Multiple inflammatory hits and the pathogenesis of severe airway disease: Fig. 1—

Pavord, Ian D.; Birring, SS; Berry, Michael A.; Green, R H; Brightling, Christopher E.; Wardlaw, Andrew J.

doi:10.1183/09031936.06.00128105

Cited by 66 publications

(37 citation statements)

References 53 publications

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“…The activation of TLR2 or NOD2 and subsequent NLRP3 activation is not dissimilar to the ''multiple hits'' hypothesis initially proposed by PAVORD et al [30] in severe refractory asthma, where multiple points of stimulation can occur to the immune system, resulting in more severe airways disease. We studied the sputum cell expression of NLRP3 and caspase-1 using immunocytochemistry and show that airway macrophages from patients with asthma, irrespective of inflammatory subtype, stained positive for both proteins.…”

Section: Discussionmentioning

confidence: 89%

Elevated expression of the NLRP3 inflammasome in neutrophilic asthma

et al. 2013

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Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1b is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1b requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1b endotype associated with the nucleotide-binding domain, leucine-rich repeat-containing family protein (NLRP)3/apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)/caspase-1 inflammasome is characteristic of patients with the neutrophilic subtype of asthma.Participants with asthma (n585) and healthy controls (n527) underwent clinical assessment, spirometry and sputum induction. Sputum was processed for differential cell count, gene expression and protein mediators. NLRP3 and caspase-1 expression was also determined by immunocytochemistry. Sputum macrophages were isolated (n58) and gene expression of NLRP3 and IL-1b determined.There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1b in participants with neutrophilic asthma. Protein levels of IL-1b were significantly higher in those with neutrophilic asthma and correlated with sputum IL-8 levels. Sputum macrophages, as well as sputum neutrophils in neutrophilic asthma, expressed NLRP3 and caspase-1 protein.NLRP3 inflammasome is upregulated in neutrophilic asthma and may regulate the inflammation process observed in this asthma phenotype through production of IL-1b. @ERSpublications The NLRP3 inflammasome may be a key regulator of neutrophilic airway inflammation in asthma through production of IL-1b

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Section: Discussionmentioning

confidence: 89%

Elevated expression of the NLRP3 inflammasome in neutrophilic asthma

et al. 2013

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“…Because the inflammation observed after cigarette smoke exposure in mice is mild, this model lacks one of the key features of the human disease. One explanation of the failure of cigarette smoke alone to induce lung disease closely resembling human disease is that an additional insult is required (37). We reasoned that P. jirovecii would be a plausible pathogen to participate in both lung damage and inflammation.…”

mentioning

confidence: 99%

Pneumocystis murinaInfection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

et al. 2008

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Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction. The main risk factor for developing COPD is cigarette smoking; however, only about 20% of smokers develop lung disease. The mechanisms by which cigarette smoke leads to pathological changes in both airways and lung parenchyma are unclear. Pulmonary inflammation, localized to the airways, is a pathological feature in the lungs of COPD patients. A predominance of macrophages and CD8 ϩ T lymphocytes are found both in bronchial biopsies (43,44) and in the lung parenchyma at sites of parenchymal destruction (29). These findings suggest that CD8 ϩ T lymphocytes may be responsible for damage to the lung, either by directly injuring neighboring cells, by secreting molecules that injure the lung, or by recruiting and activating additional inflammatory cells.The stimuli responsible for triggering inflammation are not known, but infectious pathogens likely play a role in the initiation or perpetuation of pulmonary inflammation in COPD. Much of the work examining the role of infection in the course and pathogenesis of COPD has focused on bacterial colonization (45), but bacterial or viral colonization may be insufficient to explain pathogenesis. An intriguing alternate pathogen that has received recent attention is the fungus Pneumocystis jirovecii. Although it was previously thought to be an opportunistic pathogen that caused serious pneumonia only in severely immunocompromised patients, recent investigations substantiate the exi...

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“…The chronic inflammatory response related to H. pylori infection is considered to be a potential risk factor for accelerated age-dependent decline in lung function which may result in lower lung function (Pavord et al, 2006).…”

Section: Hmentioning

confidence: 99%

The Impact of <i>Helicobacter Pylori</i> Infection on Lung Function and Severity of Bronchial Hyperresponsiveness in Subjects with Allergic Asthma

Минов¹,

Karadžinska-Bislimovska²,

Vasilevska³

et al. 2011

American Journal of Immunology

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Problem statement:There is evidence that Helicobacter pylori (H. pylori) infection may modify immune response and decrease the risk of asthma and other allergic diseases, as well. Approach: To assess the impact of H. pylori infection on lung function parameters and severity of Bronchial Hyperresponsiveness (BHR) in subjects with allergic asthma. A cross-sectional study including 38 H. pylori positive subjects with allergic asthma (18 males and 20 females, aged 21-54 years) and an equal number of H. pylori negative subjects with allergic asthma studied as a control was carried out. The impact of H. pylori infection was assessed by comparison of mean values of spirometric parameters and BHR severity (measured by histamine challenge and expressed as provocative concentration of histamine that causes FEV 1 fell by more than 20% of its base value-PC 20) between two examined groups. Results: The mean values of spirometric parameters were similar in both examined groups. The mean PC20 was lower in the group of subjects with allergic asthma and serological evidence of exposure to H. pylori but statistical significance was not reached (2.89 Vs. 3.14 mg mL −1 , P > 0.05). Conclusion: Our findings indicate that in cross-sectional analysis there is no significant relation between H. pylori seropositivity and the values of spirometric parameters and the degree of BHR severity in subjects with allergic asthma.

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Multiple inflammatory hits and the pathogenesis of severe airway disease: Fig. 1—

Cited by 66 publications

References 53 publications

Elevated expression of the NLRP3 inflammasome in neutrophilic asthma

Elevated expression of the NLRP3 inflammasome in neutrophilic asthma

Pneumocystis murinaInfection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

The Impact of <i>Helicobacter Pylori</i> Infection on Lung Function and Severity of Bronchial Hyperresponsiveness in Subjects with Allergic Asthma

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