Acute lung injury: apoptosis in effector and target cells of the upper and lower airway compartment

Z’graggen, Birgit Roth; Tornic, Jure; Müller‐Edenborn, Björn; Reyes, Livia; Booy, Christa; Beck‐Schimmer, Beatrice

doi:10.1111/j.1365-2249.2010.04175.x

Cited by 38 publications

(31 citation statements)

References 22 publications

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“…We speculate that the mechanism by which reduced apoptosis correlates with reduced BALT numbers and size is related to a decrease in selfantigen processing. In hypoxia, the pattern of apoptosis induced is cell type-specific in acute hypoxia (27) versus chronic hypoxia (15). Furthermore, the extent of apoptosis is much less obvious compared with MCT.…”

Section: Discussionmentioning

confidence: 91%

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Colvin¹,

Cripe²,

Ivy³

et al. 2013

Am J Respir Crit Care Med

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Rationale: Autoimmunity has long been associated with pulmonary hypertension. Bronchus-associated lymphoid tissue plays important roles in antigen sampling and self-tolerance during infection and inflammation. Objectives: We reasoned that activated bronchus-associated lymphoid tissue would be evident in rats with pulmonary hypertension, and that loss of self-tolerance would result in production of pathologic autoantibodies that drive vascular remodeling. Methods: We used animal models, histology, and gene expression assays to evaluate the role of bronchus-associated lymphoid tissue in pulmonary hypertension. Measurements and Main Results: Bronchus-associated lymphoid tissue was more numerous, larger, and more active in pulmonary hypertension compared with control animals. We found dendritic cells in and around lymphoid tissue, which were composed of CD31 T cells over a core of CD45RA 1 B cells. Antirat IgG and plasma from rats with pulmonary hypertension decorated B cells in lymphoid tissue, resistance vessels, and adventitia of large vessels. Lymphoid tissue in diseased rats was vascularized by aquaporin-1 1 high endothelial venules and vascular cell adhesion molecule-positive vessels. Autoantibodies are produced in bronchus-associated lymphoid tissue and, when bound to pulmonary adventitial fibroblasts, change their phenotype to one that may promote inflammation. Passive transfer of autoantibodies into rats caused pulmonary vascular remodeling and pulmonary hypertension. Diminution of lymphoid tissue reversed pulmonary hypertension, whereas immunologic blockade of CCR7 worsened pulmonary hypertension and hastened its onset. Conclusions: Bronchus-associated lymphoid tissue expands in pulmonary hypertension and is autoimmunologically active. Loss of self-tolerance contributes to pulmonary vascular remodeling and pulmonary hypertension. Lymphoid tissue-directed therapies may be beneficial in treating pulmonary hypertension.Keywords: hypertension; pulmonary; lymphoid tissue; inflammation; autoimmunity Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary artery pressure and pulmonary vascular resistance resulting in right ventricular failure (1). The primary histopathologic finding in PH is vascular remodeling, in which the pulmonary vasculature becomes stiff, occluded, and fibrotic (2). Vascular remodeling seems to require lung infiltration of inflammatory cells, and continual influx likely sustains a cycle of perpetual inflammation and remodeling by poorly defined mechanisms (3).The bronchovascular space is a structure that marries sterile (vasculature) and nonsterile (airway) components. Bronchusassociated lymphoid tissues (BALTs) are tertiary lymphoid organs that provide an elegant immune surveillance apparatus ensuring airway and vessel homeostatic patency. They are histologically similar to lymph nodes containing afferent lymphatic connection, B cells, T cells, antigen-presenting cells, stroma, and a vascular supply (4). The chief antigen-presenting cells in BALT are dendritic ce...

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Section: Discussionmentioning

confidence: 91%

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Colvin¹,

Cripe²,

Ivy³

et al. 2013

Am J Respir Crit Care Med

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“…LPS has been shown to cause lung injury in rats and can induce apoptosis in lung epithelial cells. [17][18][19] However, no apoptotic effects in static cells, treated with LPS, were observed possibly due to differing experimental conditions such as a shorter time period (24 h instead of 48 h) for incubating cells and always freshly isolated ATII cells. Also the concentrations of LPS (20 mg/mL) was higher and only a moderate increase of apoptotic cells (2-8%) was shown.…”

Section: Discussionmentioning

confidence: 98%

Interaction of cyclic mechanical stretch and toll‐like receptor 4‐mediated innate immunity in rat alveolar type II cells

Kühn¹,

Petzold²,

Hammerschmidt³

et al. 2013

Respirology

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“…5). Both IT LPS (32,53) and VILI (45) have been shown to cause airway injury with increased airway edema associated with increased airway epithelial permeability and apoptosis. Thus it is possible that PDE2A knockdown in this cellular compartment could significantly contribute to the beneficial effects we observed in the overall LPS/VILI insult in mice infected with Ad.PDE2A-shRNA.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Rentsendorj

Damarla

Aggarwal

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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is stimulated by cGMP to hydrolyze cAMP, a potent endothelial barrier-protective molecule. We previously found that lung PDE2A contributed to a mouse model of ventilator-induced lung injury (VILI). The purpose of the present study was to determine the contribution of PDE2A in a two-hit mouse model of 1-day intratracheal (IT) LPS followed by 4 h of 20 ml/kg tidal volume ventilation. Compared with IT water controls, LPS alone (3.75 g/g body wt) increased lung PDE2A mRNA and protein expression by 6 h with a persistent increase in protein through day 4 before decreasing to control levels on days 6 and 10. Similar to the PDE2A time course, the peak in bronchoalveolar lavage (BAL) neutrophils, lactate dehydrogenase (LDH), and protein concentration also occurred on day 4 post-LPS. IT LPS (1 day) and VILI caused a threefold increase in lung PDE2A and inducible nitric oxide synthase (iNOS) and a 24-fold increase in BAL neutrophilia. Compared with a control adenovirus, PDE2A knockdown with an adenovirus expressing a short hairpin RNA administered IT 3 days before LPS/VILI effectively decreased lung PDE2A expression and significantly attenuated BAL neutrophilia, LDH, protein, and chemokine levels. PDE2A knockdown also reduced lung iNOS expression by 53%, increased lung cAMP by nearly twofold, and improved survival from 47 to 100%. We conclude that in a mouse model of LPS/VILI, a synergistic increase in lung PDE2A expression increased lung iNOS and alveolar inflammation and contributed significantly to the ensuing acute lung injury.lipopolysaccharide; ventilator-induced; cyclic guanosine monophosphate; inducible nitric oxide synthase; cAMP SEVERE PNEUMONIA IS A FREQUENT cause of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) (49). ARDS is characterized by neutrophil infiltration, the generation of toxic cytokines and reactive oxygen species (ROS), increased NO production and the loss of endothelial and epithelial barrier function (4). These features can be reproduced in animal models by the installation of intratracheal (IT) LPS (10, 24, 31), a key component of the gram-negative bacterial cell wall. LPS, through Toll-like receptor-4 signaling, was shown to cause increased NO from phosphorylated endothelial (eNOS) (11) and inducible nitric oxide synthase (iNOS) (24, 31) in alveolar macrophages, neutrophils, epithelium, and endothelium. NO from both eNOS and iNOS was found to play a major pathogenic role in ALI from LPS (24, 31, 42) and in ventilator-induced lung injury (VILI) (33, 39). These injurious effects of endogenous NO have been attributed to a reaction with superoxide to generate peroxynitrite (31, 33). In both LPS-induced ALI (47) and VILI (39), however, NO also activates soluble guanylyl cyclase (sGC), increasing production of cGMP in multiple cell types including endothelium (39), epithelium (9, 17), and macrophages (3).The effects of cGMP signaling in ALI are complex, depending on cell type, intracellular compartmentalization, and the downstream cGMP targets (39). These targets include...

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Acute lung injury: apoptosis in effector and target cells of the upper and lower airway compartment

Cited by 38 publications

References 22 publications

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Interaction of cyclic mechanical stretch and toll‐like receptor 4‐mediated innate immunity in rat alveolar type II cells

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

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