Prophylactic effects of recombinant human superoxide dismutase in neonatal lung injury

To determine if recombinant human Cu-Zn superoxide dismutase (rhSOD) would prevent acute lung injury caused by hyperoxia and barotrauma, 26 newborn piglets were studied. Ten piglets were hyperventilated (arterial PCO2 15–20 Torr) with 100% O2 for 48 h. A second group received identical treatment for 4 h (n = 2) or 48 h (n = 8) but was given 5 mg/kg of rhSOD intratracheally at time 0. Six piglets were normally ventilated (arterial PCO2 40–45 Torr) for 48 h with 21% O2. Pulmonary function and tracheal aspirates were examined at time 0 and at 24 and 48 h, and bronchoalveolar lavage was performed at 48 h. In piglets treated with hyperoxia and hyperventilation, lung compliance decreased 42%, and tracheal aspirates showed an increase in neutrophil chemotactic activity (32%), total cell counts (135%), elastase activity (93%), and albumin concentration (339%) over 48 h (P < 0.05). All variables were significantly lower in rhSOD-treated piglets and comparable to normoxic control values. Surfactant remained active in all groups. Immunohistochemistry demonstrated that at 48 h significant rhSOD was distributed homogeneously in terminal airways. Adding rhSOD to tracheal aspirates of hyperoxic hyperventilated piglets did not alter neutrophil chemotaxis, suggesting that rhSOD protected the lung by reducing the production of chemotactic mediators. Results indicate that acute lung injury caused by 48 h of hyperoxia and hyperventilation is significantly ameliorated by prophylactic intratracheal administration of rhSOD.

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Prophylactic effects of dexamethasone in lung injury caused by hyperoxia and hyperventilation

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.4.1320 ◽

1992 ◽

Vol 72 (4) ◽

pp. 1320-1325 ◽

Cited By ~ 7

Author(s):

J. M. Davis ◽

J. Whitin

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Tracheal Aspirate ◽

Lung Compliance ◽

Lung Damage ◽

Control Group ◽

High Dose ◽

Albumin Concentration ◽

High Dose Dexamethasone ◽

Cell Counts

To determine if prophylactic corticosteroids would prevent acute lung injury caused by hyperoxia and barotrauma, 29 piglets (1.2 +/- 0.3 kg, 1–2 days of age) were studied. Ten piglets were hyperventilated [arterial PCO2 (PaCO2) 15–20 Torr] with 100% O2 for 48 h and compared with 10 piglets treated with the identical management but given 0.7 mg/kg of dexamethasone at time 0 and every 12 h for the 48-h study. Six piglets were normally ventilated (PaCO2 40–45 Torr) for 48 h with 21% O2 as an additional control group. Pulmonary function and tracheal aspirates were examined at time 0 and every 24 h. Bronchoalveolar lavage was performed for surfactant analyses at the conclusion of the study. In animals treated with hyperoxia and hyperventilation, lung compliance decreased 32% and tracheal aspirate polymorphonuclear leukocyte (PMN) chemotactic activity increased by 51%, cell counts by 204%, number of PMNs by 277%, elastase activity by 111%, and albumin concentration by 328% over 48 h (P less than 0.05). In contrast, dexamethasone-treated piglets had increases in only tracheal aspirate albumin concentration (206%) over the 48-h study. All cellular and biochemical variables were lower in dexamethasone-treated compared with hyperoxic hyperventilated piglets. Room air normal ventilation controls had only a 108% increase in tracheal aspirate albumin concentration noted. Despite quantitative differences in surfactant among the three groups, activity was unaffected. Results indicate that hyperoxia and hyperventilation for 48 h causes significant inflammatory changes and acute lung injury and that prophylactic high-dose dexamethasone significantly ameliorates this lung damage.

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Recombinant human superoxide dismutase reduces lung injury caused by inhaled nitric oxide and hyperoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.272.5.l903 ◽

1997 ◽

Vol 272 (5) ◽

pp. L903-L907 ◽

Cited By ~ 11

Author(s):

C. G. Robbins ◽

S. Horowitz ◽

T. A. Merritt ◽

A. Kheiter ◽

J. Tierney ◽

...

Keyword(s):

Nitric Oxide ◽

Superoxide Dismutase ◽

Acute Lung Injury ◽

Lung Injury ◽

Lung Tissue ◽

Pulmonary Inflammation ◽

Inhaled Nitric Oxide ◽

Newborn Piglets ◽

Markers Of Inflammation ◽

Cell Counts

We previously demonstrated that 48 h of 100 ppm inhaled nitric oxide (NO) and 90% O2 causes surfactant dysfunction and pulmonary inflammation in mechanically ventilated newborn piglets. Because peroxynitrite (the product of NO and superoxide) is thought to play a major role in the injury process, recombinant human superoxide dismutase (rhSOD, a scavenger of superoxide) might minimize this insult. Four groups of newborn piglets (1-3 days of age) were ventilated with 100 ppm NO and 90% O2 for 48 h. Piglets received no drug, 5 mg/kg rhSOD intratracheally at time 0, 5 mg/kg rhSOD intratracheally at 0 and 24 h, or 10 mg/kg rhSOD by nebulization at time 0. At 48 h, bronchoalveolar lavage (BAL) was performed, and lung tissue was analyzed for markers of inflammation, oxidative injury, acute lung injury, and surfactant function. There were significant differences between rhSOD-treated piglets and untreated controls with respect to BAL neutrophil chemotactic activity, cell counts, and protein concentration as well as lung tissue malondialdehyde concentrations. Minimum surface tension of BAL surfactant from all groups studied was increased, with no differences found among groups. These data suggest that rhSOD, at the doses used, mitigated the inflammatory changes, oxidative damage, and acute lung injury from exposure to 100 ppm NO and 90% O2 but did not appear to improve surfactant function. This has important clinical implications for infants treated with hyperoxia and NO for neonatal lung disorders.

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K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Scientific Reports ◽

10.1038/s41598-020-78886-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tatiana Zyrianova ◽

Benjamin Lopez ◽

Riccardo Olcese ◽

John Belperio ◽

Christopher M. Waters ◽

...

Keyword(s):

Lung Injury ◽

Lung Compliance ◽

Alveolar Epithelial Cells ◽

Pharmacological Intervention ◽

Alveolar Epithelial ◽

Protein Levels ◽

Cell Counts ◽

Novel Approach ◽

Intracellular Ca ◽

Cell Depolarization

AbstractNo targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

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Management of Acute Lung Injury: Palmitoylethanolamide as a New Approach

International Journal of Molecular Sciences ◽

10.3390/ijms22115533 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5533

Author(s):

Alessio Filippo Peritore ◽

Ramona D’Amico ◽

Rosalba Siracusa ◽

Marika Cordaro ◽

Roberta Fusco ◽

...

Keyword(s):

Acute Lung Injury ◽

B Cells ◽

Lung Injury ◽

Weight Ratio ◽

Dry Weight ◽

Mitogen Activated Protein Kinase ◽

Histopathological Analysis ◽

Nuclear Factor ◽

Intratracheal Administration ◽

Mitogen Activated Protein

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.

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Keratinocyte growth factor therapy in murine oleic acid-induced acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00450.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. L1179-L1192 ◽

Cited By ~ 40

Author(s):

K. Ulrich ◽

M. Stern ◽

M. E. Goddard ◽

J. Williams ◽

J. Zhu ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Lung Injury ◽

Gene Delivery ◽

Lung Injury ◽

Time Course ◽

Lung Compliance ◽

Alveolar Type ◽

Protein Therapy ◽

Cell Numbers ◽

Atii Cell

Alveolar type II (ATII) cell proliferation and differentiation are important mechanisms in repair following injury to the alveolar epithelium. KGF is a potent ATII cell mitogen, which has been demonstrated to be protective in a number of animal models of lung injury. We have assessed the effect of recombinant human KGF (rhKGF) and liposome-mediated KGF gene delivery in vivo and evaluated the potential of KGF as a therapy for acute lung injury in mice. rhKGF was administered intratracheally in male BALB/c mice to assess dose response and time course of proliferation. SP-B immunohistochemistry demonstrated significant increases in ATII cell numbers at all rhKGF doses compared with control animals and peaked 2 days following administration of 10 mg/kg rhKGF. Protein therapy in general is very expensive, and gene therapy has been suggested as a cheaper alternative for many protein replacement therapies. We evaluated the effect of topical and systemic liposome-mediated KGF-gene delivery on ATII cell proliferation. SP-B immunohistochemistry showed only modest increases in ATII cell numbers following gene delivery, and these approaches were therefore not believed to be capable of reaching therapeutic levels. The effect of rhKGF was evaluated in a murine model of OA-induced lung injury. This model was found to be associated with significant alveolar damage leading to severe impairment of gas exchange and lung compliance. Pretreatment with rhKGF 2 days before intravenous OA challenge resulted in significant improvements in Po2, Pco2, and lung compliance. This study suggests the feasibility of KGF as a therapy for acute lung injury.

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MRSA-Induced Endothelial Permeability and Acute Lung Injury are Attenuated by FTY720 S-Phosphonate

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00100.2021 ◽

2021 ◽

Author(s):

Lichun Wang ◽

Eleftheria Letsiou ◽

Huashan Wang ◽

Patrick Belvitch ◽

Lucille Meliton ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Neutrophil Infiltration ◽

Post Treatment ◽

Fiber Formation ◽

Actin Stress Fiber ◽

Intratracheal Administration ◽

Barrier Disruption

Disruption of the lung endothelial barrier is a hallmark of acute respiratory distress syndrome (ARDS), for which no effective pharmacologic treatments exist. Prior work has demonstrated that FTY720 S-phosphonate (Tys), an analog of sphingosine-1-phosphate (S1P) and FTY720, exhibits potent endothelial cell (EC) barrier protective properties. In this study we investigated the in vitro and in vivo efficacy of Tys against methicillin-resistant Staphylococcus aureus (MRSA), a frequent bacterial cause of ARDS. Tys protected human lung EC from barrier disruption induced by heat-killed MRSA (HK-MRSA) or staphylococcal α-toxin and attenuated MRSA-induced cytoskeletal changes associated with barrier disruption, including actin stress fiber formation and loss of peripheral VE-cadherin and cortactin. Tys inhibited Rho and MLC activation after MRSA and blocked MRSA-induced NF-κB activation and release of the pro-inflammatory cytokines, IL-6 and IL-8. In vivo, intratracheal administration of live MRSA in mice caused significant vascular leakage and leukocyte infiltration into the alveolar space. Pre- or post-treatment with Tys attenuated MRSA-induced lung permeability and levels of alveolar neutrophils. Post-treatment with Tys significantly reduced levels of BAL VCAM-1 and plasma IL-6 and KC induced by MRSA. Dynamic intravital imaging of mouse lungs demonstrated Tys attenuation of HK-MRSA-induced interstitial edema and neutrophil infiltration into lung tissue. Tys did not directly inhibit MRSA growth or viability in vitro. In conclusion, Tys inhibits lung EC barrier disruption and pro-inflammatory signaling induced by MRSA in vitro and attenuates acute lung injury induced by MRSA in vivo. These results support the potential utility of Tys as a novel ARDS therapeutic strategy.

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