Bronchial hyperreactivity is associated with enhanced grain dust-induced airflow obstruction

Bronchial hyperreactivity (BHR) is associated with the presence of airway inflammation in asthma and is seen in individuals occupationally exposed to grain dust. To better understand the relationship between BHR and pulmonary inflammation after grain dust exposure, we carried out an inhalation challenge to corn dust extract (CDE) on seven subjects with BHR [a 20% or greater decrease in forced expiratory volume in 1 s (FEV1) compared with diluent FEV1 with a cumulative dose of histamine ≤47.3 breath units] and compared their physiological and inflammatory responses with those of seven matched control subjects. BHR subjects were exposed to nebulized CDE (target dose of 0.16 μg/kg endotoxin) as tolerated; matched controls received equal amounts of CDE. Subjects with BHR complained of chest tightness and dyspnea within the 2 h after inhalation of CDE significantly more frequently than controls. Similarly, subjects with BHR developed significantly greater percent declines in FEV1 at time points up to 4 h after exposure to CDE. Significant increases in total cells, neutrophils, tumor necrosis factor-α, interleukin-6, and interleukin-8 were detected in bronchoalveolar lavage fluid 4 h after inhalation of CDE in all subjects, but no differences were detected between the control and BHR groups. These results suggest that, although subjects with BHR develop a more precipitous decline in FEV1 after exposure to CDE, the inflammatory response to CDE is similar in subjects with and without BHR.

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Eosinophil-derived IL-13 promotes emphysema

European Respiratory Journal ◽

10.1183/13993003.01291-2018 ◽

2019 ◽

Vol 53 (5) ◽

pp. 1801291 ◽

Cited By ~ 10

Author(s):

Alfred D. Doyle ◽

Manali Mukherjee ◽

William E. LeSuer ◽

Tyler B. Bittner ◽

Saif M. Pasha ◽

...

Keyword(s):

Mouse Model ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Chronic Type ◽

Obstructive Pulmonary Disease ◽

Lung Eosinophilia

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.

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Modulation of the NLRP3 inflammasome by Sars-CoV-2 Envelope protein

Scientific Reports ◽

10.1038/s41598-021-04133-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mustafa Yalcinkaya ◽

Wenli Liu ◽

Mohammad N. Islam ◽

Andriana G. Kotini ◽

Galina A. Gusarova ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Protein A ◽

Lavage Fluid ◽

Viral Rna ◽

Poly I:C ◽

Inflammasome Activation ◽

E Protein ◽

Nlrp3 Inflammasome Activation

AbstractDespite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1β and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1β, levels of IL-1β and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.

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Targeting NLRP3 Inflammasome Activation in Severe Asthma

Journal of Clinical Medicine ◽

10.3390/jcm8101615 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1615 ◽

Cited By ~ 5

Author(s):

Efthymia Theofani ◽

Maria Semitekolou ◽

Ioannis Morianos ◽

Konstantinos Samitas ◽

Georgina Xanthou

Keyword(s):

Severe Asthma ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Airflow Obstruction ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Reversible Airflow Obstruction

Severe asthma (SA) is a chronic lung disease characterized by recurring symptoms of reversible airflow obstruction, airway hyper-responsiveness (AHR), and inflammation that is resistant to currently employed treatments. The nucleotide-binding oligomerization domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome is an intracellular sensor that detects microbial motifs and endogenous danger signals and represents a key component of innate immune responses in the airways. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis. Accumulating evidence proposes that NLRP3 activation is critically involved in asthma pathogenesis. In fact, although NLRP3 facilitates the clearance of pathogens in the airways, persistent NLRP3 activation by inhaled irritants and/or innocuous environmental allergens can lead to overt pulmonary inflammation and exacerbation of asthma manifestations. Notably, administration of NLRP3 inhibitors in asthma models restrains AHR and pulmonary inflammation. Here, we provide an overview of the pathophysiology of SA, present molecular mechanisms underlying aberrant inflammatory responses in the airways, summarize recent studies pertinent to the biology and functions of NLRP3, and discuss the role of NLRP3 in the pathogenesis of asthma. Finally, we contemplate the potential of targeting NLRP3 as a novel therapeutic approach for the management of SA.

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The importance of leukotrienes in airway inflammation in a mouse model of asthma.

Journal of Experimental Medicine ◽

10.1084/jem.184.4.1483 ◽

1996 ◽

Vol 184 (4) ◽

pp. 1483-1494 ◽

Cited By ~ 230

Author(s):

W R Henderson ◽

D B Lewis ◽

R K Albert ◽

Y Zhang ◽

W J Lamm ◽

...

Keyword(s):

Mouse Model ◽

Murine Model ◽

Airway Hyperresponsiveness ◽

Pulmonary Inflammation ◽

Late Phase ◽

Lavage Fluid ◽

Bronchial Hyperreactivity ◽

Leukocytic Infiltration ◽

Specific Inhibitors

Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.

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Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/5219056 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Silvie Kremserova ◽

Tomas Perecko ◽

Karel Soucek ◽

Anna Klinke ◽

Stephan Baldus ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Bronchoalveolar Lavage Fluid ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Lavage Fluid ◽

Surface Expression ◽

Wild Type ◽

Inflammatory Site ◽

Chemotactic Factors ◽

Deficient Mice

Systemic inflammation accompanying diseases such as sepsis affects primarily lungs and induces their failure. This remains the most common cause of sepsis induced mortality. While neutrophils play a key role in pulmonary failure, the mechanisms remain incompletely characterized. We report that myeloperoxidase (MPO), abundant enzyme in neutrophil granules, modulates the course of acute pulmonary inflammatory responses induced by intranasal application of lipopolysaccharide. MPO deficient mice had significantly increased numbers of airway infiltrated neutrophils compared to wild-type mice during the whole course of lung inflammation. This was accompanied by higher levels of RANTES in bronchoalveolar lavage fluid from the MPO deficient mice. Other markers of lung injury and inflammation, which contribute to recruitment of neutrophils into the inflamed lungs, including total protein and other selected proinflammatory cytokines did not significantly differ in bronchoalveolar lavage fluid from the wild-type and the MPO deficient mice. Interestingly, MPO deficient neutrophils revealed a decreased rate of cell death characterized by phosphatidylserine surface expression. Collectively, the importance of MPO in regulation of pulmonary inflammation, independent of its putative microbicidal functions, can be potentially linked to MPO ability to modulate the life span of neutrophils and to affect accumulation of chemotactic factors at the inflammatory site.

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An Exploratory Study of the Relationships Between Diesel Engine Exhaust Particle Inhalation, Pulmonary Inflammation and Anxious Behavior

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18031166 ◽

2021 ◽

Vol 18 (3) ◽

pp. 1166

Author(s):

Sunyoung Jeong ◽

Jong-Hwa Lee ◽

Jung-Heun Ha ◽

Jinhee Kim ◽

Inyong Kim ◽

...

Keyword(s):

Diesel Engine ◽

Large Scale ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Central Zone ◽

Lavage Fluid ◽

Dependent Manner ◽

Engine Exhaust ◽

Diesel Engine Exhaust ◽

Technical Developments

Recent technical developments brought negative side effects such as air pollution and large-scale fires, increasingly exposing people to diesel engine exhaust particles (DEP). Testing how DEP inhalation triggers pathophysiology in animal models could be useful in determining how it affects humans. To this end, the aim of this study was to investigate the effects of pulmonary exposure to DEP for seven consecutive days in experimental male C5BL6/N mice. Twenty-four C5BL6/N mice were treated with one of the three test materials: distilled water for control, a low DEP exposure (5 mg/kg), or a high DEP exposure (15 mg/kg). Exposure to DEP induced decreased body weight; however, it gradually increased pulmonary weight in a DEP-dose-dependent manner. DEP exposure significantly elevated soot accumulation in the lungs, with the alteration of pulmonary homeostasis. It also elevated infiltrated immune cells, thus significantly increasing inflammatory cytokine mRNA and protein production in the lungs and broncho-alveolar lavage fluid, respectively. Pulmonary DEP exposure also altered behavioral responses in the open field test (OFT). Low exposure elevated moving distance and speed, while significantly decreasing the number of trials to enter the central zone. Different concentrations of DEP resulted in different behavioral changes; however, while anxiety levels increased, their degree was independent of DEP concentrations. Results suggest that DEP exposure may possess pro-inflammatory responses in the lungs and trigger anxiety.

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Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies

Journal of Applied Physiology ◽

10.1152/japplphysiol.00007.2011 ◽

2011 ◽

Vol 111 (1) ◽

pp. 177-184 ◽

Cited By ~ 12

Author(s):

Anthony D. Dorr ◽

Michael R. Wilson ◽

Kenji Wakabayashi ◽

Alicia C. Waite ◽

Brijesh V. Patel ◽

...

Keyword(s):

Mechanical Ventilation ◽

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophage ◽

Pulmonary Inflammation ◽

Lavage Fluid ◽

Epithelial Permeability ◽

Alveolar Epithelial ◽

Factor Α

Elevated soluble tumor necrosis factor-α receptor (sTNFR) levels in bronchoalveolar lavage fluid (BALF) are associated with poor patient outcome in acute lung injury (ALI). The mechanisms underlying these increases are unknown, but it is possible that pulmonary inflammation and increased alveolar epithelial permeability may individually contribute. We investigated mechanisms of elevated BALF sTNFRs in two in vivo mouse models of ALI. Anesthetized mice were challenged with intratracheal lipopolysaccharide or subjected to injurious mechanical ventilation. Lipopolysaccharide instillation produced acute intra-alveolar inflammation, but minimal alveolar epithelial permeability changes, with increased BALF sTNFR p75, but not p55. Increased p75 levels were markedly attenuated by alveolar macrophage depletion. In contrast, injurious ventilation induced substantial alveolar epithelial permeability, with increased BALF p75 and p55, which strongly correlated with total protein. BALF sTNFRs were not increased in isolated buffer-perfused lungs (devoid of circulating sTNFRs) subjected to injurious ventilation. These results suggest that lipopolysaccharide-induced intra-alveolar inflammation upregulates alveolar macrophage-mediated production of sTNFR p75, whereas enhanced alveolar epithelial permeability following mechanical ventilation leads to increased BALF p75 and p55 via plasma leakage. These data provide new insights into differential regulation of intra-alveolar sTNFR levels during ALI and may suggest sTNFRs as potential markers for evaluating the pathophysiology of ALI.

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Mechanical Ventilation with Lower Tidal Volumes and Positive End-expiratory Pressure Prevents Pulmonary Inflammation in Patients without Preexisting Lung Injury

Anesthesiology ◽

10.1097/01.anes.0000296068.80921.10 ◽

2008 ◽

Vol 108 (1) ◽

pp. 46-54 ◽

Cited By ~ 172

Author(s):

Esther K. Wolthuis ◽

Goda Choi ◽

Mark C. Dessing ◽

Paul Bresser ◽

Rene Lutter ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Bronchoalveolar Lavage ◽

Bronchoalveolar Lavage Fluid ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Lavage Fluid ◽

Positive End Expiratory Pressure ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein

Background Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without preexisting lung injury. Methods Patients scheduled to undergo an elective surgical procedure (lasting > or = 5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h thereafter, bronchoalveolar lavage fluid and/or blood was investigated for polymorphonuclear cell influx, changes in levels of inflammatory markers, and nucleosomes. Results Mechanical ventilation with lower tidal volumes and PEEP (n = 21) attenuated the increase of pulmonary levels of interleukin (IL)-8, myeloperoxidase, and elastase as seen with higher tidal volumes and no PEEP (n = 19). Only for myeloperoxidase, a difference was found between the two ventilation strategies after 5 h of mechanical ventilation (P < 0.01). Levels of tumor necrosis factor alpha, IL-1alpha, IL-1beta, IL-6, macrophage inflammatory protein 1alpha, and macrophage inflammatory protein 1beta in the bronchoalveolar lavage fluid were not affected by mechanical ventilation. Plasma levels of IL-6 and IL-8 increased with mechanical ventilation, but there were no differences between the two ventilation groups. Conclusion The use of lower tidal volumes and PEEP may limit pulmonary inflammation in mechanically ventilated patients without preexisting lung injury. The specific contribution of both lower tidal volumes and PEEP on the protective effects of the lung should be further investigated.

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Efficient killing of inhaled bacteria in ΔF508 mice: role of airway surface liquid composition

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.1.l183 ◽

1999 ◽

Vol 277 (1) ◽

pp. L183-L190 ◽

Cited By ~ 13

Author(s):

Paul B. McCray ◽

Joseph Zabner ◽

Hong Peng Jia ◽

Michael J. Welsh ◽

Peter S. Thorne

Keyword(s):

Cystic Fibrosis ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Lavage Fluid ◽

Liquid Composition ◽

Airway Surface Liquid ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Radiotracer Technique ◽

Surface Liquid

Cystic fibrosis mice have been generated by gene targeting but show little lung disease without repeated exposure to bacteria. We asked if murine mucosal defenses and airway surface liquid (ASL) Cl−were altered by the ΔF508 cystic fibrosis transmembrane conductance regulator mutation. Naive ΔF508 −/− and +/− mice showed no pulmonary inflammation and after inhaled Pseudomonas aeruginosa had similar inflammatory responses and bacterial clearance rates. We therefore investigated components of the innate immune system. Bronchoalveolar lavage fluid from mice killed Escherichia coli, and the microbicidal activity was inhibited by NaCl. Because β-defensins are salt-sensitive epithelial products, we looked for pulmonary β-defensin expression. A mouse homolog of human β-defensin-1 (termed “MBD-1”) was identified; the mRNA was expressed in the lung. Using a radiotracer technique, ASL volume and Cl−concentration ([Cl−]) were measured in cultured tracheal epithelia from normal and ΔF508 −/− mice. The estimated ASL volume was similar for both groups. There were no differences in ASL [Cl−] in ΔF508 −/− and normal mice (13.8 ± 2.6 vs. 17.8 ± 5.6 meq/l). Because ASL [Cl−] is low in normal and mutant mice, salt-sensitive antimicrobial factors, including MBD-1, may be normally active.

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The Effects of Interleukin-1βin Tumor Necrosis Factor-α-Induced Acute Pulmonary Inflammation in Mice

Mediators of Inflammation ◽

10.1155/2009/958658 ◽

2009 ◽

Vol 2009 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Sara Saperstein ◽

Heidie Huyck ◽

Elizabeth Kimball ◽

Carl Johnston ◽

Jacob Finkelstein ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Pulmonary Inflammation ◽

Lavage Fluid ◽

Neutrophil Accumulation ◽

Double Knockout ◽

Necrosis Factor Alpha ◽

Factor Α ◽

Necrosis Factor

We determined the role of interleukin-1β(IL-1β) signaling on tumor necrosis factor alpha-induced (TNF-α) lung neutrophil influx as well as neutrophil chemoattractant macrophage inflammatory protein (MIP-2) and KC and soluble TNF-αreceptor (TNFR) levels utilizing wildtype (WT), TNF receptor double knockout (TNFR1/TNFR2 KO), and IL-1βKO mice after oropharyngeal instillation with TNF-α. A significant increase in neutrophil accumulation in bronchoalveolar lavage fluid (BALF) and lung interstitium was detected in the WT mice six hours after TNF-αexposure. This correlated with an increase in BALF MIP-2. In contrast, BALF neutrophil numbers were not increased by TNF-αtreatment of IL-1βKOs, correlating with a failure to induce BALF MIP-2 and a trend toward increased BALF soluble TNFR1. TNF-α-instillation increased lavage and serum KC and soluble TNFR2 irrespective of IL-1βexpression. These results suggest IL-1βcontributes, in part, to TNF-α-mediated, chemokine release, and neutrophil recruitment to the lung, potentially associated with altered soluble TNFR1 release into the BALF.

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