Diminished Pulmonary Lecithin Synthesis in Acidosis: Experimental Findings as Related to the Respiratory Distress Syndrome

Lung slices from term fetal rats were incubated in vitro at various pH values and the rates of the two de novo pathways for lecithin biosynthesis were determined by measuring the conversion of either 14C-choline (pathway 1) or 14C-methionine (pathway 2) to the phospholipid. It was observed that the choline pathway, but not phosphatidyle-thanolamine methylation, is pH-sensitive with maximum rates occurring at pH levels between 7.3 and 7.5; significantly less activity was found at pH levels between 7.0 and 7.2 and at pH levels between 7.6 and 8.0. Adjustment of the pH from 7.0 to 7.4 in vitro, simulating the clinical correction of acidosis by alkali infusion, was found to increase the conversion of choline to lecithin to a rate approximating that observed at pH 7.4. Since lecithins are the principal phospholipid components of pulmonary surfactant, and since pathway 1 is predominantly responsible for lung lecithin synthesis, the demonstration of impaired production with reduced pH offers a biochemical explanation for the pathophysiological effects of acidosis in the respiratory distress syndrome. A comparison of pH effects on choline pathway rate with the pH profiles of pathway enzymes suggests that these effects are mediated by the catalysts of lecithin synthesis.

Download Full-text

Inhibition of surfactant subtype convertase in radiation model of adult respiratory distress syndrome

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1991.260.4.l311 ◽

1991 ◽

Vol 260 (4) ◽

pp. L311-L317 ◽

Cited By ~ 3

Author(s):

N. J. Gross

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Adult Respiratory Distress Syndrome ◽

Distress Syndrome ◽

Radiation Pneumonitis ◽

Buoyant Density ◽

Lavage Fluid ◽

Exogenous Surfactant ◽

Vitro Model

The accompanying paper [Am. J. Physiol. 260 (Lung Cell. Mol. Physiol. 4): L302-L310, 1991] showed that in the radiation pneumonitis model of adult respiratory distress syndrome (ARDS) there was an excess of the proximate, higher buoyant density subtypes of alveolar surfactant, and a decrease in the light buoyant density form. Because the surfactant subtypes normally evolve from the former to the latter a delay in the alveolar metabolism of surfactant could explain this disproportion. Three possible mechanisms of a delay in surfactant metabolism in radiation pneumonitis were explored using an in vitro model of surfactant subtype metabolism called “cycling”. The first was that the surfactant of mice with radiation pneumonitis was intrinsically less capable of conversion to the light subtype. It was found, however, that the proximate forms of surfactant of mice with radiation pneumonitis were as capable of generating light subtype as those of control mice. The second was that there was a deficit in the serine protease activity, called “convertase”, that mediates the conversion. But it was found that lungs of mice with radiation pneumonitis released convertase activity to the same extent as control lungs. The third was that an inhibitor of convertase activity was present in the alveoli. It was found that the alveolar lavage fluid of mice with radiation pneumonitis inhibited the conversion of exogenous surfactant by exogenous convertase. Moreover, it contained an 18-fold excess of antiprotease activity. The present data are interpreted as suggesting that an inhibitor in the alveolar space is responsible for the delay in surfactant subtype metabolism in radiation pneumonitis, resulting in the disproportion of surfactant subtypes in radiation pneumonitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Unexpected High Mortality Rate Due to Acute Respiratory Distress Syndrome Among Infants with AML Enrolled on JPLSG AML-05 Trial

Blood ◽

10.1182/blood.v116.21.2146.2146 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2146-2146 ◽

Cited By ~ 1

Author(s):

Daisuke Tomizawa ◽

Akiko Moriya Saito ◽

Takashi Taga ◽

Souichi Adachi ◽

Hideki Nakayama ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

De Novo ◽

Conflicts Of Interest ◽

Tumor Lysis Syndrome ◽

Age Groups ◽

The Other ◽

Cell Transplant

Abstract Abstract 2146 Background: Infants (age <1 year) with AML are naturally vulnerable to intensive cytotoxic therapy, however, usually treated with the same protocol as older children with or without dose modification. We report here the unexpected high treatment-related mortality (TRM) mainly due to acute respiratory distress syndrome (ARDS) observed among this age subgroup in the JPLSG AML-05 study. Patients & Methods: AML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, opened on 11/1/2006 for children (age ≤18 years) with de novo AML excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome. The study stratifies patients by the specific cytogenetic characters and treatment response into 3 risk groups. All patients receive two common induction courses; the first induction course (Ind-1), “ECM,” is based on the predecessor trial AML99, consisted of etoposide (150 mg/m2 i.v. on days 1 to 5), Ara-C (200 mg/m2 for 12-hour i.v. on days 6 to 12), mitoxantrone (5 mg/m2 i.v. on days 6 to 10), and a single dose of triple IT on day 6. For patients <2 years old, drug dosages are reduced by calculating on body weight basis. TRM among infants in AML99 was as low as 7.4% (2/27). Nine early deaths (= deaths of any cause before initiating the second induction course) were reported among the first 275 patients enrolled on AML-05, and mortality was exceptionally high in infants (7/32, 21.8%). This prompted suspension of the protocol accrual for this age subgroup on 4/2/2009 and comprehensive review of induction adverse events (AEs) were carried out. Results: Among the 7 early deaths in infants, 4 deaths occurred during Ind-1 phase, and the other 3 after being off protocol therapy due to severe Ind-1 AEs. The causes of deaths were as follows; one of resistant disease, 4 of ARDS, one of interstitial pneumonia, and one of bacterial sepsis after receiving haploidentical stem cell transplant because of prolonged pancytopenia. Among the 4 ARDS cases, two had preceding RS virus infection, and the other 2 developed ARDS during marrow recovery with G-CSF use. We also evaluated grade 3 and 4 AEs in all age groups, of which 248/275 cases were evaluable. When comparing the infant group (N=27) and the older age group (≥ 1 year, N=221), there were no difference in hematological toxicities, however, non-hematological toxicities, such as renal, cardiac, pulmonary, neurological complications, and tumor lysis syndrome were significantly more common in the infant group. Conclusions: Early death rate among infants in AML-05 study was unacceptably high, and we decided to make the following changes to the AML-05: 1) additional dose reduction by 33% in Ind-1 for infants; 2) enhancing supportive care guidelines regarding infection prevention; 3) close prospective monitoring of induction toxic death. The enrollment of infants was re-opened on 8/11/2009, and no fatal cases are observed since then. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

In vitro evaluation of surfactants with eucalyptus oil for respiratory distress syndrome

Respiration Physiology ◽

10.1016/s0034-5687(01)00201-8 ◽

2001 ◽

Vol 126 (2) ◽

pp. 141-151 ◽

Cited By ~ 5

Author(s):

R Banerjee ◽

Jayesh R Bellare

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

In Vitro Evaluation ◽

Eucalyptus Oil

Download Full-text

Assessment of Alveolar Macrophage Dysfunction Using an in vitro Model of Acute Respiratory Distress Syndrome

Frontiers in Medicine ◽

10.3389/fmed.2021.737859 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rahul Y. Mahida ◽

Aaron Scott ◽

Dhruv Parekh ◽

Sebastian T. Lugg ◽

Kylie B. R. Belchamber ◽

...

Keyword(s):

Gene Expression ◽

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Alveolar Macrophage ◽

Distress Syndrome ◽

Lung Resection ◽

Macrophage Dysfunction

Background: Impaired alveolar macrophage (AM) efferocytosis may contribute to acute respiratory distress syndrome (ARDS) pathogenesis; however, studies are limited by the difficulty in obtaining primary AMs from patients with ARDS. Our objective was to determine whether an in vitro model of ARDS can recapitulate the same AM functional defect observed in vivo and be used to further investigate pathophysiological mechanisms.Methods: AMs were isolated from the lung tissue of patients undergoing lobectomy and then treated with pooled bronchoalveolar lavage (BAL) fluid previously collected from patients with ARDS. AM phenotype and effector functions (efferocytosis and phagocytosis) were assessed by flow cytometry. Rac1 gene expression was assessed using quantitative real-time PCR.Results: ARDS BAL treatment of AMs decreased efferocytosis (p = 0.0006) and Rac1 gene expression (p = 0.016); however, bacterial phagocytosis was preserved. Expression of AM efferocytosis receptors MerTK (p = 0.015) and CD206 (p = 0.006) increased, whereas expression of the antiefferocytosis receptor SIRPα decreased following ARDS BAL treatment (p = 0.036). Rho-associated kinase (ROCK) inhibition partially restored AM efferocytosis in an in vitro model of ARDS (p = 0.009).Conclusions: Treatment of lung resection tissue AMs with ARDS BAL fluid induces impairment in efferocytosis similar to that observed in patients with ARDS. However, AM phagocytosis is preserved following ARDS BAL treatment. This specific impairment in AM efferocytosis can be partially restored by inhibition of ROCK. This in vitro model of ARDS is a useful tool to investigate the mechanisms by which the inflammatory alveolar microenvironment of ARDS induces AM dysfunction.

Download Full-text

MiR-124-3p helps to protect against acute respiratory distress syndrome by targeting p65

Bioscience Reports ◽

10.1042/bsr20192132 ◽

2020 ◽

Vol 40 (5) ◽

Cited By ~ 2

Author(s):

Yufeng Liang ◽

Junjie Xie ◽

Di Che ◽

Chunmin Zhang ◽

Yongmin Lin ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Cell Apoptosis ◽

Distress Syndrome ◽

Direct Interaction ◽

Pulmonary Injury ◽

Nr8383 Cells

Abstract Background: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury that has a high mortality rate and leads to substantial healthcare costs. MicroRNA-124-3p (miR-124-3p) helps to suppress inflammation during a pulmonary injury. However, its mechanism of action is largely unknown, and its role in ARDS remains to be determined. Methods: Mice and NR8383 cells were exposed to lipopolysaccharides (LPS) to induce ARDS, and their miR-124-3p levels were determined. After a miRNA agomir was administrated to the mice, their pulmonary injuries were evaluated by H&E staining and assays for peripheral inflammatory cytokine levels. The direct interaction between miR-124-3p and p65 was predicted, and then confirmed by a luciferase activity assay. The role played by miRNA-124-3p in regulating p65 expression was further examined by transfection with its agomir, and its role in cell apoptosis was investigated by observing the effects of miRNA overexpression in vitro and in vivo. Results: After exposure to LPS, there was a consistent decrease in miR-124-3p expression in the lungs of mice and in NR8383 cells. After treatment with the miR-124-3p agomir, the degrees of pulmonary injury (e.g. alveolar hemorrhage and interstitial edema), and the increases in IL-1β, IL-6, and TNF-α levels induced by LPS were significantly attenuated. Overexpression of miR-124-3p in NC8383 cells and lung tissues significantly suppressed LPS-induced p65 expression and cell apoptosis. Conclusions: These results suggest that miR-124-3p directly targeted p65, and thereby decreased the levels of inflammation and pulmonary injury in a mouse model of ARDS.

Download Full-text

Letters to the Editor

PEDIATRICS ◽

10.1542/peds.36.3.452 ◽

1965 ◽

Vol 36 (3) ◽

pp. 452-453

Author(s):

JOHN A. CLEMENTS ◽

MARSHALL H. KLAUS ◽

WILLIAM H. TOOLEY

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

Letters To The Editor ◽

Low Flows ◽

Interesting Possibility ◽

Idiopathic Respiratory Distress Syndrome ◽

Vascular Obstruction ◽

Pulmonary Vascular Obstruction

Dr. Ivanhoe suggests the interesting possibility that pulmonary venoconstriction may be an important feature of the idiopathic respiratory distress syndrome. While our physiological studies are consistent with pulmonary vascular obstruction on either the pre-or postcapillary side, there is evidence that the major obstruction is precapillary. The small pulmonary arterioles in lungs of infants dying with respiratory distress have thick walls and small lumina. When we perfused these lungs in vitro with blood or plasma, very low flows were observed unless pressures in excess of 200 cm of water were applied.

Download Full-text

Alveolar Fluid Clearance in Pathologically Relevant Conditions: In Vitro and In Vivo Models of Acute Respiratory Distress Syndrome

Frontiers in Immunology ◽

10.3389/fimmu.2017.00371 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 17

Author(s):

Laura A. Huppert ◽

Michael A. Matthay

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

Alveolar Fluid Clearance ◽

In Vivo Models

Download Full-text

SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target

Cell Research ◽

10.1038/s41422-021-00519-4 ◽

2021 ◽

Author(s):

Bingqing Xia ◽

Xurui Shen ◽

Yang He ◽

Xiaoyan Pan ◽

Feng-Liang Liu ◽

...

Keyword(s):

Cell Death ◽

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

Dominant Negative ◽

Dominant Negative Mutation ◽

E Protein

AbstractCytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.

Download Full-text