Research progress of megakaryocytes and platelets in lung injury.

The lung is an important site of extramedullary platelet formation, and megakaryocytes in the lung participate in immune responses in addition to platelet production. In acute lung injury and chronic lung injury, megakaryocytes and platelets play a promoting or protective role through different mechanisms. The authors reviewed the role of megakaryocytes and platelets in common clinical lung injuries with different course of disease and different pathogenic factors in order to provide new thinking for the diagnosis and treatment of lung injuries.

What is the context?Platelets are specialized non-nucleated blood cells produced by cytoplasmic lysis of megakaryocytes.HSCs differentiate into granular mature megakaryocytes and produce platelets.Lung is a reservoir of megakaryocytes and a site where platelets are produced in addition to bone marrow and spleen.Lung injury can be divided into acute lung injury and chronic lung injury, and characterized by different pathogenesis.Platelets and megakaryocytes are involved in hemostasis and regulation of the body 's inflammatory response.The disease state of the lung affects the functions of megakaryocytes and platelets.The role of megakaryocytes and platelets in acute and chronic lung injury is poorly studied.What is new?Platelets in the lung are derived not only from the spleen and bone marrow, but also from megakaryocytes in the pulmonary circulation. In this study, we demonstrated that pulmonary megakaryocytes not only produce platelets to play a hemostatic role in lung injury, but also participate in inflammation and immune response with platelets to promote the process of lung injury or play a protective role.Therefore, it was suggested in our analysis that targeting lung megakaryocytes and platelets is currently a new direction for the treatment of a variety of lung injuries.What is the impact?This review intends to explain the relationship between megakaryocytes, platelets and many types of lung injury from the mechanism of platelet production in the lung, and make a prospect in the new progress in the diagnosis and treatment of lung injury.

CT Quantification of Interstitial Lung Abnormalities and Changes of Agerelated Pathomorphology.

BACKGROUND: Interstitial lung abnormalities (ILA) are associated with further disease progression, increased mortality risk, and decline in lung function in the elderly, which deserves enough attention. OBJECTIVE: The objective of this study was to quantify the extent of interstitial lung abnormalities (ILA) in a non-smoking asymptomatic urban cohort in China using low-dose CT (LDCT) and to analyze the age-related pathological changes. METHODS: We retrospectively analyzed clinical data and chest LDCT images from a cohort of 733 subjects who were categorized into 3 groups: 18-39, 40-59, and ≥60 years old according to age. Furthermore, we selected 40 cases of wax-embedded lung tissue blocks archived after pulmonary bullectomy and the same age groups were categorized. Four representative CT signs of ILA, including interlobular septal thickening (ILST), intralobular interstitial thickening (ILIT), ground-glass opacity (GGO), and reticular shadow (RS), were semi-quantified based on the percentage of the affected area. The scores and distribution of four CT signs of ILA were compared between different sex and age groups. The age-related pathological changes were analyzed. RESULTS: The ILA findings were found predominantly in the lower lobes and the subpleural region. The semi-quantitative scores of four CT signs in all subjects under 40 were 0. However, in subjects over 40 years old, the scores gradually increased with age, although most of them remained low. The size of the alveoli increased, the number of alveoli decreased, the alveolar septum became thinner, and the number of ATII cells increased with age. A statistically significant difference was observed among the different age groups (χ2=50.624, P=0.033; χ2=80.000, P=0.043; χ2=33.833, P=0.000; χ2=13.525, P=0.031). The macrophage population and the percentage of collagen fibers in the alveolar septum increased, while the percentage of elastic fibers decreased with age. There was no significant difference among the different age groups (χ2=19.817, P=0.506; χ2=52.419, P=0. 682; χ2=54.868, P=0.518). CONCLUSION: When the four CT signs mentioned above are in the upper central area, and the score has a medium or high score, it is crucial to determine the underlying pathological causes. ILA may be the result of chronic lung injury.

HSP70 Is a Critical Regulator of HSP90 Inhibitor's Effectiveness in Preventing HCl-Induced Chronic Lung Injury and Pulmonary Fibrosis.

Exposure to hydrochloric acid (HCl) can provoke acute and chronic lung injury. Because of its extensive production for industrial use, frequent accidental exposures occur, making HCl one of the top five chemicals causing inhalation injuries. There are no Food and Drug Administration (FDA)-approved treatments for HCl exposure. Heat shock protein 90 (HSP90) inhibitors modulate transforming growth factor-ß (TGF-ß) signaling and the development of chemical-induced pulmonary fibrosis. However, little is known on the role of Heat Shock Protein 70 (HSP70) during injury and treatment with HSP90 inhibitors. We hypothesized that administration of geranylgeranyl-acetone (GGA), an HSP70 inducer, or gefitinib (GFT), an HSP70 suppressant, alone or in combination with the HSP90 inhibitor, TAS-116, would improve or worsen, respectively, HCl-induced chronic lung injury in vivo and endothelial barrier dysfunction in vitro. GGA, alone, improved HCl-induced human lung microvascular endothelial cells (HLMVEC) barrier dysfunction and, in combination with TAS-116, improved the protective effect of TAS-116. In mice, GGA reduced HCl toxicity and while TAS-116 alone blocked HCl-induced chronic lung injury, co-administration with GGA, resulted in further improvement. Conversely, GFT potentiated HCl-induced barrier dysfunction and impaired the antidotal effects of TAS-116. We conclude that combined treatments with HSP90 inhibitors and HSP70 inducers may represent a novel therapeutic approach to manage HCl-induced chronic lung injury and pulmonary fibrosis.

Inhibition of Fatty Acid Amide Hydrolase (FAAH) Regulates NF-kb Pathways Reducing Bleomycin-Induced Chronic Lung Inflammation and Pulmonary Fibrosis.

The deadly interstitial lung condition known as idiopathic pulmonary fibrosis (IPF) worsens over time and for no apparent reason. The traditional therapy approaches for IPF, which include corticosteroids and immunomodulatory drugs, are often ineffective and can have noticeable side effects. The endocannabinoids are hydrolyzed by a membrane protein called fatty acid amide hydrolase (FAAH). Increasing endogenous levels of endocannabinoid by pharmacologically inhibiting FAAH results in numerous analgesic advantages in a variety of experimental models for pre-clinical pain and inflammation. In our study, we mimicked IPF by administering intratracheal bleomycin, and we administered oral URB878 at a dose of 5 mg/kg. The histological changes, cell infiltration, pro-inflammatory cytokine production, inflammation, and nitrosative stress caused by bleomycin were all reduced by URB878. Our data clearly demonstrate for the first time that the inhibition of FAAH activity was able to counteract not only the histological alteration bleomycin-induced but also the cascade of related inflammatory events.

A rare case of silicosis with hepatitis B infection.

Introduction: Silicosis is a type of diffuse interstitial lung disease caused by inhalation of crystalline silicon dioxide. The number of silicosis cases have been rapidly increasing over the years. Complete cure is not possible so early diagnosis and prevention is required. Case presentation: Our patient came with chief complaints of productive cough, breathlessness progressing to MRC grade 4 and fever. He worked in a flour mill for 15 years and has been symptomatic for the past 4-5 years. Chest examination showed tracheal deviation to the right, bilateral decreased breath sounds and fine crepitations. Chest X ray showed multiple tiny nodular opacities in all lung zones. Pulmonary function test confirmed restrictive lung disease. On CT scan, miliary mottled densities were noted bilaterally along with fibrosis in upper lobes and ground glass appearance in lower lobes. Echocardiography revealed mild pericardial effusion and Abdominal Ultrasound revealed coarse liver texture, splenomegaly and right sided pleural effusion. Patient was also Hepatitis B positive.Patient was treated with Prednisolone, Entecavir, Moxaclav along with symptomatic management. Discussion: Male gender, HIV infection, Smoking, Occupation, Age at first exposure, Duration of exposure and Concentration of inhaled silica dust are the risk factors of silicosis. Individuals with Silicosis are at high risk of developing Tuberculosis and Hepatitis B infection. Pulmonary function test, HRCT and Lung biopsies help in diagnosis of Silicosis. Serological markers and Liver Function Test helps in diagnosis of Hepatitis B infection. Early diagnosis and prevention is essential for better prognosis and Lung transplant is the only definitive management. Complications like progressive fibrosis, infections, cor pulmonale and pneumothorax may result due to Silicosis. Conclusion: Silicosis is a rare chronic inflammatory condition which leads to an immunosuppressed state and may predispose individuals to opportunistic conditions like Hepatitis B. Therefore, early identification of risk factors and clinical features is required.

Imbalance of alveolar epithelial type I and type â ¡ cells in lipopolysaccharide-induced chronic lung injury young mouse model.

Children are susceptible to pneumonia, which affects their growth and development. Immune disorders and unrepaired alveolar mucosal epithelium following pneumonia cause chronic lung injury. The mechanism of chronic lung injury is unknown and lacks animal models for reference. Therefore, we developed a chronic lung injury young mouse model to simulate the pathological process of children. 3-week-old mice were intratracheal instillation of lipopolysaccharide (LPS) every other day for six weeks. Consequently, the histopathology showed damaged integrity of lung tissue, fibrosis, and abnormally distributed alveolar epithelial cells. The total protein concentration in bronchoalveolar lavage fluid (BALF) was increased, alveolar epithelial type (AT) I cells were abnormal distribution, and AT II cells were reduced. The phosphorylation levels of IKBα and the expression levels of NF-κB p65 in lung tissue were up-regulated. In serum and BALF, the IL-6 was oversecretion, nitric oxide (NO) and superoxide dismutase (SOD) were perturbed secretion, oxidative stress imbalance. In addition, blood viscosity, plasma viscosity, and erythrocyte sedimentation rate (ESR) indexes in hemorheology were increased. In conclusion, it is feasible to construct the mouse model of chronic lung injury, and AT I and AT Ⅱ cells were imbalanced, which paves the way for further investigations on the pathogenesis of chronic lung injury and the efficacy of novel treatments.

Pathophysiological Role of Vimentin Intermediate Filaments in Lung Diseases.

Vimentin intermediate filaments, a type III intermediate filament, are among the most widely studied IFs and are found abundantly in mesenchymal cells. Vimentin intermediate filaments localize primarily in the cytoplasm but can also be found on the cell surface and extracellular space. The cytoplasmic vimentin is well-recognized for its role in providing mechanical strength and regulating cell migration, adhesion, and division. The post-translationally modified forms of Vimentin intermediate filaments have several implications in host-pathogen interactions, cancers, and non-malignant lung diseases. This review will analyze the role of vimentin beyond just the epithelial to mesenchymal transition (EMT) marker highlighting its role as a regulator of host-pathogen interactions and signaling pathways for the pathophysiology of various lung diseases. In addition, we will also examine the clinically relevant anti-vimentin compounds and antibodies that could potentially interfere with the pathogenic role of Vimentin intermediate filaments in lung disease.

Açaí (Euterpe Oleraceae Mart.) Seeds Regulate NF-κB and Nrf2/ARE Pathways Protecting Lung against Acute and Chronic Inflammation.

BACKGROUND/AIMS: Respiratory diseases are the world's biggest cause of mortality and disability. Specific nutrients have been proposed to positively affect disease progression as novel therapy alternatives to glucocorticosteroids. There has been a lot of attention in the possible health advantages of dietary assumption of Açai Seeds, popular native fruit found in the Amazon region which is rich in bioactive compounds. Until today nobody investigated the beneficial property of Açai Seeds administration in lung disease. METHODS: In our study we use two model of lung disease: for acute lung disease we use an intrapleural injection of Carrageenan; for chronic disease we used an intratracheal instillation of bleomycin. Açai Seeds was administered orally dissolved in saline. RESULTS: We found that Açai Seeds was able to reduce histological alteration, cells infiltration, pro inflammatory cytokine release, inflammation, and oxidative stress in both acute and chronic model of lung disease. CONCLUSION: Our data clearly demonstrate for the first time that Açai Seeds administration was useful against lung disease by the reduction of NF-κB nuclear translocation and by the stimulation of Nrf2/ARE pathways promoting the physiological antioxidant defense.

Adenosine at the Interphase of Hypoxia and Inflammation in Lung Injury.

Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine signaling to inhibit the inflammatory response in ARDS, while in chronic lung diseases, it promotes inflammation and tissue injury. In this review, we discuss the role of adenosine at the interphase of hypoxia and inflammation in ARDS and chronic lung diseases, as well as the current strategy for therapeutic targeting of the adenosine signaling pathway.

Autoimmune Biomarkers, Antibodies, and Immunologic Evaluation of the Patient with Fibrotic Lung Disease.

This review summarizes the current state of knowledge on experimental and clinical biomarkers of autoimmunity and aims to highlight important aspects of the immunologic evaluation of a patient with fibrotic lung disease.

Acute exposure of mice to hydrochloric acid leads to the development of chronic lung injury and pulmonary fibrosis.

Objective: Accidental exposure to hydrochloric acid (HCl) is associated with acute lung injury in humans, development of long-term chronic airway obstruction, and fibrosis. However, the mechanisms responsible for the progression to pulmonary fibrosis remain unclear. We utilized a mouse model of progressive lung injury from a single exposure to HCl to investigate the effects of HCl on the lower respiratory tract. Materials and methods: HCl (0.05-0.3 N) or saline was injected intratracheally into male C57Bl/6J mice. At 1, 4, 10 and 30 days post instillation, bronchoalveolar lavage fluid (BALF) and lung tissues were collected and examined for multiple outcomes. Results and discussion: We observed an early inflammatory response and a late mild inflammation present even at 30 d post HCl exposure. Mice treated with HCl exhibited higher total leukocyte and protein levels in the BALF compared to the vehicle group. This was characterized by increased number of neutrophils, monocytes, and lymphocytes as well as pro-inflammatory cytokines during the first 4 d of injury. The late inflammatory response exhibited a predominant presence of mononuclear cells, increased permeability to protein, and higher levels of the pro-fibrotic mediator TGFß. Pro-fibrotic protein biomarkers, phosphorylated ERK, and HSP90, were also overexpressed at 10 and 30 d following HCl exposure. In vivo lung function measurements demonstrated lung dysfunction and chronic lung injury associated with increased lung hydroxyproline content and increased expression of extracellular matrix (ECM) proteins. The acute inflammation and severity of fibrosis increased in HCl-concentration dependent manner. Conclusions: Our findings suggest that the initial inflammatory response and pro-fibrotic biomarker upregulation may be linked to the progression of pulmonary fibrosis and airway dysfunction and may represent valuable therapeutic targets.

Bronchopulmonary Dysplasia: Where Have All the Stem Cells Gone?: Origin and (Potential) Function of Resident Lung Stem Cells.

Celebrating its 50th anniversary in 2017, bronchopulmonary dysplasia (BPD)-the chronic lung disease of prematurity that follows ventilator and oxygen therapy for acute respiratory failure-remains the most frequent complication of extreme prematurity. Survival of premature infants born at increasingly earlier stages of gestation has made the prevention of lung injury increasingly challenging. BPD is postulated to be a misdirection of many functions in the developing lung, including growth factor signalling and matrix as well as cellular composition, resulting in impaired alveolar and lung vascular growth. Despite improvements in understanding the mechanisms that regulate normal lung development, BPD remains without therapies. Insights into stem cell biology have identified the repair potential of stem cells. Promising preclinical studies demonstrated the lung protective effects of stem cell-based therapies in animal models mimicking BPD, leading to early-phase clinical trials. Although the time is ripe to conduct well-designed early-phase clinical trials, much more needs to be learned about the biology of these cells to develop safe, efficient, high-quality, clinical-grade cell products. Stem cells are essential for normal organ development, maintenance, and repair. It is therefore biologically plausible that exhaustion/dysfunction of resident lung stem cells contributes to the inability of the immature lung to repair itself. Understanding how normal lung stem cells function and how these cells are perturbed in BPD may prove useful in designing superior cell products with enhanced repair capabilities to ensure the successful translation of basic research into clinical practice.

Simvastatin prevents and reverses chronic pulmonary hypertension in newborn rats via pleiotropic inhibition of RhoA signaling.

Chronic neonatal pulmonary hypertension (PHT) frequently results in early death. Systemically administered Rho-kinase (ROCK) inhibitors prevent and reverse chronic PHT in neonatal rats, but at the cost of severe adverse effects, including systemic hypotension and growth restriction. Simvastatin has pleiotropic inhibitory effects on isoprenoid intermediates that may limit activity of RhoA, which signals upstream of ROCK. We therefore hypothesized that statin treatment would safely limit pulmonary vascular RhoA activity and prevent and reverse experimental chronic neonatal PHT via downstream inhibitory effects on pathological ROCK activity. Sprague-Dawley rats in normoxia (room air) or moderate normobaric hypoxia (13% O2) received simvastatin (2 mg·kg-1·day-1 ip) or vehicle from postnatal days 1-14 (prevention protocol) or from days 14-21 (rescue protocol). Chronic hypoxia increased RhoA and ROCK activity in lung tissue. Simvastatin reduced lung content of the isoprenoid intermediate farnesyl pyrophosphate and decreased RhoA/ROCK signaling in the hypoxia-exposed lung. Preventive or rescue treatment of chronic hypoxia-exposed animals with simvastatin decreased pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary arterial remodeling. Preventive simvastatin treatment improved weight gain, did not lower systemic blood pressure, and did not cause apparent toxic effects on skeletal muscle, liver or brain. Rescue therapy with simvastatin improved exercise capacity. We conclude that simvastatin limits RhoA/ROCK activity in the chronic hypoxia-exposed lung, thus preventing or ameliorating hemodynamic and structural markers of chronic PHT and improving long-term outcome, without causing adverse effects.

Alveolar-like Stem Cell-derived Myb(-) Macrophages Promote Recovery and Survival in Airway Disease.

RATIONALE: Abnormal alveolar macrophages (AM) are found in chronic obstructive pulmonary disease, asthma, cystic fibrosis, and adenosine deaminase deficiency (ADA(-/-)). There is no specific treatment strategy to compensate for these innate immune abnormalities. Recent findings suggest AMs are of early embryonic or fetal origin. Pluripotent stem cells (PSCs) as a source of embryonic-derived AMs for therapeutic use in acute and chronic airway diseases has yet to be investigated. OBJECTIVES: To determine if embryonic Myb(-/-) alveolar-like macrophages have therapeutic value on pulmonary transplantation in acute and chronic airway diseases. METHODS: Directed differentiation of murine PSCs was used in factor-defined media to produce expandable embryonic macrophages conditioned to an alveolar-like phenotype with granulocyte-macrophage colony-stimulating factor. AMs were partially depleted in mice to create an acute lung injury. To model a chronic lung disease, ADA(-/-) mice were used. Alveolar-like macrophages were intratracheally transplanted to the injured animals and therapeutic potential was determined. MEASUREMENTS AND MAIN RESULTS: The differentiation protocol is highly efficient and adaptable to human PSCs. The PSC macrophages are phenotypically like AMs both functionally and by ligand marker characterization. They engulf bacteria and apoptotic cells and are better phagocytes than bone marrow-derived macrophages. In vivo, these macrophages remain in healthy airways for at least 4 weeks, can engulf neutrophils during acute lung injury, enhance pulmonary tissue repair, and promote survival in ADA(-/-) mice. Animals receiving the macrophages do not develop abnormal pathology or teratomas. CONCLUSIONS: PSCs are a reliable source to produce therapeutically active alveolar-like macrophages to treat airway disease.

Prior cardiac surgery is independently associated with decreased survival following infant tracheostomy.

INTRODUCTION: Previous reports have demonstrated that prior cardiac surgery is independently associated with in-hospital mortality after infant tracheostomy. We aimed to determine whether these infants would continue to be at increased risk for death following hospital discharge. METHODS: A retrospective review was performed on subjects < 2 y of age who recovered from tracheostomy in the pediatric ICU at our institution between January 2007 and December 2011, with follow-up to December 2013. Survival to 1 y following tracheostomy was the primary outcome variable for the study. Multivariate Cox regression analysis was then performed to determine independent risk factors for death after infant tracheostomy. RESULTS: Forty-two subjects met inclusion criteria, 18 of whom had undergone prior cardiac surgery. Twenty-six subjects (62%) were alive at 1 y post-tracheostomy. Age at tracheostomy, concomitant genetic abnormalities or prematurity, and ventilator dependence at discharge were not statistically different between survivors and those who died. Subjects who died, however, were more likely to have had cardiac surgery prior to tracheostomy (11 [69%] vs 7 [27%], P = .008) and had longer hospital stay (median 3.4 months [interquartile range: 2.6-4.6] vs 2.2 months [interquartile range: 1.1-3.5], P = .045). Multivariate Cox regression analysis revealed only prior cardiac surgery to be independently associated with decreased survival after tracheostomy (hazard ratio 4.7, 95% CI 1.3-16.4, P = .02). CONCLUSIONS: Prior cardiac surgery is independently associated with decreased survival within 1 y following tracheostomy. Clinicians and families of infants with prior cardiac surgery in whom tracheostomy after cardiac surgery is deemed necessary should consider this risk when planning long-term care.