Lung Neutrophil Burden Correlates With Increased Pro-Inflammatory Cytokines and Decreased Lung Function in Individuals With α1-Antitrypsin Deficiency

Rouhani, Farshid N.; Paone, Gregorino; Smith, Norman H.; Krein, Peter M.; Barnes, Peter J.; Brantly, Mark

doi:10.1378/chest.117.5_suppl_1.250s

Cited by 49 publications

(39 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our smoke exposure system elicits neutrophilic inflammation. This was a central readout of our study because of the importance of chronic neutrophilia in the pathogenesis of COPD (32,33). Our experimental system also reproduces other clinical hallmarks associated with cigarette smoking, such as airspace enlargement and changes in ventilation and perfusion following prolonged cigarette smoke exposure (31).…”

Section: Figurementioning

confidence: 96%

Cigarette Smoke Primes the Pulmonary Environment to IL-1α/CXCR-2–Dependent Nontypeable Haemophilus influenzae–Exacerbated Neutrophilia in Mice

Nikota

Shen

Morissette

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Cigarette smoke has a broad impact on the mucosal environment with the ability to alter host defense mechanisms. Within the context of a bacterial infection, this altered host response is often accompanied by exacerbated cellular inflammation, characterized by increased neutrophilia. The current study investigated the mechanisms of neutrophil recruitment in a murine model of cigarette smoke exposure and, subsequently, a model of both cigarette smoke exposure and bacterial infection. We investigated the role of IL-1 signaling in neutrophil recruitment and found that cigarette smoke-induced neutrophilia was dependent on IL-1α produced by alveolar macrophages. In addition to being the crucial source of IL-1α, alveolar macrophages isolated from smoke-exposed mice were primed for excessive IL-1α production in response to bacterial ligands. To test the relevance of exaggerated IL-1α production in neutrophil recruitment, a model of cigarette smoke exposure and nontypeable Haemophilus influenzae infection was developed. Mice exposed to cigarette smoke elaborated an exacerbated CXCR2-dependent neutrophilia in response to nontypeable Haemophilus influenzae. Exacerbated neutrophilia was dependent on IL-1α priming of the pulmonary environment by cigarette smoke as exaggerated neutrophilia was dependent on IL-1 signaling. These data characterize a novel mechanism of cigarette smoke priming the lung mucosa toward greater IL-1–driven neutrophilic responses to bacteria, with a central role for the alveolar macrophage in this process.

show abstract

Section: Figurementioning

confidence: 96%

Cigarette Smoke Primes the Pulmonary Environment to IL-1α/CXCR-2–Dependent Nontypeable Haemophilus influenzae–Exacerbated Neutrophilia in Mice

Nikota

Shen

Morissette

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…An increased lung neutrophil burden has been described even in AATD subjects with mild functional lung impairment (13) and also in asymptomatic nonsmoking heterozygotes for the Z allele or intermediate deficiency (PiMZ) without airflow obstruction (14). However, the reason for the observed increased neutrophil burden has never been fully elucidated, and with the aim of clarifying the important role of AAT in chronic neutrophilic infiltration, we investigated whether dysregulated neutrophil chemotaxis is associated with changes in neutrophil properties of AATD individuals.…”

mentioning

confidence: 99%

α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8

Bergin¹,

Reeves²,

Meleady³

et al. 2010

J. Clin. Invest.

253

305

View full text Add to dashboard Cite

Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1-and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositolanchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AATdeficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

show abstract

“…Thus, polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem. Other studies reported that even PiZZ patients with near-normal lung function had high concentrations of neutrophils on respiratory epithelial surfaces (Rouhani et al, 2000). Neutrophil burden in PiZZ and in PiMZ (on a lesser extent) is attributed to leukotriene B4 or IL-8 released from neutrophils or epithelial cells (Woolhouse et al, 2002;Malerba et al, 2006).…”

Section: Z Variantmentioning

confidence: 98%

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

Topić¹,

Radojković²

2012

Lung Diseases - Selected State of the Art Reviews

View full text Add to dashboard Cite

Lung Neutrophil Burden Correlates With Increased Pro-Inflammatory Cytokines and Decreased Lung Function in Individuals With α1-Antitrypsin Deficiency

Cited by 49 publications

References 0 publications

Cigarette Smoke Primes the Pulmonary Environment to IL-1α/CXCR-2–Dependent Nontypeable Haemophilus influenzae–Exacerbated Neutrophilia in Mice

Cigarette Smoke Primes the Pulmonary Environment to IL-1α/CXCR-2–Dependent Nontypeable Haemophilus influenzae–Exacerbated Neutrophilia in Mice

α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

Contact Info

Product

Resources

About