Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency

Richmond, Bradley W.; Brucker, Robert M.; Han, Wei; Du, Rui-Hong; Zhang, Yongqin; Cheng, Dong-Sheng; Gleaves, Linda A.; Abdolrasulnia, Rasul; Polosukhina, Dina; Clark, Peter E.; Bordenstein, Seth R.; Blackwell, Timothy S.; Polosukhin, Vasiliy V.

doi:10.1038/ncomms11240

Cited by 87 publications

(100 citation statements)

References 52 publications

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“…This study is complementary to our recently published work showing that mice with a defective SIgA immune system in the lungs develop a COPD-like phenotype as they age with airway wall remodeling, an influx of macrophages and neutrophils, bacterial invasion across the epithelial barrier, and activation of NF-kB (17). All these findings were manifest in SIgA(2) airways in humans.…”

Section: Discussionsupporting

confidence: 82%

“…Consistent with these observations, cultured airway epithelial cells from patients with COPD were reported to express lower levels of pIgR than airway epithelial cells from healthy control subjects (16). The importance of SIgA in COPD is further supported by our recent demonstration that pIgR-deficient mice, which cannot transcytose IgA to mucosal surfaces, develop a spontaneous COPD-like phenotype, including emphysema and fibrotic remodeling of small airways (17).…”

supporting

confidence: 56%

“…Our data suggest that impairment of the epithelial immune barrier allows bacteria (and possibly other foreign antigens) to penetrate the airway surface liquid, intercalate within the epithelium, and activate innate immune responses. Given that increased numbers of bacteria were identified within the epithelium of SIgA(2) airways in humans and COPDlike lung remodeling is abrogated in pIgRdeficient mice raised in germ-free housing (17), our findings suggest that long-term interventions to reduce or modify the bacterial burden in the lungs could have a beneficial impact on COPD progression.…”

Section: Discussionmentioning

confidence: 81%

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Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

Polosukhin

Richmond

et al. 2017

Am J Respir Crit Care Med

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Rationale: Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood.Objectives: We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD).Methods: We studied 1,104 small airways (,2 mm in diameter) from 50 former smokers with COPD and 39 control subjects. Small airways were identified on serial tissue sections and examined for epithelial morphology, SIgA, bacterial DNA, nuclear factor-kB activation, neutrophil and macrophage infiltration, and airway wall thickness.Measurements and Main Results: Morphometric evaluation of small airways revealed increased mean airway wall thickness and inflammatory cell counts in lungs from patients with COPD compared with control subjects, whereas SIgA level on the mucosal surface was decreased. However, when small airways were classified as SIgA intact or SIgA deficient, we found that pathologic changes were localized almost exclusively to SIgAdeficient airways, regardless of study group. SIgA-deficient airways were characterized by (1) abnormal epithelial morphology, (2) invasion of bacteria across the apical epithelial barrier, (3) nuclear factor-kB activation, (4) accumulation of macrophages and neutrophils, and (5) fibrotic remodeling of the airway wall.Conclusions: Our findings support the concept that localized, acquired SIgA deficiency in individual small airways of patients with COPD allows colonizing bacteria to cross the epithelial barrier and drive persistent inflammation and airway wall remodeling, even after smoking cessation.

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Section: Discussionsupporting

confidence: 82%

supporting

confidence: 56%

Section: Discussionmentioning

confidence: 81%

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Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

Polosukhin

Richmond

et al. 2017

Am J Respir Crit Care Med

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“…54 This is consistent with the findings that targeting of the lung microbiota by innate immunity, as a result of pIgR/ sIgA deficiency, results in progressive small airway remodeling and emphysema. 55 Collectively, these observations support an emerging model that exposure of the pulmonary immune system to oral-derived microbiota (notably Prevotella spp.) during health is part of the central homeostatic processes that regulate pulmonary inflammatory responses.…”

Section: Lung Microbiota and Immunitymentioning

confidence: 61%

The respiratory tract microbiome and lung inflammation: a two-way street

2017

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The lungs are not sterile or free from bacteria; rather, they harbor a distinct microbiome whose composition is driven by different ecological rules than for the gastrointestinal tract. During disease, there is often a shift in community composition towards Gammaproteobacteria, the bacterial class that contains many common lung-associated gram-negative “pathogens.” Numerous byproducts of host inflammation are growth factors for these bacteria. The extracellular nutrient supply for bacteria in the lungs, which is severely limited during health, markedly increases due to the presence of mucus and vascular permeability. While Gammaproteobacteria benefit from airway inflammation, they also encode molecular components that promote inflammation, potentially creating a cyclical inflammatory mechanism. In contrast, Prevotella species that are routinely acquired via microaspiration from the oral cavity may participate in immunologic homeostasis of the airways. v Areas of future research include determining for specific lung diseases (1) whether an altered lung microbiome initiates disease pathogenesis, promotes chronic inflammation, or is merely a marker of injury and inflammation, (2) whether the lung microbiome can be manipulated therapeutically to change disease progression, (3) what molecules (metabolites) generated during an inflammatory response promote cross-kingdom signaling, and (4) how the lung “ecosystem” collapses during pneumonia, to be dominated by a single pathogen.

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“…Recently, Richmond et al reported that polymeric immunoglobulin receptor-deficient mice, which lack secretory immunoglobulin A, spontaneously developed fragmentation of alveolar wall and small airway fibrosis with the activation of NF-κB associated with chronological aging [100]. These mice showed an altered lung microbiome, increased bacterial penetration into bronchial epithelium, enhanced macrophage accumulation, and increased MMP-12 levels [100].…”

Section: The Impacts Of Cellular Senescence In Age-related Lung DImentioning

confidence: 99%

The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections

Yanagi

Tsubouchi

Miura

et al. 2017

IJMS

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Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP). These properties are beneficial if the sequence of senescence–clearance–regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections.

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Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency

Cited by 87 publications

References 52 publications

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

The respiratory tract microbiome and lung inflammation: a two-way street

The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections

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