely working through symptoms of sickness behavior, affects both subjectively perceived health for the moment as well as how health status on the more general level is appraised.

Sickness hurts: Human pain sensitivity in response to experimental inflammatory stimulation

67. Sickness hurts: Human pain sensitivity in response to experimental inflammatory stimulation M. Lekander , B. Karshikoff , M. Ingvar , E. Kosek , A. Soop , C. Olgart Höglund , J. Axelsson b a Stress Research Institute, Stockholm University, Stockholm SE-106 91, Sweden b Osher Center for Integrative Medicine, Karolinska Institutet, Sweden c Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Sweden d Department of Medicine, Karolinska Institutet, Sweden e Department of Physiology and Pharmacology, Karolinska Institutet, Sweden

BDNF expression in response to academic stress in asthmatic and healthy subjects

381 BDNF expression in response to academic stress in asthmatic and healthy subjects C. Kemi , M. Lekander , J. Grunewald , J. Axén , S. Jernelöv , C. Müller-Suur , Y. Smith , R. Grönneberg , A. Eklund , P. Stierna , C. Olgart Höglund a,e,f,g a Dept. of Medicine Solna, Karolinska Institutet, Stockholm, Sweden b Dept. of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden c Stress Research Institute, Stockholm University, Stockholm, Sweden d Dept. of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden e Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden f Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden g Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden Stress may modulate immune responses and has been shown to regulate allergic inflammation in an unfavourable way. The neurotrophin brain-derived neurotrophic factor (BDNF) was originally discovered as a neuronal growth factor, but is today also recognized as a critical mediator of allergic inflammation and asthma. Recent studies have suggested a role for BDNF as a survival factor for eosinophils and inducer of bronchial hyperreactivity in asthma. Stress has been shown to regulate neurotrophins in brain and blood. However, if stress can regulate BDNF release from immune cells and if this regulation differs between asthmatic and healthy subjects is unknown. The aim of the study was to determine the regulation of BDNF secretion from white blood cells in asthmatic and healthy subjects, in parallel to studies of inflammatory parameters and bronchial hyperreactivity, in response to stress. Thirtyfive medical students were examined during a low-stress and stressful (academic exams) study period. ELISA analysis of white blood cells revealed generally higher secreted levels of BDNF in asthmatic compared to healthy subjects. At the stress period, BDNF secretion increased in healthy subjects only and correlated positively to IL-5 and CD4+ T-cells in asthmatics. A possible role for BDNF in the pathogenesis of asthma and stress-mediated neuroimmune regulation is therefore suggested. doi:10.1016/j.bbi.2010.07.135