Reinitiation of compensatory lung growth after subsequent lung resection

ObjectiveIn experimental animals, pneumonectomy results in rapid, hyperplastic compensatory growth of the remaining lung. The limits of this induced growth are unknown. We tested the hypothesis that compensatory growth can be reinitiated in the same lung after subsequent lung resection.MethodsA left thoracotomy (Sham group) or left pneumonectomy (PNX group) was performed in Sprague–Dawley rats. A third group underwent left pneumonectomy followed 4 weeks later by a bilobectomy of the right upper and middle lobes (PNX+LBX group). Four weeks after bilobectomy in the PNX+LBX group (8 weeks in the Sham and PNX groups), right ventricular pressures were measured by using the open chest technique, and total lung weight and lower plus cardiac lobe weight indices were measured. Lungs were inflation fixed at 25 cm H2O to measure lobe volume index and to perform morphometric measurements on lung sections. Right ventricle/left ventricle plus septum weight index was measured as another index of pulmonary hypertension.ResultsTotal lung weight index was similar in all groups. Pneumonectomy resulted in increased lower plus cardiac lobe weight and volume indices, which were significantly augmented in the PNX+LBX group. The PNX+LBX group underwent a significant increase in total volume of respiratory region, airspace, and tissue and a decrease in alveolar surface density versus the PNX group. The PNX+LBX group also had significantly increased right ventricular systolic pressure and right ventricle/left ventricle plus septum index.ConclusionThese results demonstrate that compensatory growth can be reinitiated in lungs that had previously undergone postpneumonectomy compensatory growth. This subsequent growth, however, is more hypertrophic, and pulmonary hypertension develops despite subsequent compensatory growth

Adenosine A1 receptor activation attenuates lung ischemia–reperfusion injury

ObjectivesIschemia–reperfusion injury contributes significantly to morbidity and mortality in lung transplant patients. Currently, no therapeutic agents are clinically available to prevent ischemia–reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury by binding to various adenosine receptors; however, the role of the adenosine A1 receptor in ischemia–reperfusion injury and inflammation is not well understood. The present study tested the hypothesis that selective, exogenous activation of the A1 receptor would be anti-inflammatory and attenuate lung ischemia–reperfusion injury.MethodsWild-type and A1 receptor knockout mice underwent 1 hour of left lung ischemia and 2 hours of reperfusion using an in vivo hilar clamp model. An A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine, was administered 5 minutes before ischemia. After reperfusion, lung function was evaluated by measuring airway resistance, pulmonary compliance, and pulmonary artery pressure. The wet/dry weight ratio was used to assess edema. The myeloperoxidase and cytokine levels in bronchoalveolar lavage fluid were measured to determine the presence of neutrophil infiltration and inflammation.ResultsIn the wild-type mice, 2-chloro-N6-cyclopentyladenosine significantly improved lung function and attenuated edema, cytokine expression, and myeloperoxidase levels compared with the vehicle-treated mice after ischemia–reperfusion. The incidence of lung ischemia–reperfusion injury was similar in the A1 receptor knockout and wild-type mice; and 2-chloro-N6-cyclopentyladenosine had no effects in the A1 receptor knockout mice. In vitro treatment of neutrophils with 2-chloro-N6-cyclopentyladenosine significantly reduced chemotaxis.ConclusionsExogenous A1 receptor activation improves lung function and decreases inflammation, edema, and neutrophil chemotaxis after ischemia and reperfusion. These results suggest a potential therapeutic application for A1 receptor agonists for the prevention of lung ischemia–reperfusion injury after transplantation

Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity

BACKGROUND: The pathogenesis of HIV-1 glycoprotein 120 (gp120) associated neuroglial toxicity remains unresolved, but oxidative injury has been widely implicated as a contributing factor. In previous studies, exposure of primary human central nervous system tissue cultures to gp120 led to a simplification of neuronal dendritic elements as well as astrocytic hypertrophy and hyperplasia; neuropathological features of HIV-1-associated dementia. Gp120 and proinflammatory cytokines upregulate inducible nitric oxide synthase (iNOS), an important source of nitric oxide (NO) and nitrosative stress. Because ascorbate scavenges reactive nitrogen and oxygen species, we studied the effect of ascorbate supplementation on iNOS expression as well as the neuronal and glial structural changes associated with gp120 exposure. METHODS: Human CNS cultures were derived from 16–18 week gestation post-mortem fetal brain. Cultures were incubated with 400 μM ascorbate-2-O-phosphate (Asc-p) or vehicle for 18 hours then exposed to 1 nM gp120 for 24 hours. The expression of iNOS and neuronal (MAP2) and astrocytic (GFAP) structural proteins was examined by immunohistochemistry and immunofluorescence using confocal scanning laser microscopy (CSLM). RESULTS: Following gp120 exposure iNOS was markedly upregulated from undetectable levels at baseline. Double label CSLM studies revealed astrocytes to be the prime source of iNOS with rare neurons expressing iNOS. This upregulation was attenuated by the preincubation with Asc-p, which raised the intracellular concentration of ascorbate. Astrocytic hypertrophy and neuronal injury caused by gp120 were also prevented by preincubation with ascorbate. CONCLUSIONS: Ascorbate supplementation prevents the deleterious upregulation of iNOS and associated neuronal and astrocytic protein expression and structural changes caused by gp120 in human brain cell cultures

Tissue-derived proinflammatory effect of adenosine A2B receptor in lung ischemia–reperfusion injury

ObjectiveIschemia–reperfusion injury after lung transplantation remains a major source of morbidity and mortality. Adenosine receptors have been implicated in both pro- and anti-inflammatory roles in ischemia–reperfusion injury. This study tests the hypothesis that the adenosine A2B receptor exacerbates the proinflammatory response to lung ischemia–reperfusion injury.MethodsAn in vivo left lung hilar clamp model of ischemia–reperfusion was used in wild-type C57BL6 and adenosine A2B receptor knockout mice, and in chimeras created by bone marrow transplantation between wild-type and adenosine A2B receptor knockout mice. Mice underwent sham surgery or lung ischemia–reperfusion (1 hour ischemia and 2 hours reperfusion). At the end of reperfusion, lung function was assessed using an isolated buffer-perfused lung system. Lung inflammation was assessed by measuring proinflammatory cytokine levels in bronchoalveolar lavage fluid, and neutrophil infiltration was assessed via myeloperoxidase levels in lung tissue.ResultsCompared with wild-type mice, lungs of adenosine A2B receptor knockout mice were significantly protected after ischemia–reperfusion, as evidenced by significantly reduced pulmonary artery pressure, increased lung compliance, decreased myeloperoxidase, and reduced proinflammatory cytokine levels (tumor necrosis factor-α; interleukin-6; keratinocyte chemoattractant; regulated on activation, normal T-cell expressed and secreted; and monocyte chemotactic protein-1). Adenosine A2B receptor knockout→adenosine A2B receptor knockout (donor→recipient) and wild-type→ adenosine A2B receptor knockout, but not adenosine A2B receptor knockout→wild-type, chimeras showed significantly improved lung function after ischemia–reperfusion.ConclusionsThese results suggest that the adenosine A2B receptor plays an important role in mediating lung inflammation after ischemia–reperfusion by stimulating cytokine production and neutrophil chemotaxis. The proinflammatory effects of adenosine A2B receptor seem to be derived by adenosine A2B receptor activation primarily on resident pulmonary cells and not bone marrow-derived cells. Adenosine A2B receptor may provide a therapeutic target for prevention of ischemia–reperfusion-related graft dysfunction in lung transplant recipients

Consideration of pannexin 1 channels in covid-19 pathology and treatment

Copyright © 2020 the American Physiological Society Pannexin 1 (PANX1) is a ubiquitously expressed, channel-forming protein found in a number of tissues throughout the body (e.g., lung, vasculature, liver, central nervous system, immune system) that is important in many key physiological and immune responses (18, 55). PANX1 channels passively flux ATP (predominantly), multiple metabolites, and likely other small anions (37, 39). PANX1 channels regulate inflammation and host responses to several pathogens, including viruses (36, 42, 53). While there is currently no evidence suggesting novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and PANX1 directly interact, there is an urgent need for therapeutic strategies, especially those targeting the hyperinflammation and cytokine storm that occurs in severe cases of COVID-19 (27, 41). Here we argue that PANX1, and drugs known to target PANX1 (including the FDA-approved drug probenecid), should be the focus of further investigation in the context of SARS-CoV-2 infection and its associated pathology in COVID-19 patients

Autocrine Regulation of Pulmonary Inflammation by Effector T-Cell Derived IL-10 during Infection with Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) infection is the leading viral cause of severe lower respiratory tract illness in young infants. Clinical studies have documented that certain polymorphisms in the gene encoding the regulatory cytokine IL-10 are associated with the development of severe bronchiolitis in RSV infected infants. Here, we examined the role of IL-10 in a murine model of primary RSV infection and found that high levels of IL-10 are produced in the respiratory tract by anti-viral effector T cells at the onset of the adaptive immune response. We demonstrated that the function of the effector T cell -derived IL-10 in vivo is to limit the excess pulmonary inflammation and thereby to maintain critical lung function. We further identify a novel mechanism by which effector T cell-derived IL-10 controls excess inflammation by feedback inhibition through engagement of the IL-10 receptor on the antiviral effector T cells. Our findings suggest a potentially critical role of effector T cell-derived IL-10 in controlling disease severity in clinical RSV infection