Cigarette smoke induces significant changes in oxidant defense responses; some of these are further amplified, but not in a linear fashion, in individuals who develop COPD.

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LPS-induced neutrophil recruitment was reduced by inhibition of CXCR2. This outcome mimicked the response previously seen in a lower airway LPS model. Hence, the nasal model offers a convenient and well-tolerated alternative for pharmacological evaluation of anti-inflammatory drugs affecting neutrophilic migration and activity.

ADAM9 levels are increased in COPD lungs and linked to key clinical variables. Adam9 promotes emphysema development, and large and small airway disease in mice. Inhibition of ADAM9 could be a therapeutic approach for multiple COPD phenotypes.

Background: Allergic rhinitis is a systemic disorder, and it is clinically well recognized that it can be aggravated by infection. Activation of the innate immune system constitutes a critical element in the process. Toll-like receptors (TLRs) comprise a part of the innate immune system, and lipopolysaccharide (LPS)-induced activation of TLR4 represents bacterial-induced interactions in various model systems. The present study examines how TLR2 and TLR4 expression is affected by symptomatic allergic rhinitis, and if LPS added upon allergen affects nasal cytokine release. Methods: In patients with pollen-induced allergic rhinitis and healthy non-allergic volunteers, nasal lavage (NAL), peripheral blood and bone marrow were sampled before and during the pollen season. TLR2 and TLR4 expression was determined flow cytometrically. Changes in the TLR receptor expression pattern were evaluated by a nasal challenge with allergen followed by LPS, or vice versa. Symptoms along with cells and cytokines in NAL were analyzed. Results: TLR4 expression increased in leukocytes in NAL, peripheral blood and bone marrow during symptomatic allergic rhinitis. A similar increase was seen for TLR2 in neutrophils in blood. Nasal challenge with allergen followed by LPS augmented the release of IL-4, IL-5, IL-10, IL-13, IFN-γ and TNF-α. Conclusion: A systemic up-regulation of TLR4 in symptomatic allergic rhinitis may explain why LPS preceded by allergen increases nasal cytokine release.

Summary. Expression of the mdr1 (multidrug resistance), mrp (multidrug resistance associated protein), and lrp (lung resistance related protein) genes is associated with transport related MDR (multidrug resistance). We quanti®ed mRNA levels of these genes using competitive reverse transcription polymerase chain reaction (RT-PCR) in 128 samples of leukaemic cells from 92 patients with acute myelogenous leukaemia (AML).There was a wide variation between the samples in mRNA levels of all three genes. The mean mdr1 mRNA level was 1´3 transcripts per cell (range undetectable to 15´8), the mean mrp level was 7´9 (range 0´1±36´2) and mean lrp 3´9 (range 0´1±29).Lrp mRNA levels were higher in samples drawn at diagnosis from the 15 patients with resistant disease than from the 37 with chemosensitive disease (4´9 SD 3´1 v 2´9 SD 2´3, P 0´016). Neither mdr1 nor mrp mRNA levels were predictive for response to chemotherapy. In samples from patients who had received chemotherapy, those that had received mitoxantrone (n 24) had higher lrp mRNA levels (mean 4´8, SD 2´5) than those that had not (n 20, mean 2´8, SD 2´4, P 0´012).In conclusion, the results indicate that lrp expression is associated with inferior response to chemotherapy in AML and that lrp expression increases after exposure to mitoxantrone.

ObjectiveThe aim was to create pathological changes in mice relevant to human smoke exposure that can be used to further understand the mechanisms and pathology of smoke-induced inflammatory disease.MethodsMice were exposed to tobacco smoke or lipopolysaccharide (LPS) to generate an inflammatory infiltrate within the lungs.ResultsTobacco smoke exposure over a 4 day period led to neutrophilia in the lungs of BALB/c mice. Within the inflammatory exudates, significant changes were also seen in protein levels of IL-1B, IL-6, MIP-2, KC (IL-8) and TIMP-1 as measured by ELISA. Further protein changes, as measured via multiplex analysis revealed increased levels of MMP-9, MDC, LIF and MCP-1, amongst other mediators. Major changes in whole lung tissue gene expression patterns were observed. The neutrophilia seen after smoke exposure was steroid-insensitive, relative to doses of steroid needed to reduce LPS-driven neutrophilia in controls. This exposes pathological switches that are changed upon exposure to tobacco smoke, rendering steroids less effective under these conditions. Challenge of chemokine receptor type 1 (CCR1) KO mice in the tobacco smoke model showed that lack of this gene protected the mice from smoke-induced inflammation.ConclusionsThis suggests the CCR1 receptor has a key role in the pathogenesis of smoke-induced inflammation.