Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens.
ABSTRACT Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease.
SourceAvailable from: Antti Joonas Koivisto[Show abstract] [Hide abstract]
ABSTRACT: Background Carbon nanotubes (CNT) represent a great promise for technological and industrial development but serious concerns on their health effects have also emerged. Rod-shaped CNT are, in fact, able to induce asbestos-like pathogenicity in mice including granuloma formation in abdominal cavity and sub-pleural fibrosis. Exposure to CNT, especially in the occupational context, happens mainly by inhalation. However, little is known about the possible effects of CNT on pulmonary allergic diseases, such as asthma.Methods We exposed mice by inhalation to two types of multi-walled CNT, rigid rod-like and flexible tangled CNT, for four hours a day once or on four consecutive days. Early events were monitored immediately and 24 hours after the single inhalation exposure and the four day exposure mimicked an occupational work week. Mast cell deficient mice were used to evaluate the role of mast cells in the occurring inflammation.ResultsHere we show that even a short-term inhalation of the rod-like CNT induces novel innate immunity-mediated allergic-like airway inflammation in healthy mice. Marked eosinophilia was accompanied by mucus hypersecretion, AHR and the expression of Th2-type cytokines. Exploration of the early events by transcriptomics analysis reveals that a single 4-h exposure to rod-shaped CNT, but not to tangled CNT, causes a radical up-regulation of genes involved in innate immunity and cytokine/chemokine pathways. Mast cells were found to partially regulate the inflammation caused by rod-like CNT, but also alveaolar macrophages play an important role in the early stages.Conclusions These observations emphasize the diverse abilities of CNT to impact the immune system, and they should be taken into account for hazard assessment.Particle and Fibre Toxicology 10/2014; 11(1):48. DOI:10.1186/s12989-014-0048-2 · 6.99 Impact Factor
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ABSTRACT: Recently, we have highlighted the immunomodulatory activity of the standardized extracts of Phyllanthus amarus and P. urinaria. The present study was carried out to correlate between the prevalent constituents of the herbs and their inhibitory effects on phagocytic activity of human neutrophils. The compounds, gallic acid, ellagic acid, corilagin, geraniin, phyllanthin and hypophyllanthin were identified and quantitatively analyzed in the extracts of Phyllanthus amarus and P. urinaria obtained from Malaysia and Indonesia by using a validated reversed phase high performance liquid chromatography (RP-HPLC) method. The standardized extracts and the pure compounds were evaluated for their effects on chemotaxis, β2 integrin (CD18) expression, phagocytosis and chemiluminescence of human phagocytes. Chemotactic activity was assessed using the Boyden chamber technique, inhibition of CD18 expression and phagocytic ability were tested with the aid of flow cytometry, while effect on the respiratory burst was investigated using a luminol-based chemiluminescence assay. All plant extracts strongly inhibited migration of the phagocytes with the Malaysian P. amarus depicting the highest inhibitory activity. Amongst the compounds tested, geraniin demonstrated the strongest inhibitory activity on chemotaxis of polymorphonuclear leukocytes (PMNs) and monocytes with IC50 values of 1.09 and 1.69 μM, respectively, which were lower than that of ibuprofen. All plant extracts and pure compounds exhibited high inhibitory activity on the oxidative burst of zymosan and PMA stimulated leukocytes. Geraniin and corilagin exhibited exceptionally strong inhibition on the reactive oxygen species (ROS) activity with IC50 values lower than aspirin. The plant extracts exhibited moderate inhibition of E. coli uptake by monocytes but weak effect on PMNs. Of all the compounds, phyllanthin at 50 μg/mL exhibited the highest engulfment inhibitory activity with percentage of phagocytizing cells of 14.2 and 27.1% for PMNs and monocytes, respectively. All plants and compounds tested possessed weak effect on CD18 expression on leukocytes except for hypophyllanthin and phyllanthin which exhibited significant inhibitory effect. The strong inhibition of the extracts on the phagocytic activity of neutrophils was due to the presence of their major constituents especially geraniin, corilagin, phyllanthin and hypophllanthin which were able to modulate the innate response of phagocytes at different steps.BMC Complementary and Alternative Medicine 12/2014; 14(1):2006. DOI:10.1186/1472-6882-14-429 · 1.88 Impact Factor
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ABSTRACT: Early life respiratory viral infections and atopic characteristics are significant risk factors for the development of childhood asthma. It is hypothesized that repeated respiratory viral infections might induce structural remodeling by interfering with the normal process of lung maturation; however, the specific molecular processes that underlie these pathological changes are not understood. To investigate the molecular basis for these changes, we used an established Sendai virus infection model in weanling rats to compare the post-infection transcriptomes of an atopic asthma susceptible strain, Brown Norway, and a non-atopic asthma resistant strain, Fischer 344. Specific to this weanling infection model and not described in adult infection models, Sendai virus in the susceptible, but not the resistant strain, results in morphological abnormalities in distal airways that persist into adulthood. Gene expression data from infected and control lungs across five time points indicated that specific features of the immune response following viral infection were heightened and prolonged in lungs from Brown Norway rats compared with Fischer 344 rats. These features included an increase in macrophage cell number and related gene expression, which then transitioned to an increase in mast cell number and related gene expression. In contrast, infected Fischer F344 lungs exhibited more efficient restoration of the airway epithelial morphology, with transient appearance of basal cell pods near distal airways. Together, these findings indicate that the pronounced macrophage and mast cell responses and abnormal re-epithelialization precede the structural defects that developed and persisted in Brown Norway, but not Fischer 344 lungs.PLoS ONE 12/2014; 9(12):e112997. DOI:10.1371/journal.pone.0112997 · 3.53 Impact Factor