Contributions to microbiology最新文献

As we age, it is common for certain phenotypic changes to arise within the population. A number of observations have led scientists to believe that these changes result from an accumulation of cellular defects over time. With enough cell damage, tissue function is compromised and the risk for disease escalates. More importantly, when these defects arise in cells of the innate immune system, the body can no longer defend itself against a variety of pathologies. The main culprit for cellular damage seen with age is thought to be reactive oxygen and nitrogen species produced from endogenous metabolic pathways. To determine how an individual will age, it is thus important to consider all of the factors involved in both the production of and the response to oxidative stress. These factors include genetics, lifestyle, environment, and gender. Understanding the mechanisms of aging can allow us to develop strategies for overcoming the negative aspects of this process and ultimately to help individuals age more gracefully.

Antimicrobial peptides (AMPs) are ancient effector molecules in the innate immune response of eukaryotes. These peptides are important for the antimicrobial efficacy of phagocytes and for the innate immune response mounted by epithelia of humans and other mammals. AMPs are generated either by de novo synthesis or by proteolytic cleavage from antimicrobially inactive proproteins. Studies of human diseases and animal studies have given important clues to the in vivo role of AMPs. It is now evident that dysregulation of the generation of AMPs in innate immune responses plays a role in certain diseases like Crohn's disease and atopic dermatitis. AMPs are attractive candidates for development of novel antibiotics due to their in vivo activity profile and some peptides may serve as templates for further drug development.

Several respiratory viruses have been shown to cause exacerbations of asthma. While the various viral responses likely have common mechanisms of activation, the respiratory syncytial virus (RSV) appears to promote specific responses that on their own can cause severe pulmonary problems. Understanding the mechanisms that promote inappropriate immune responses and local damage may lead to better therapy. The activation and recruitment of T cells that amplify and skew the immune response toward more intense pathology, including mucus production and remodeling of the airways, are likely scenarios that lead to more severe disease and clinical crisis in asthmatic patients. These mechanisms may also contribute to a significant proportion of exacerbations in chronic obstructive pulmonary disease. This review will focus on recent research on specific pathways of RSV-mediated activation of the innate host defense, including chemokine biology and TLR pathways, as well as on acquired immunity.

Chronic obstructive pulmonary disease (COPD) exacerbations are common events that punctuate the natural history of COPD contributing to disease severity progression and being the major cause of COPD-related morbidity and mortality. Currently available pharmacological strategies are only partially effective at reducing or preventing COPD exacerbations. Viral infections are the most frequent cause of COPD exacerbations. The recent development of a human experimental model of rhinovirus-induced COPD exacerbations represents an innovative tool with the potential to increase our understanding of the inflammatory and immunological mechanisms that lead COPD patients to exacerbate after respiratory virus infections. Moreover this model will provide the opportunity to test, in a carefully controlled setting, novel pharmacological compounds with a potential for treating and preventing COPD exacerbations. In this chapter we will focus on the role of viral infections in COPD exacerbations and will discuss preliminary reports regarding the development of this human model of virus-induced COPD exacerbation.

House dust mite (HDM) is the most pervasive indoor aeroallergen source worldwide. Allergens derived from HDM are associated with sensitization and allergic asthma. Allergic asthma is an immunologically driven disease characterized by a Th2-polarized immune response, eosinophilic inflammation, airway hyperreactivity, and remodeling. Animal models of asthma utilizing ovalbumin (OVA) exposure have afforded us considerable insight with respect to the mediators and cell types involved in allergic airway inflammation. However, OVA preparations and HDM are two vastly different materials. This chapter is specifically concerned with modeling responses to HDM exposure in mice. These studies have furnished new information and unlocked new lines of inquiry regarding biological responses to common aeroallergens. The complexity of HDM as an allergen source, with its plethora of protein and nonprotein immunogenic components, may influence the mechanisms underlying sensitization, inflammation and remodeling. Here, we will discuss this issue, along with giving critical thought to the use of experimental models.

Endotoxin, or lipopolysaccharide (LPS), is a constituent of the outer cell membrane of Gram-negative bacteria. LPS is a highly potent proinflammatory substance, that, when inhaled, dose-dependently causes fever, chills, and bronchoconstriction. These symptoms are accompanied by a proinflammatory response in sputum and bronchoalveolar lavage fluid with elevation of neutrophils, macrophages and certain cytokines/chemokines. This response can be partially modified with certain drugs. Similar inflammatory changes are observed both in the stable state of chronic obstructive lung disease (COPD) and during exacerbations of this disease. Cigarette smoke, which contains bioactive LPS, is the most common cause of COPD and may also precipitate exacerbations. In addition, the presence of Gram-negative bacteria in the lower airways is a distinguishing feature both of stable COPD and of exacerbations. Based on this knowledge we argue here that inhaled LPS provocation of healthy volunteers can be used as a model or COPD as well as for exacerbations of this disease.

Recent years have seen an explosion of animal models of cigarette smoke-induced chronic obstructive lung disease (COPD). Almost all of these have concentrated on the induction and prevention of emphysema. Neutrophils and neutrophil elastase, macrophages and macrophage-derived metalloproteases, lymphocytes, TNF-alpha, and oxidants have all been shown to play a role in the pathogenesis of emphysema in animal models, and interventions using either knockout mice or drugs have indicated possible preventive/therapeutic avenues. There is less in the way of models of smoke-induced small airway remodeling and almost nothing is known of its pathogenesis. Cigarette smoke has been shown to induce vascular remodeling and pulmonary hypertension in laboratory animals, and these mechanisms are beginning to be understood. A major limitation of existing animal models is that most produce relatively mild disease (no more severe than corresponding to the GOLD 2 stage of human COPD), and none of the models show the smoke-independent progressive disease seen in humans with GOLD 3 or 4 COPD. There are no models of cigarette smoke-induced chronic bronchitis in animals and there are no models of acute exacerbations of COPD.