Guanylyl cyclase activation reverses resistive breathing–induced lung injury and inflammation

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure–volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC–cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases

MAPKs and NF-kappa B differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress

Sigala I, Zacharatos P, Toumpanakis D, Michailidou T, Noussia O, Theocharis S, Roussos C, Papapetropoulos A, Vassilakopoulos T. MAPKs and NF-kappa B differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress. Am J Physiol Regul Integr Comp Physiol 300: R1152-R1162, 2011. First published February 16, 2011; doi:10.1152/ajpregu.00376.2010.-Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-kappa B and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-kappa B (BAY-11-7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-kappa B, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-alpha, IL-10, IL-2, IL-1 beta) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-kappa B. Inhibition of NF-kappa B and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-kappa B/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-kappa B/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-kappa B. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-kappa B independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm

Acute life-threatening cardiac tamponade in a mechanically ventilated patient with COVID-19 pneumonia

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently evolved as a pandemic disease. Although the respiratory system is predominantly affected, cardiovascular complications have been frequently identified, including acute myocarditis, myocardial infarction, acute heart failure, arrhythmias and venous thromboembolic events. Pericardial disease has been rarely reported. We present a case of acute life-threatening cardiac tamponade caused by a small pericardial effusion in a mechanically ventilated patient with severe COVID-19 associated pneumonia. The patient presented acute circulatory collapse with hemodynamic features of cardiogenic or obstructive shock. Bedside echocardiography permitted prompt diagnosis and life-saving pericardiocentesis. Further investigation revealed no other apparent cause of pericardial effusion except for SARS-CoV-2 infection. Cardiac tamponade may complicate COVID-19 and should be included in the differential diagnosis of acute hemodynamic deterioration in mechanically ventilated COVID-19 patients

Inspiratory Resistive Breathing Induces Acute Lung Injury

Rationale Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation. Objectives: To determine the effects of resistive breathing on the healthy lung. Methods: Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing. Measurements and Main Results: After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by Tc-99m-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and I kappa B alpha (nuclear factor-kappa B inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing. Conclusions: Resistive breathing induces acute lung injury and inflammation