Kevin C. Ma

Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease

Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis.

Bronchoscopic intubation is an effective airway strategy in critically ill patients.

Purpose: American Society of Anesthesiologists guidelines recommend the use of bronchoscopic intubation as a rescue technique in critically ill patients. We sought to assess the safety and efficacy of bronchoscopic intubation as an initial approach in critically ill patients. Methods: We performed a retrospective cohort study of patients who underwent endotracheal intubation in the medical intensive care unit of a tertiary urban referral center over 1 academic year. The primary outcome was first‐pass success rate. Measurements and main results: We identified 219 patients who underwent either bronchoscopic (n = 52) or laryngoscopic guided (n = 167) intubation as the initial attempt. There was a higher first‐pass success rate in the bronchoscopic intubation group than in the laryngoscopic group (96% vs 78%; P = .003). The bronchoscopic intubation group had a higher body mass index (28.4 vs 25.9; P = .027) and higher preintubation fraction of inspired oxygen requirement (0.73 ± 0.27 vs 0.63 ± 0.30; P = .044) than the laryngoscopic group. There were no cases of right mainstem intubation, esophageal intubation, or pneumothorax with bronchoscopic intubation. Rates of postintubation hypotension and hypoxemia were similar in both groups. The association with first‐pass success remained with multivariate and propensity matched analysis. Conclusions: Bronchoscopic intubation as an initial strategy in critically ill patients is associated with a higher first‐pass success rate than laryngoscopic intubation, and is not associated with an increase in complications.

Diagnosis and management of latent tuberculosis.

Purpose of review Latent tuberculosis infection (LTBI) may affect over two billion individuals and serves as a potential reservoir for future active tuberculosis. The identification and treatment of LTBI in those at highest risk for progression is an essential part of tuberculosis control. Recent findings Interferon-&ggr; release assays are increasingly used for targeted testing and diagnosis of latent disease. The performance of these immunodiagnostic tests has been studied in various groups and may be better than the tuberculin skin test in certain populations. Ongoing research is focused on new biomarkers that may diagnose LTBI or predict progression to active tuberculosis. Isoniazid preventive treatment is effective at reducing risk of active disease, but length of treatment and potential side-effects limit patient acceptance and compliance. Rifamycin-based regimens are increasingly studied as a shorter and perhaps less toxic alternative for preventive therapy. Summary Identification of those with LTBI is important as it allows treatment of those at highest risk of progression to active disease and thus decreases the overall burden of tuberculosis. The development of new immunodiagnostics may further improve identification of those at risk and alternative medication regimens may increase compliance with and efficacy of preventive therapy.

Carbon monoxide in lung cell physiology and disease

Carbon monoxide (CO) is an endogenously produced gas that has gained recognition as a biological signal transduction effector with properties similar, but not identical, to that of nitric oxide (NO). CO, which binds primarily to heme iron, may activate the hemoprotein guanylate cyclase, although with lower potency than NO. Furthermore, CO can modulate the activities of several cellular signaling molecules such as p38 MAPK, ERK1/2, JNK, Akt, NF-κB, and others. Emerging studies suggest that mitochondria, the energy-generating organelle of cells, represent a key target of CO action in eukaryotes. Dose-dependent modulation of mitochondrial function by CO can result in alteration of mitochondrial membrane potential, mitochondrial reactive oxygen species production, release of proapoptotic and proinflammatory mediators, as well as the inhibition of respiration at high concentration. CO, through modulation of signaling pathways, can impact key biological processes including autophagy, mitochondrial biogenesis, programmed cell death (apoptosis), cellular proliferation, inflammation, and innate immune responses. Inhaled CO is widely known as an inhalation hazard due to its rapid complexation with hemoglobin, resulting in impaired oxygen delivery to tissues and hypoxemia. Despite systemic and cellular toxicity at high concentrations, CO has demonstrated cyto- and tissue-protective effects at low concentration in animal models of organ injury and disease. These include models of acute lung injury (e.g., hyperoxia, hypoxia, ischemia-reperfusion, mechanical ventilation, bleomycin) and sepsis. The success of CO as a candidate therapeutic in preclinical models suggests potential clinical application in inflammatory and proliferative disorders, which is currently under evaluation in clinical trials.

RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury

In patients requiring ventilator support, mechanical ventilation (MV) may induce acute lung injury (ventilator-induced lung injury [VILI]). VILI is associated with substantial morbidity and mortality in mechanically ventilated patients with and without acute respiratory distress syndrome. At the cellular level, VILI induces necrotic cell death. However, the contribution of necroptosis, a programmed form of necrotic cell death regulated by receptor-interacting protein-3 kinase (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), to the development of VILI remains unexplored. Here, we show that plasma levels of RIPK3, but not MLKL, were higher in patients with MV (i.e., those prone to VILI) than in patients without MV (i.e., those less likely to have VILI) in two large intensive care unit cohorts. In mice, RIPK3 deficiency, but not MLKL deficiency, ameliorated VILI. In both humans and mice, VILI was associated with impaired fatty acid oxidation (FAO), but in mice this association was not observed under conditions of RIPK3 deficiency. These findings suggest that FAO-dependent RIPK3 mediates pathogenesis of acute lung injury.

Autophagy and Obesity-Related Lung Disease

Obesity-related disease is a significant source of premature death and economic burden globally. It is also a common comorbidity in patients suffering from lung disease, affecting both severity and treatment success. However, this complex association between obesity and the lung is poorly understood. Autophagy is a self-recycling homeostatic process that has been linked to beneficial or deleterious effects, depending on the specific lung disease. Obesity affects autophagy in a tissue-specific manner, activating autophagy in adipocytes and impairing autophagy in hepatocytes, immune cells, and pancreatic β-cells, among others. Obesity is also characterized by chronic low-grade inflammation that can be modulated by the pro- and antiinflammatory effects of the autophagic machinery. Scant evidence exists regarding the impact of autophagy in obesity-related lung diseases, but there are communal pathways that could be related to disease pathogenesis. Important signaling molecules in obesity, including IL-17, leptin, adiponectin, NLRP3 inflammasome, and TLR-4, have been implicated in the pathogenesis of lung disease. These mediators are known to be modulated by autophagy activity. In this perspective, we highlight the recent advances in the understanding of autophagy in obesity-related conditions, as well as the potential mechanisms that can link autophagy and obesity in the pathogenesis of lung disease.

RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction

Sepsis causes acute kidney injury (AKI) in critically ill patients, although the pathophysiology remains unclear. The receptor-interacting protein kinase-3 (RIPK3), a cardinal regulator of necroptosis, has recently been implicated in the pathogenesis of human disease. In mice subjected to polymicrobial sepsis, we demonstrate that RIPK3 promotes sepsis-induced AKI. Utilizing genetic deletion and biochemical approaches in vitro and in vivo, we identify a potentially novel pathway by which RIPK3 aggravates kidney tubular injury independently of the classical mixed lineage kinase domain-like protein-dependent (MLKL-dependent) necroptosis pathway. In kidney tubular epithelial cells, we show that RIPK3 promotes oxidative stress and mitochondrial dysfunction involving upregulation of NADPH oxidase-4 (NOX4) and inhibition of mitochondrial complex I and -III, and that RIPK3 and NOX4 are critical for kidney tubular injury in vivo. Furthermore, we demonstrate that RIPK3 is required for increased mitochondrial translocation of NOX4 in response to proinflammatory stimuli, by a mechanism involving protein-protein interactions. Finally, we observed elevated urinary and plasma RIPK3 levels in human patients with sepsis-induced AKI, representing potential markers of this condition. In conclusion, we identify a pathway by which RIPK3 promotes kidney tubular injury via mitochondrial dysfunction, independently of MLKL, which may represent a promising therapeutic target in sepsis-induced AKI.

Beclin-1 regulates cigarette smoke–induced kidney injury in a murine model of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD), associated with cigarette smoke-induced (CS-induced) emphysema, contributes significantly to the global health care burden of disease. Although chronic kidney disease (CKD) may occur in patients with COPD, the relationship between COPD and CKD remains unclear. Using a murine model of experimental COPD, we show that chronic CS exposure resulted in marked kidney injury and fibrosis, as evidenced by histological and ultrastructural changes, altered macrophage subpopulations, and expression of tissue injury, fibrosis, and oxidative stress markers. CS induced mitochondrial dysfunction, and increased autophagic flux in kidney tissues and in kidney tubular epithelial (HK-2) cells, as determined by LC3B turnover assays. Mice heterozygous for Beclin-1 (Becn1+/-) were protected from the development of kidney tissue injury and renal fibrosis in response to CS exposure, and displayed impaired basal and inducible mitochondrial turnover by mitophagy. Interestingly, CS caused a reduction of Beclin-1 expression in mouse kidneys and kidney tubular epithelial cells, attributed to increased autophagy-dependent turnover of Beclin-1. These results suggest that Beclin-1 is required for CS-induced kidney injury and that reduced levels of Beclin-1 may confer renoprotection. These results identify the kidney as a target for CS-induced injury in COPD and the Beclin-1-dependent autophagy pathway as a potential therapeutic target in CKD.

Circulating RIPK3 levels are associated with mortality and organ failure during critical illness

BACKGROUND Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. METHODS Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data. RESULTS In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure. CONCLUSIONS Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure. FUNDING Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

Reduct: A Puzzle Game for Children About Evaluating Code

We present Reduct, a puzzle game to teach programming language semantics to novices, especially children. Unlike previous puzzle games, Reduct gamifies the actual evaluation steps involved in executing code. Players discover behavior of language constructs through play by evaluating code snippets towards a goal. The game progression covers several basic concepts of JavaScript ES2015, including functions, Booleans, ternary conditionals, arrays, Array.map(), variables, and more. To help reduce self-handicapping behavior, code representations begin in a concrete form and fade to abstract notation over time.