Roles of Lung Epithelium in Neutrophil Recruitment During Pneumococcal Pneumonia

ArticleinAmerican Journal of Respiratory Cell and Molecular Biology 50(2) · September 2013with20 Reads
DOI: 10.1165/rcmb.2013-0114OC · Source: PubMed
Abstract
Epithelial cells line the respiratory tract and interface with the external world. Epithelial cells contribute in some fashion to pulmonary inflammation, but specific epithelial roles have proven difficult to define. To discover unique epithelial activities that influence immunity during infection, we generated mice with NF-κB RelA mutated throughout all epithelial cells of the lung, and we coupled this approach with epithelial cell isolation from infected and uninfected lungs for cell-specific analyses of gene induction. The RelA mutant mice appeared normal basally, but in response to pneumococcus in the lungs they were unable to rapidly recruit neutrophils to the air spaces. Epithelial cells expressed multiple neutrophil-stimulating cytokines during pneumonia, all of which depended on RelA. Cytokine expression by non-epithelial cells was unaltered by the epithelial mutation of RelA. Epithelial cells were the predominant sources of CXCL5 and GM-CSF, while non-epithelial cells were major sources for other neutrophil-activating cytokines. Epithelial RelA mutation decreased whole lung levels of CXCL5 and GM-CSF during pneumococcal pneumonia, while lung levels of other neutrophil-recruiting factors were unaffected. Defective neutrophil recruitment in epithelial mutant mice could be rescued by administration of CXCL5 or GM-CSF. These results reveal a specialized immune function for the pulmonary epithelium, the induction of CXCL5 and GM-CSF to accelerate neutrophil recruitment in the infected lung.
    • "Given recent demonstrations that PMNs can modify their transcriptional profile following an inflammatory insult [13], genome-wide transcriptional analysis provides a powerful tool to identify novel targets relevant to altered PMN functions, and has been 5 Juss et al. 2015 successfully applied in asthma, pulmonary arterial hypertension and ARDS [14]; however, studies in ARDS are based on the analysis of total peripheral white blood cells rather than purified neutrophils. Lung epithelial cells [15] synthesize granulocyte macrophage-colony stimulating factor (GM- CSF), a cytokine essential for alveolar macrophage function [16][17]and surfactant homeostasis [18][19] . Conversely, during inflammation GM-CSF potentiates superoxideanion production [20], promotes PMN survival [21], and is detrimental in models of acute lung injury [22]. "
    [Show abstract] [Hide abstract] ABSTRACT: Rationale: The acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease’s complex pathophysiology, yet these cells have been little studied. Objectives: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared to healthy volunteer cells, and define their sensitivity to phosphoinositide 3-kinase inhibition. Methods: Twenty three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis and adhesion molecules were quantified by flow cytometry, and oxidase responses by chemiluminescence. Cytokine and transcriptional profiling utilized multiplex and GeneChip arrays. Measurements and Main Results: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the pro-survival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal and cell death pathways in patient cells, aligning closely to sepsis and burns data sets but not phosphoinositide 3-kinase signatures. Conclusions: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed, pro-survival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent, but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.
    Full-text · Article · Apr 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterised by a state of chronic pulmonary inflammation punctuated by microbial exacerbations. Despite advances in treatment options, COPD remains difficult to manage. In this study, we investigated the potential of peroxisome proliferator-activated receptor (PPAR)γ activation as a new therapy against cigarette smoke-induced inflammation and its associated bacterial exacerbation. C57BL/6 mice were exposed to room air or cigarette smoke for either 4 days or 4 weeks and treated either prophylactically or therapeutically with rosiglitazone. The impact of rosiglitazone on cigarette smoke-induced exacerbated response to the bacterial pathogen nontypeable Haemophilus influenzae (NTHi) was studied using the therapeutic treatment protocol. We found that rosiglitazone was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically or therapeutically. Therapeutic intervention with rosiglitazone was also effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection. Moreover, the anti-inflammatory effects of rosiglitazone did not lead to an increase in the pulmonary bacterial burden, unlike dexamethasone. Altogether, our data suggest that pharmacological activation of PPARγ may be an effective therapeutic approach to improve COPD management, as it is able to reduce cigarette smoke-induced inflammation and decrease the magnitude of bacterial exacerbations, without compromising the ability of the immune system to control the infection.
    Full-text · Article · Jul 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps. Expected final online publication date for the Annual Review of Physiology Volume 77 is February 10, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Article · Aug 2014
Show more