A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury

Dib, Marwan; Zsengellér, Zsuzsanna K.; Mitsialis, S. Alex; Liu, Bao; Craig, Stewart; Gérard, Craig; Gerard, Norma P.

doi:10.1152/ajplung.90509.2008

Cited by 13 publications

(14 citation statements)

References 69 publications

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“…In our present study, we demonstrate evidence of HALI in the absence of a significant cellular inflammatory response (total BAL cell recovery). We have previously reported a similar response in IL-13 null mutant mice on hyperoxia exposure (28), and such has also been noted in peptide substance P receptor (NK1R) null mutant mice on hyperoxia exposure (46). It is plausible that there may be defects in inflammatory cell transmigration to and/or from the parenchymal compartment to the bronchial tree, leading to low BAL total cell counts, despite evidence of increased cell injury and death in the IL-13, NOS2, and NK1R null mutant mouse lungs exposed to hyperoxia.…”

Section: Discussionsupporting

confidence: 63%

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

Bhandari

Choo-Wing

Harijith

et al. 2012

Am J Respir Cell Mol Biol

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Supplemental oxygen is frequently prescribed. However, prolonged exposure to high concentrations of oxygen causes hyperoxic acute lung injury (HALI), which manifests as acute respiratory distress syndrome in adults and leads to bronchopulmonary dysplasia in newborns (NBs). Nitric oxide (NO), NO synthases (NOSs), and angiopoietin (Ang) 2 have been implicated in the pathogenesis of HALI. However, the mechanisms of the contributions of NOS/NO and the relationship(s) between NOS/NO and Ang2 have not been addressed. In addition, the relevance of these moieties in adults and NBs has not been evaluated. To address these issues, we compared the responses in hyperoxia of wild-type (NOS [1/1]) and NOS null (2/2) young adult and NB mice. When compared with NOS21/1 adult controls, NOS2 2/2 animals manifest exaggerated alveolar-capillary protein leak and premature death. These responses were associated with enhanced levels of structural cell death, enhanced expression of proapoptotic regulatory proteins, and Ang2. Importantly, silencing RNA knockdown of Ang2 decreased the levels of cell death and the expression of proapoptotic mediators. These effects were at least partially NOS2 specific, and were development dependent, because survival was similar in adult NOS3 1/1 and NOS3 2/2 mice and NB NOS2 1/1 and NOS2 2/2 mice, respectively. These studies demonstrate that NOS2 plays an important protective role in HALI in adult animals. They also demonstrate that this response is mediated, at least in part, by the ability of NOS2 to inhibit hyperoxia-induced Ang2 production and thereby decrease Ang2-induced tissue injury.Keywords: cytokines; hyperoxia; lung Supplemental oxygen is commonly employed to counteract tissue hypoxemia. Although this is lifesaving in most circumstances, prolonged exposure to high concentrations of oxygen can lead to untoward effects. In the lung, exposure to hyperoxia is characterized by an inflammatory response (mediated by cytokines) and breakdown of the alveolar-capillary barrier, leading to pulmonary edema and endothelial and epithelial cell injury/ death (1). In adults, hyperoxic acute lung injury (HALI) causes acute respiratory distress syndrome (2). In neonates, HALI has been shown to lead to a pulmonary phenotype suggestive of bronchopulmonary dysplasia (3). Hence, HALI is a major cause of morbidity and mortality in both adult (2) and neonatal (3,4) populations.In addition, nitric oxide (NO) is known to have oxidant effects (5), and has been implicated in the pathogenesis of HALI. NO is generated via the action of NO synthases (NOSs). The inflammatory response in HALI is initiated and propagated, to a large extent, by the release of cytokines (1), which are known to induce NOS (6, 7). Most data suggest that hyperoxia exposure up-regulates inducible NOS (NOS2) and endothelial NOS (NOS3) expression in adult (8-16) and neonatal (7,(16)(17)(18)(19) lungs. In ALI and cell death, the endogenous production of NO is said to be mostly contributed by up-regulation of NOS2 in the lung (20)(21)(22).Previous work...

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Section: Discussionsupporting

confidence: 63%

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

Bhandari

Choo-Wing

Harijith

et al. 2012

Am J Respir Cell Mol Biol

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“…After sacrifice, the lungs were fixed, and tissues were imbedded in paraffin, sectioned, and stained with hematoxylin and eosin, as described previously (25).…”

Section: Histopathologymentioning

confidence: 99%

“…Lung wet-to-dry weights and extravasation of Evans blue dye were determined as described previously (9,25). Evans blue content (mg dye/g lung) was determined by extrapolation from a standard curve.…”

Section: Evaluation Of Pulmonary Edemamentioning

confidence: 99%

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C5L2, the Second C5a Anaphylatoxin Receptor, Suppresses LPS-Induced Acute Lung Injury

Wang

Liu

Gérard

et al. 2016

Am J Respir Cell Mol Biol

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LPS-induced lung injury in the mouse is one of the most robust experimental models used for studies of acute lung injury (ALI) and acute respiratory distress syndrome in humans. Prior clinical and experimental studies support an important role for complement activation, particularly production of C5a, in the pathophysiology of human ALI/acute respiratory distress syndrome. In the mouse model, however, the precise role of C5a and its receptors is unclear. C5L2, an enigmatic second receptor for C5a, has been characterized, and results have generated substantial debate regarding its in vivo function. Our previous work with human neutrophils revealed a unique role for C5L2 in negatively modulating C5a-C5a receptor (C5aR)-mediated cellular activation, in which antibody-mediated blockade of C5L2 resulted in augmented C5a-C5aR responses. Here, we demonstrate that C5L2 2/2 mice (BALB/c background) administered intranasal LPS exhibit significantly more airway edema and hemorrhage than do wild-type animals. Bronchoalveolar lavage fluid and lung homogenates have significantly more neutrophils and myeloperoxidase activity, as well as proinflammatory cytokines and chemokines. When a blocking antibody against the C5aR was administered before LPS administration, the increased neutrophilic infiltration and cytokine levels were reversed. Thus, our data show not only that C5a contributes significantly to LPS-induced ALI in the mouse, but also that C5L2 plays an important antiinflammatory role in this model through actions resulting at least in part from negative modulation of C5a receptor activation.

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“…OZONE, NK-1R, AND THE POSTNATAL LUNG importance of the SP/NK-1R/Nur77 pathway in stabilizing the airway during acute injury is illustrated by numerous studies that show exacerbated airway injury and inflammatory responses when this pathway is disrupted (13,39,43,49). Postnatal age and conducting airway region drive acute ozone response.…”

Section: L477mentioning

confidence: 99%

Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung

Murphy

Oslund

Hyde

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Children are uniquely susceptible to ozone because airway and lung growth continue for an extensive period after birth. Early-life exposure of the rhesus monkey to repeated ozone cycles results in region-specific disrupted airway/lung growth, but the mediators and mechanisms are poorly understood. Substance P (SP), neurokinin-1 receptor (NK-1R); and nuclear receptor Nur77 (NR4A1) are signaling pathway components involved in ozone-induced cell death. We hypothesize that acute ozone (AO) exposure during postnatal airway development disrupts SP/NK-1R/Nur77 pathway expression and that these changes correlate with increased ozone-induced cell death. Our objectives were to 1) spatially define the normal development of the SP/NK-1R/Nur77 pathway in conducting airways; 2) compare how postnatal age modulates responses to AO exposure; and 3) determine how concomitant, episodic ozone exposure modifies age-specific acute responses. Male infant rhesus monkeys were assigned at age 1 mo to two age groups, 2 or 6 mo, and then to one of three exposure subgroups: filtered air (FA), FA+AO (AO: 8 h/day × 2 days), or episodic biweekly ozone exposure cycles (EAO: 8 h/day × 5 days/14-day cycle+AO). O3 = 0.5 ppm. We found that 1) ozone increases SP/NK-1R/Nur77 pathway expression in conducting airways, 2) an ozone exposure cycle (5 days/cycle) delivered early at age 2 mo resulted in an airway that was hypersensitive to AO exposure at the end of 2 mo, and 3) continued episodic exposure (11 cycles) resulted in an airway that was hyposensitive to AO exposure at 6 mo. These observations collectively associate with greater overall inflammation and epithelial cell death, particularly in early postnatal (2 mo), distal airways.

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A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury

Cited by 13 publications

References 69 publications

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

C5L2, the Second C5a Anaphylatoxin Receptor, Suppresses LPS-Induced Acute Lung Injury

Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung

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