Inflammatory Mediators in the Immunobiology of Bronchopulmonary Dysplasia

Ryan, Rita M.; Ahmed, Qadeer; Lakshminrusimha, Satyanarayana

doi:10.1007/s12016-007-8031-4

Cited by 108 publications

(77 citation statements)

References 205 publications

(255 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Resident epithelial cells secrete various chemotactic inflammatory cytokines in response to pro-oxidant exposure. These cytokines play an important role in the augmentation and the resolution of inflammation (26,27). The activation of circulating neutrophils and their subsequent transmigration into the alveolar air space after an injurious insult were linked to the development of ALI.…”

Section: Discussionmentioning

confidence: 99%

Conditional Deletion of Nrf2 in Airway Epithelium Exacerbates Acute Lung Injury and Impairs the Resolution of Inflammation

Reddy

Potteti

Mariani

et al. 2011

Am J Respir Cell Mol Biol

101

View full text Add to dashboard Cite

Oxidant stress, resulting from an excess of reactive electrophiles produced in the lung by both resident (epithelial and endothelial) and infiltrated leukocytes, is thought to play an obligatory role in tissue injury and abnormal repair. Previously, using a conventional (whole-body) knockout model, we showed that antioxidative gene induction regulated by the transcription factor Nrf2 is critical for mitigating oxidant-induced (hyperoxic) stress, as well as for preventing and resolving tissue injury and inflammation in vivo. However, the contribution to pathogenic acute lung injury (ALI) of the cellular stress produced by resident versus infiltrated leukocytes remains largely undefined in vivo. To address this critical gap in our knowledge, we generated mice with a conditional deletion of Nrf2 specifically in Clara cells, subjected these mice to hyperoxic insult, and allowed them to recover. We report that a deficiency of Nrf2 in airway epithelia alone is sufficient to contribute to the development and progression of ALI. When exposed to hyperoxia, mice lacking Nrf2 in Clara cells showed exacerbated lung injury, accompanied by greater levels of cell death and epithelial sloughing than in their wildtype littermates. In addition, we found that an Nrf2 deficiency in Clara cells is associated with a persistent inflammatory response and epithelial sloughing in the lungs during recovery from sublethal hyperoxic insult. Our results demonstrate (for the first time, to the best of our knowledge) that Nrf2 signaling in Clara cells is critical for conferring protection from hyperoxic lung injury and for resolving inflammation during the repair process.Keywords: oxidative stress; lung injury and repair; inflammation Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), are common clinical syndromes caused by various injurious insults. These syndromes can lead to the development of lung pathogenesis and cause major public health problems throughout the world (1, 2). Various studies, using various experimental models of ALI/ARDS (including the hyperoxic ALI model), established that oxidants inflict damage on lung tissue by generating reactive oxygen and nitrogen species (ROS/RNS), resulting in proteinaceous edema and inflammation and a subsequent impairment of respiratory function, as well as morbidity and mortality. The production of excessive ROS during prolonged exposure to hyperoxia can trigger damage to lung tissue and cause the death of both endothelial and alveolar Type I and Type II epithelial cells in vitro and in vivo (3-5). The infiltrated leukocytes, which are generally recruited to the lung during injury, are known to generate ROS/RNS, which contribute to or perpetuate lung injury in various experimental models of ALI/ARDS (6). However, the exact contribution of the oxidative stress generated by various cell types to ALI/ARDS and to the subsequent development of lung pathogenesis is not well-defined.The Nrf2 transcription factor regulates the expression levels of several ant...

show abstract

Section: Discussionmentioning

confidence: 99%

Conditional Deletion of Nrf2 in Airway Epithelium Exacerbates Acute Lung Injury and Impairs the Resolution of Inflammation

Reddy

Potteti

Mariani

et al. 2011

Am J Respir Cell Mol Biol

101

View full text Add to dashboard Cite

show abstract

“…As inflammation entered this paradigm, it included external sources (chorioamnionitis, postnatal infections), iatrogenic sources (ventilation, oxygen), and the internal host response. [9][10][11][12][13][14][15] In 1999, Jobe 16 amended Philip's model to incorporate multiple dimensions of inflammation and created a unified model of "new BPD." However, even as this paradigm was confirmed by experimental data, few innovative therapies have proven efficacious.…”

Section: General and Methodologic Considerationsmentioning

confidence: 99%

Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights Be Translated Into Therapies?

2011

View full text Add to dashboard Cite

Bronchopulmonary dysplasia (BPD) frequently complicates preterm birth and leads to significant long-term morbidity. Unfortunately, few therapies are known to effectively prevent or treat BPD. Ongoing research has been focusing on potential therapies to limit inflammation in the preterm lung. In this review we highlight recent bench and clinical research aimed at understanding the role of inflammation in the pathogenesis of BPD. We also critically assess currently used therapies and promising developments in the field.

show abstract

“…Chronic pulmonary hypertension (PHT) is common in infants with severe BPD, heralding a greatly increased morbidity and mortality (11,31,34,47). The pathogenesis of BPD is multifactorial, with upregulation of inflammatory mediators leading to, or caused by, infiltration of inflammatory cells playing a major role (38,43,46). However, the specific mediators contributing to inflammatory neonatal lung injury remain unclear, and there are presently no effective treatments.…”

mentioning

confidence: 99%

Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Kantores

Ivanovska

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Ee MT, Kantores C, Ivanovska J, Wong MJ, Jain A, Jankov RP. Leukotriene B4 mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury. Am J Physiol Lung Cell Mol Physiol 311: L292-L302, 2016. First published June 17, 2016 doi:10.1152/ajplung.00120.2016.-Systemically-administered bleomycin causes inflammation, arrested lung growth, and pulmonary hypertension (PHT) in the neonatal rat, similar to human infants with severe bronchopulmonary dysplasia (BPD). Leukotrienes (LTs) are inflammatory lipid mediators produced by multiple cell types in the lung. The major LTs, LTB4 and cysteinyl LTs, are suggested to contribute to BPD, but their specific roles remain largely unexplored in experimental models. We hypothesized that LTs are increased in bleomycin-induced BPD-like injury, and that inhibition of LT production would prevent inflammatory cell influx and thereby ameliorate lung injury. Rat pups were exposed to bleomycin (1 mg·kg Ϫ1 ·day Ϫ1 ip) or vehicle (control) from postnatal days 1-14 and were treated with either zileuton (5-lipoxygenase inhibitor), montelukast (cysteinyl LT1 receptor antagonist), or SC57461A (LTA4 hydrolase inhibitor) 10 mg·kg Ϫ1 ·day Ϫ1 ip. Bleomycin led to increased lung content of LTB4, but not cysteinyl LTs. Bleomycininduced increases in tissue neutrophils and macrophages and lung contents of LTB4 and tumor necrosis factor-␣ were all prevented by treatment with zileuton. Treatment with zileuton or SC57461A also prevented the hemodynamic and structural markers of chronic PHT, including raised pulmonary vascular resistance, increased Fulton index, and arterial wall remodeling. However, neither treatment prevented impaired alveolarization or vascular hypoplasia secondary to bleomycin. Treatment with montelukast had no effect on macrophage influx, PHT, or on abnormal lung structure. We conclude that LTB4 plays a crucial role in lung inflammation and PHT in experimental BPD. Agents targeting LTB4 or LTB4-mediated signaling may have utility in infants at risk of developing BPD-associated PHT. rat; newborn; inflammation; lung injury THE SURVIVAL OF EXTREMELY low-birth-weight infants has improved over recent decades, but at the cost of a high risk of developing chronic lung injury, known as bronchopulmonary dysplasia (BPD) (3). Chronic pulmonary hypertension (PHT) is common in infants with severe BPD, heralding a greatly increased morbidity and mortality (11,31,34,47). The pathogenesis of BPD is multifactorial, with upregulation of inflammatory mediators leading to, or caused by, infiltration of inflammatory cells playing a major role (38,43,46). However, the specific mediators contributing to inflammatory neonatal lung injury remain unclear, and there are presently no effective treatments.Leukotrienes (LTs) are potent lipid mediators, first described in 1979 by Borgeat and Samuelsson (5) as a new lineage of arachidonic acid-derived metabolites. LTs are produced by, recruit, and activate immune cells, thus initiating, augmenting, and sustaining tissue in...

show abstract

Inflammatory Mediators in the Immunobiology of Bronchopulmonary Dysplasia

Cited by 108 publications

References 205 publications

Conditional Deletion of Nrf2 in Airway Epithelium Exacerbates Acute Lung Injury and Impairs the Resolution of Inflammation

Conditional Deletion of Nrf2 in Airway Epithelium Exacerbates Acute Lung Injury and Impairs the Resolution of Inflammation

Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights Be Translated Into Therapies?

Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Contact Info

Product

Resources

About

Inflammatory Mediators in the Immunobiology of Bronchopulmonary Dysplasia

Cited by 108 publications

References 205 publications

Conditional Deletion of Nrf2 in Airway Epithelium Exacerbates Acute Lung Injury and Impairs the Resolution of Inflammation

Conditional Deletion of Nrf2 in Airway Epithelium Exacerbates Acute Lung Injury and Impairs the Resolution of Inflammation

Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights Be Translated Into Therapies?

Leukotriene B4mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Contact Info

Product

Resources

About

Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury