Attenuation of pulmonary injury by an inhaled MMP inhibitor in the endotoxin lung injury model

Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema and poor gas exchange resulting from severe inflammatory lung injury. Neutrophilic infiltration and increased pulmonary vascular permeability are hallmarks of early ARDS and precipitate a self-perpetuating cascade of inflammatory signaling. The biochemical processes initiating these events remain unclear. Typically associated with extracellular matrix degradation, recent data suggest matrix metalloproteinases (MMPs) are regulators of pulmonary inflammation. To demonstrate that inhalation of a broad MMP inhibitor attenuates LPS induced pulmonary inflammation. Nebulized CGS27023AM (CGS) was administered to LPS-injured mice. Pulmonary CGS levels were examined by mass spectroscopy. Inflammatory scoring of hematoxylin-eosin sections, examination of vascular integrity via lung wet/dry and bronchoalveolar lvage/serum FITC-albumin ratios were performed. Cleaved caspase-3 levels were also assessed. Differential cell counts and pulse-chase labeling were utilized to determine the effects of CGS on neutrophil migration. The effects of CGS on human neutrophil migration and viability were examined using Boyden chambers and MTT assays. Nebulization successfully delivered CGS to the lungs. Treatment decreased pulmonary inflammatory scores, edema, and apoptosis in LPS treated animals. Neutrophil chemotaxis was reduced by CGS treatment, with inhalation causing significant reductions in both the total number and newly produced bromodeoxyuridine-positive cells infiltrating the lung. Mechanistic studies on cells isolated from humans demonstrate that CGS-treated neutrophils exhibit decreased chemotaxis. The protective effect observed following treatment with a nonspecific MMP inhibitor indicates that one or more MMPs mediate the development of pulmonary edema and neutrophil infiltration in response to LPS injury. In accordance with this, inhaled MMP inhibitors warrant further study as a potential new therapeutic avenue for treatment of acute lung injury.

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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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Sesame Oil Attenuates Ovalbumin-Induced Pulmonary Edema and Bronchial Neutrophilic Inflammation in Mice

BioMed Research International ◽

10.1155/2013/905670 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Dur-Zong Hsu ◽

Chuan-Teng Liu ◽

Pei-Yi Chu ◽

Ya-Hui Li ◽

Srinivasan Periasamy ◽

...

Keyword(s):

Pulmonary Edema ◽

Allergic Asthma ◽

Inflammatory Diseases ◽

Pulmonary Inflammation ◽

Allergic Airway Inflammation ◽

Neutrophil Infiltration ◽

Lavage Fluid ◽

Sesame Oil ◽

Neutrophilic Inflammation ◽

Nitrite Level

Background. Allergic asthma is one of the most common chronic inflammatory diseases of airways. Severe asthma may lead to hospitalization and death. Sesame oil is a natural product with anti-inflammatory property. However, the effect of sesame oil on allergic asthma has never been studied.Objective. We investigate the effect of sesame oil on pulmonary inflammation in allergic asthma model.Methods. Allergic airway inflammation was induced by sensitizing with two doses of 10 mg ovalbumin (OVA) and then challenged with 1% OVA nebulizer exposure (1 h/day) for 3 days. Sesame oil (0.25, 0.5, or 1 mL/kg/day) was given orally 30 min before each challenge. Samples were collected 24 h after the last challenge.Results. Data showed that sesame oil inhibited pulmonary edema and decreased interleukin (IL)-1βand IL-6 levels in bronchoalveolar lavage fluid in OVA-treated mice. Sesame oil also decreased pulmonary nitrite level, inducible nitric oxide synthase expression, and neutrophil infiltration induced by OVA. Further, sesame oil decreased serum IgE level in OVA-treated mice.Conclusion. Sesame oil may attenuate pulmonary edema and bronchial neutrophilic inflammation by inhibiting systemic IgE level in allergic asthma.

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Atrial natriuretic peptide attenuates agonist-induced pulmonary edema in mice with targeted disruption of the gene for natriuretic peptide receptor-A

Journal of Applied Physiology ◽

10.1152/japplphysiol.01249.2011 ◽

2013 ◽

Vol 114 (3) ◽

pp. 307-315 ◽

Cited By ~ 5

Author(s):

James R. Klinger ◽

Shu-Whei Tsai ◽

Sabrina Green ◽

Katie L. Grinnell ◽

Jason T. Machan ◽

...

Keyword(s):

Lung Injury ◽

Atrial Natriuretic Peptide ◽

Pulmonary Edema ◽

Natriuretic Peptide ◽

Protein Concentration ◽

Natriuretic Peptide Receptor ◽

Edema Formation ◽

Peptide Receptor ◽

Cell Counts ◽

Natriuretic Peptide Receptor A

Atrial natriuretic peptide (ANP) inhibits agonist-induced pulmonary edema formation, but the signaling pathway responsible is not well defined. To investigate the role of the particulate guanylate cyclase-linked receptor, natriuretic peptide receptor-A (NPR-A), we measured acute lung injury responses in intact mice and pulmonary microvascular endothelial cells (PMVEC) with normal and disrupted expression of NPR-A. NPR-A wild-type (NPR-A+/+), heterozygous (NPR-A+/−), and knockout (NPR-A−/−) mice were anesthetized and treated with thrombin receptor agonist peptide (TRAP) or lipopolysaccharide (LPS). Lung injury was assessed by lung wet-to-dry (W/D) weight and by protein and cell concentration of bronchoalveolar lavage (BAL) fluid. No difference in pulmonary edema formation was seen between NPR-A genotypes under baseline conditions. TRAP and LPS increased lung W/D weight and BAL fluid cell counts more in NPR-A−/− mice than in NPR-A+/− or NPR-A+/+ mice, but no genotype-related differences were seen in TRAP-induced increases in bloodless lung W/D weight or LPS-induced increases in BAL protein concentration. Pretreatment with ANP infusion completely blocked TRAP-induced increases in lung W/D weight and blunted LPS-induced increases in BAL cell counts and protein concentration in both NPR-A−/− and NPR-A+/+ mice. Thrombin decreased transmembrane electrical resistance in monolayers of PMVECs in vitro, and this effect was attenuated by ANP in PMVECs isolated from both genotypes. Administration of the NPR-C-specific ligand, cANF, also blocked TRAP-induced increases in lung W/D weight and LPS-induced increases in BAL cell count and protein concentration in NPR-A+/+ and NPR-A−/− mice. We conclude that ANP is capable of attenuating agonist-induced lung edema in the absence of NPR-A. The protective effect of ANP on agonist-induced lung injury and pulmonary barrier function may be mediated by NPR-C.

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Low-dose carbon monoxide treatment attenuates early pulmonary neutrophil recruitment after acid aspiration

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00324.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. L644-L653 ◽

Cited By ~ 21

Author(s):

Jean A. Nemzek ◽

Christopher Fry ◽

Omorodola Abatan

Keyword(s):

Carbon Monoxide ◽

Lung Injury ◽

Low Dose ◽

Acidic Solution ◽

Pulmonary Inflammation ◽

Neutrophil Recruitment ◽

Acute Lung Inflammation ◽

Vascular Integrity ◽

Acid Aspiration ◽

Blood Neutrophils

Exogenous carbon monoxide (CO) has anti-inflammatory and cytoprotective properties that show promise in the treatment of numerous pulmonary diseases. However, the effectiveness of CO in acute pulmonary injury associated with direct lung insult has not been shown conclusively. The purpose of this study was to determine if exogenous CO would modulate the pulmonary inflammation and lung injury that develops after acid aspiration. Groups of mice were given intratracheal (IT) injections of either saline or an acidic solution. After the IT injection, some of the mice in each group were allowed to spontaneously inhale CO (500 ppm). Mice exposed to CO for 6 h after IT acid had a significant decrease in bronchoalveolar lavage (BAL) fluid neutrophil counts and in histological evidence of lung injury. These results could not be explained by changes in BAL fluid chemokine levels or altered CXCR2 expression. The reduced neutrophil recruitment was associated with a decrease in the percentage of peripheral blood neutrophils expressing CD11b protein. However, within 24 h, the BAL neutrophil counts increased and were not different from animals without CO exposure. In addition, indices of vascular integrity were not different between animals with acid aspiration regardless of CO exposure at the later time point. These results showed that CO can modulate the early development of acute lung inflammation in this model of acid aspiration. Although these effects were eventually overwhelmed, the results suggest that CO may have efficacy during the initial treatment of aspiration lung injury.

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Regional pulmonary inflammation in an endotoxemic ovine acute lung injury model

Respiratory Physiology & Neurobiology ◽

10.1016/j.resp.2012.06.015 ◽

2012 ◽

Vol 183 (2) ◽

pp. 149-158 ◽

Cited By ~ 8

Author(s):

A. Fernandez-Bustamante ◽

R.B. Easley ◽

M. Fuld ◽

D. Mulreany ◽

D. Chon ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Pulmonary Inflammation ◽

Injury Model ◽

Lung Injury Model

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Total alveolar lavage with oxygen fine bubble dispersion directly improves lipopolysaccharide-induced acute respiratory distress syndrome of rats

Scientific Reports ◽

10.1038/s41598-020-73768-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Kenta Kakiuchi ◽

Takehiro Miyasaka ◽

Shinji Takeoka ◽

Kenichi Matsuda ◽

Norikazu Harii

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Acute Lung Injury ◽

Treatment Group ◽

Lung Injury ◽

Respiratory Distress Syndrome ◽

Distress Syndrome ◽

Pulmonary Inflammation ◽

Treatment Groups ◽

Injury Model ◽

Lung Injury Model

Abstract Severe respiratory disorder induced by pulmonary inflammation is one of the causes of acute respiratory distress syndrome, which still has high mortality. It is crucial to remove causative substances and inflammatory mediators early in order to inhibit the progression of pulmonary inflammation. Total alveolar lavage (TAL) may avert the inflammatory response by eliminating causative substances in certain inflammatory lung diseases. We developed an efficient TAL system and examined the efficacy of short-term TAL treatment performed for acute lung injury models of rats. In the first experiment with a severe lung injury model, 15 rats were divided into 3 groups: sham group, mechanical gas ventilation (MGV) treatment group, and TAL treatment group. The treatments were conducted for 5 min, 20 min after the provocation of inflammation. Two days after treatment, the TAL and MGV treatment groups exhibited significant differences in blood oxygen levels, mean arterial pressure, weight-loss ratio, and inflammatory cytokine levels in the lungs. In contrast, almost no differences were observed between the TAL treatment and sham groups. In the second experiment with a lethal lung injury model, the TAL treatment dramatically improved the survival rate of the rats compared to the MGV treatment groups (p = 0.0079). Histopathological analysis confirmed pronounced differences in neutrophil accumulation and thickening of the interstitial membrane between the TAL and MGV treatment groups in both experiments. These results indicate that as little as 5 min of TAL treatment can protect rats from acute lung injury by removing causative substances from the lungs.

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Alkaline phosphatase in pulmonary inflammation—a translational study in ventilated critically ill patients and rats

Intensive Care Medicine Experimental ◽

10.1186/s40635-020-00335-x ◽

2020 ◽

Vol 8 (S1) ◽

Author(s):

Jenny Juschten ◽

◽

Sarah A. Ingelse ◽

Lieuwe D. J. Bos ◽

Armand R. J. Girbes ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Lung Injury ◽

Critically Ill ◽

Inflammatory Mediators ◽

Critically Ill Patients ◽

Pulmonary Inflammation ◽

Markers Of Inflammation ◽

Injury Model ◽

Lung Injury Model ◽

Epithelial Dysfunction

Abstract Background Alkaline phosphatase (AP), a dephosphorylating enzyme, is involved in various physiological processes and has been shown to have anti-inflammatory effects. Aim To determine the correlation between pulmonary AP activity and markers of inflammation in invasively ventilated critically ill patients with or without acute respiratory distress syndrome (ARDS), and to investigate the effect of administration of recombinant AP on pulmonary inflammation in a well-established lung injury model in rats Methods AP activity was determined and compared with levels of various inflammatory mediators in bronchoalveolar lavage fluid (BALF) samples obtained from critically ill patients within 2 days of start of invasive ventilation. The endpoints of this part of the study were the correlations between AP activity and markers of inflammation, i.e., interleukin (IL)-6 levels in BALF. In RccHan Wistar rats, lung injury was induced by intravenous administration of 10 mg/kg lipopolysaccharide, followed by ventilation with a high tidal volume for 4 h. Rats received either an intravenous bolus of 1500 IU/kg recombinant AP or normal saline 2 h after intravenous LPS administration, right before start of ventilation. Endpoints of this part of the study were pulmonary levels of markers of inflammation, including IL-6, and markers of endothelial and epithelial dysfunction. Results BALF was collected from 83 patients; 10 patients had mild ARDS, and 15 had moderate to severe ARDS. AP activity correlated well with levels of IL-6 (r = 0.70), as well as with levels of other inflammatory mediators. Pulmonary AP activity between patients with and without ARDS was comparable (0.33 [0.14–1.20] vs 0.55 [0.21–1.42] U/L; p = 0.37). Animals with acute lung injury had markedly elevated pulmonary AP activity compared to healthy controls (2.58 [2.18–3.59] vs 1.01 [0.80–1.46] U/L; p < 0.01). Intravenous administration of recombinant AP did neither affect pulmonary inflammation nor endothelial and epithelial dysfunction. Conclusions In ventilated critically ill patients, pulmonary AP activity correlates well with markers of pulmonary inflammation, such as IL-6 and IL-8. In animals with lung injury, pulmonary AP activity is elevated. Administration of recombinant AP does not alter pulmonary inflammation and endothelial or epithelial dysfunction in the acute phase of a murine lung injury model.

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Resveratrol-Loaded Lipid-Core Nanocapsules Modulate Acute Lung Inflammation and Oxidative Imbalance Induced by LPS in Mice

Pharmaceutics ◽

10.3390/pharmaceutics13050683 ◽

2021 ◽

Vol 13 (5) ◽

pp. 683

Author(s):

Maria Talita Pacheco de Oliveira ◽

Diego de Sá Coutinho ◽

Sílvia Stanisçuaski Guterres ◽

Adriana Raffin Pohlmann ◽

Patrícia Machado Rodrigues e Silva ◽

...

Keyword(s):

Lung Injury ◽

Pulmonary Inflammation ◽

Pharmacological Therapy ◽

Free Form ◽

Therapeutic Effects ◽

Acute Lung Inflammation ◽

Lung Injury Model ◽

Anti Inflammatory ◽

Pre Treatment ◽

Antioxidant Effects

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory and oxidative imbalance lung conditions with no successful pharmacological therapy and a high mortality rate. Resveratrol (RSV) is a plant-derived stilbene that presents anti-inflammatory and antioxidant effects. However, its therapeutic application remains limited due to its poor bioavailability, which can be solved by the use of nanocarriers. Previously, we demonstrated that nanoencapsulated RSV (RSV-LNC) pre-treatment, performed 4 h before lipopolysaccharide (LPS) stimulation in mice, increased its anti-inflammatory properties. In this study, we evaluated the anti-inflammatory and antioxidant effects, and lung distribution of RSV-LNCs administered therapeutically (6 h post LPS exposure) in a lung injury mouse model. The results showed that RSV-LNCs posttreatment improved lung function and diminished pulmonary inflammation. Moreover, RSV-LNC treatment enhanced the antioxidant catalase level together with a decrease in the oxidative biomarker in mouse lungs, which was accompanied by an increase in pulmonary Nrf2 antioxidant expression. Finally, the presence of RSV in lung tissue was significantly detected when mice received RSV-LNCs but not when they received RSV in its free form. Together, our results confirm that RSV nanoencapsulation promotes an increase in RSV bioavailability, enhancing its therapeutic effects in an LPS-induced lung injury model.

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Endothelin ETB receptor-mediated mechanisms involved in oleic acid-induced acute lung injury in mice

Clinical Science ◽

10.1042/cs103s340s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 340S-344S ◽

Cited By ~ 16

Author(s):

Cláudio L. GUIMARÃES ◽

Patricia G. TRENTIN ◽

Giles A. RAE

Keyword(s):

Oleic Acid ◽

Lung Injury ◽

Mononuclear Cells ◽

Neutrophil Infiltration ◽

Lavage Fluid ◽

Plasma Extravasation ◽

Receptor Antagonists ◽

Cell Counts ◽

Etb Receptor ◽

Eta Receptor Antagonist

The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1mg·kg-1 intravenously), but not endothelin-1 (up to 1nmol·kg-1 intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8±3.9 to 98.6±10.7µg 1h after injection. Bosentan, the antagonist of endothelin receptors (ETA and ETB) or the selective ETB receptor antagonists Ro 46-8443 or A-192621 (administered 1h before oleic acid at doses of 30, 10 and 30mg·kg-1 respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ETA receptor antagonist A-127722.5 (10mg·kg-1) was inactive. Oleic acid (2mg·kg-1, intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10mg·kg-1 respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ETB receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ETB or mixed ETA/ETB receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.

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