Inhaled GM-CSF for Pulmonary Alveolar Proteinosis

Tazawa, Ryushi; Ueda, Takahiro; Abe, Mitsuhiro; Tatsumi, Koichiro; Eda, Ryosuke; Kondoh, Shotaro; Morimoto, Konosuke; Tanaka, Takeshi; Yamaguchi, Etsuro; Takahashi, A; Oda, Miku; Ishii, Haruyuki; Izumi, Shinyu; Sugiyama, Haruhito; Nakagawa, Atsushi; Tomii, Keisuke; Suzuki, Masaru; Konno, Satoshi; Ohkouchi, Shinya; Tode, Naoki; Handa, Tomohiro; Hirai, Toyohiro; Inoue, Yoshikazu; Arai, Toru; Asakawa, Katsuaki; Sakagami, Takuro; Hashimoto, Atsushi; Tanaka, Takahiro; Takada, Toshinori; Mikami, Ayako; Kitamura, Nobuto; Nakata, Koh

doi:10.1056/nejmoa1816216

Cited by 119 publications

(120 citation statements)

References 26 publications

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“…In SARS-CoV-2 affected lung, production of the surfactant proteins are found to be deregulated (Figure 8) Considering all these, lung surfactants might be useful in the treatment of COVID-19 patients, as lung surfactant replacement therapies were previously reported to be successful in other respiratory infections and acute lung injury to reduce the lung damage of the patients [104,108,109] and also our analysis found it as an alternative from enrichment of related process deregulated genes (data not shown). Also, other drugs like-respiratory stimulants for COPD [110], sargramostim for treating pulmonary alveolar proteinosis [111], and oseltamivir in curing influenza-related lower respiratory tract complications [112] showed potential improvements in lung's and respiratory system's overall condition. Further in vitro and invivo research may be turn out to be useful for the patients who cannot tolerate painful ventilator.…”

Section: Discussionmentioning

confidence: 99%

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

Islam

Khan

2020

Preprint

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Clinical management of COVID-19 is still complicated due to the lack of therapeutic interventions to reduce the breathing problems, respiratory complications and acute lung injury -which are the major complications of most of the mild to critically affected patients and the molecular mechanisms behind these clinical features are still largely unknown. In this study, we have used the RNA-seq gene expression pattern in the COVID-19 affected lung biopsy cells and compared it with the effects observed in typical cell lines infected with SARS-CoV-2 and SARS-CoV. We performed functional overrepresentation analyses using these differentially expressed genes to signify the processes/pathways which could be deregulated during SARS-CoV-2 infection resulting in the symptomatic impairments observed in COVID-19. Our results showed that the significantly altered processes include inflammatory responses, antiviral cytokine signaling, interferon responses, and interleukin signaling etc. along with downmodulated processes related to lung's functionality likeresponses to hypoxia, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism. We also found that the viral protein interacting host's proteins involved in similar pathways like: respiratory failure, lung diseases, asthma, and hypoxia responses etc., suggesting viral proteins might be deregulating the processes related to acute lung injury/breathing complications in COVID-19 patients. Protein-protein interaction networks of these processes and map of gene expression of deregulated genes revealed that several viral proteins can directly or indirectly modulate the host genes/proteins of those lung related processes along with several host transcription factors and miRNAs. Surfactant proteins and their regulators SPD, SPC, TTF1 etc. which maintains the stability of the pulmonary tissue are found to be downregulated through viral NSP5, NSP12 that could lead to deficient gaseous exchange by the surface films. Mitochondrial dysfunction owing to the aberration of NDUFA10, NDUFAF5, SAMM50 etc. by NSP12; abnormal thrombosis in lungs through atypical PLAT, EGR1 functions by viral ORF8, NSP12; dulled hypoxia responses due to unusual shift in HIF-1 downstream signaling might be the causative elements behind the acute lung injury in COVID-19 patients. Our study put forward a distinct mechanism of probable virus induced lung damage apart from cytokine storm and advocate the need of further research for alternate therapy in this direction.

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Section: Discussionmentioning

confidence: 99%

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

Islam

Khan

2020

Preprint

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“…In previous studies, inhaled GM-CSF treatment was prescribed in patients with moderate to severe disease [15][16][17][18][19], and the mean PaO 2 level in a large prospective study of inhaled GM-CSF treatment on aPAP patients is 61.7 ± 1.4 mmHg [11]. During preparation of our manuscript, a randomized placebo-controlled study of inhaled GM-CSF was published, A-aDO 2 and CT density quantitative measurement were significantly improved though they concluded that clinical benefits were not significant [20]. The major differences in design between our study and Tazawa However, Tazawa, et al has answered this question with a randomized placebo-controlled study.…”

Section: Discussionmentioning

confidence: 99%

Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a phase II randomized study for 6 months and follow-up to 24 months

Tian

Yang

Chen

et al. 2020

Preprint

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Abstract Background: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by inhaled granulocyte-macrophage colony stimulating factor (GM-CSF) is considered safe and effective. Evidences of benefit from GM-CSG inhalation for mild to moderate aPAP patients are limited. Methods: In this multicenter, randomized, open-labeled clinical trial, 36 aPAP patients with mild to moderate disease severity were randomized into either GM-CSF treatment group or control group. Inhaled GM-CSF was prescribed for 6 months, and patients were followed-up for another 18 months without treatment. Physiological features of the patients were analyzed.Results: There were 36 patients (19 in treatment group, 17 in control group) included. No significant difference in primary endpoints measured by the change of alveolar arterial oxygen gradient (A-aDO2) from the baseline value to the values obtained during treatment or during the following 18-month non-treatment observation period [control group vs. treatment group: 0.51±12.09 mmHg vs. -0.35±13.76 mmHg, p=0.848 (3 month); 1.85±11.21 mmHg vs. 7.31±8.81 mmHg, p=0.146 (6 months); 6.05±11.14 mmHg vs. 6.61±10.64mmHg, p=0.899 (24 months)]). Percentage of diffusion capacity predicted (DLCO%) and percentage of total lung capacity predicted (TLC%), however, were significantly improved in the treatment group at the end of the study (P=0.010 and 0.027). St. George Respiratory questionnaire (SGRQ) scores were better after 6 months treatment with GM-CSF than control group, and the benefits of treatment were maintained throughout the observation period. No severe side effects were observed during the study. Conclusion: Six months of inhaled GM-CSF treatment had no effect on the alveolar–arterial oxygen gradient in patients with mild to moderate pulmonary alveolar proteinosis. There were changes in some clinical or laboratory measures, but no clinically important changes were noted at the end of study.

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“…In the context of anti-GM-CSF autoAb production, exogenous GM-CSF administration leads to the production of polyclonal anti-GM-CSF autoAbs with different functions [71,78]. Previous reports have evaluated the activity of each monoclonal GM-CSF autoAb derived from B cells in aPAP patients, and two mechanisms have been considered: neutralization or depletion of GM-CSF, regarding the pathogenicity of anti-GM-CSF autoAbs [70,79]. By clarifying what induces a selective clone of anti-GM-CSF autoAbs to be pathogenic, it may be possible to predict outcomes and discover new drugs.…”

Section: Autoimmune Pulmonary Alveolar Proteinosismentioning

confidence: 99%

“…Third, there are only a few treatment options, such as whole lung lavage and inhaled GM-CSF therapy. The high invasiveness of whole lung lavage may be problematic to perform, and inhaled GM-CSF treatment is not standardized because it is currently being investigated in clinical trials and its beneficial effects in terms of clinical outcomes have not been determined [79,82].…”

Section: Autoimmune Pulmonary Alveolar Proteinosismentioning

confidence: 99%

Natural Autoantibodies in Chronic Pulmonary Diseases

Fukushima

Tsujino

Futami

et al. 2020

IJMS

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In autoantibody-mediated autoimmune diseases, pathogenic autoantibodies generated by a failure of central or peripheral tolerance, have different effects mediated by a variety of mechanisms. Interestingly, even non-autoimmune chronic diseases have a set of disease-specific natural autoantibodies that are maintained for a long time. Because most of these natural autoantibodies target intracellular proteins or long non-coding RNAs, they are speculated to be non-pathological and have some important as yet unrecognized physiological functions such as debris clearance. Recently, we revealed a set of disease-specific natural autoantibodies of chronic pulmonary diseases with unknown etiology by protein arrays that enable detection of specific autoantibodies against >8000 targets. Surprisingly, some of the targeted antigens of disease-specific autoantibodies were subsequently reported by other laboratories as strongly associated with the disease, suggesting that these antigens reflect the pathology of each disease. Furthermore, some of these autoantibodies that target extracellular antigens might modify the original course of each disease. Here, we review the disease-specific natural autoantibodies of chronic pulmonary diseases, including chronic fibrosing idiopathic interstitial pneumonias, sarcoidosis, and autoimmune pulmonary alveolar proteinosis, and discuss their utility and effects.

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Inhaled GM-CSF for Pulmonary Alveolar Proteinosis

Cited by 119 publications

References 26 publications

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a phase II randomized study for 6 months and follow-up to 24 months

Natural Autoantibodies in Chronic Pulmonary Diseases

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