TRPV4 channels augment macrophage activation and ventilator-induced lung injury

Hamanaka, Kazutoshi; Jian, Ming; Townsley, Mary I.; King, Judy; Liedtke, Wolfgang; Weber, David S.; Eyal, Fabien G.; Clapp, Mary M.; Parker, James C.

doi:10.1152/ajplung.00315.2009

Cited by 166 publications

(193 citation statements)

References 47 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…cAMP also serves as a critical regulator of lung macrophage function suppressing cytokine and chemokine production as well as iNOS expression (40). Given the critical importance of lung macrophages in mediating both LPS-induced lung injury (15) and VILI (19), our results raise the possibility that increased macrophage PDE2A expression may play an important role in our combined injury model. Additional experiments are planned to elucidate the specific cellular populations responsible for the PDE2A-mediated effects when LPS and VILI are combined.…”

Section: Discussionmentioning

confidence: 86%

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 86%

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

View full text Add to dashboard Cite

show abstract

“…TRPV4 is expressed across a wide range of non-neuronal human cell types in the airways, including structural cells such as airway smooth muscle, epithelial cells, fibroblasts and pulmonary vessels and inflammatory cells including macrophages (but not highly differentiated surrogates: the circulating monocytic precursor cell, monocyte derived macrophages, in vitro differentiated promonocytic THP-1 and U937 cells or promyelocytic HL-60 leukaemia cells), neutrophils and T-cells [99,107,111,112,114,[128][129][130][131][132]. However, in the respiratory system, the function of TRPV4 is probably best understood in relation to its role in acute lung injury, which is not covered in this review [133].…”

Section: Trpv4mentioning

confidence: 99%

The emerging role of transient receptor potential channels in chronic lung disease

Belvisi

Birrell

2017

Eur Respir J

View full text Add to dashboard Cite

Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis are a major and increasing global health burden with a high unmet need. Drug discovery efforts in this area have been largely disappointing and so new therapeutic targets are needed. Transient receptor potential ion channels are emerging as possible therapeutic targets, given their widespread expression in the lung, their role in the modulation of inflammatory and structural changes and in the production of respiratory symptoms, such as bronchospasm and cough, seen in chronic lung disease.

show abstract

“…Recently, the force-sensitive transient receptor potential vanilloid 4 (TRPV4) ion channel in the alveolar macrophage cell membrane was shown to mediate murine lung vascular permeability from highpressure mechanical ventilation (HPMV) (6,7). TRPV4 is a Ca 21 -permeable cation channel gated by numerous stimuli, including integrin-and osmosis-dependent mechanical forces (8)(9)(10), heat (11,12), and endogenous and synthetic compounds (12)(13)(14)(15).…”

mentioning

confidence: 99%

“…TRPV4 is a Ca 21 -permeable cation channel gated by numerous stimuli, including integrin-and osmosis-dependent mechanical forces (8)(9)(10), heat (11,12), and endogenous and synthetic compounds (12)(13)(14)(15). It is expressed in many tissues (16,17), including pulmonary bronchiolar and alveolar epithelia (13), alveolar macrophages, and extra-alveolar vessel smooth muscle cells and endothelium (6,13). In vitro data suggest that TRPV4 can be activated within 5 milliseconds of stimulation by mechanical forces (8).…”

mentioning

confidence: 99%

“…To test this hypothesis, we developed a nanoparticulate formulation containing the TRPV4 inhibitor ruthenium red (RR) (6,9,18) for inhalational delivery in the mouse. We focus on the inhaled route because inhalational drug delivery would generate high pulmonary drug levels relative to systemic delivery, thereby minimizing systemic side effects (19,20), which is important considering the ubiquitous nature of TRPV4 (21).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Prevention of Ventilator-Induced Lung Edema by Inhalation of Nanoparticles Releasing Ruthenium Red

Jurek

Hirano-Kobayashi

Chiang

et al. 2014

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

The acute respiratory distress syndrome (ARDS), a devastating lung disease that has no cure, is exacerbated by life-supportive mechanical ventilation that worsens lung edema and inflammation through the syndrome of ventilator-induced lung injury. Recently, the membrane ion channel transient receptor potential vanilloid 4 (TRPV4) on alveolar macrophages was shown to mediate murine lung vascular permeability induced by high-pressure mechanical ventilation. The objective of this study was to determine whether inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red (RR) prevents ventilator-induced lung edema in mice. Poly-lactic-co-glycolic acid NPs containing RR were evaluated in vitro for their ability to block TRPV4-mediated calcium signaling in alveolar macrophages and capillary endothelial cells. Lungs from adult C57BL6 mice treated with nebulized NPs were then used in ex vivo ventilation perfusion experiments to assess the ability of the NPs to prevent high-pressure mechanical ventilation-induced lung edema. Poly-lactic-co-glycolic acid NPs (300 nm) released RR for 150 hours in vitro, and blocked TRPV4-mediated calcium signaling in cells up to 7 days after phagocytosis. Inhaled NPs deposited in alveoli of spontaneously breathing mice were rapidly phagocytosed by alveolar macrophages, and blocked increased vascular permeability from high-pressure mechanical ventilation for 72 hours in ex vivo ventilation perfusion experiments. These data offer proof of principle that inhalation of NPs containing a TRPV4 inhibitor prevents ventilator damage for several days, and imply that this novel drug delivery strategy could be used to target alveolar macrophages in patients at risk of ventilator-induced lung injury before initiating mechanical ventilation.

show abstract

TRPV4 channels augment macrophage activation and ventilator-induced lung injury

Cited by 166 publications

References 47 publications

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

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

The emerging role of transient receptor potential channels in chronic lung disease

Prevention of Ventilator-Induced Lung Edema by Inhalation of Nanoparticles Releasing Ruthenium Red

Contact Info

Product

Resources

About