Endostatin and vascular endothelial cell growth factor (VEGF) in piglet lungs: effect of inhaled nitric oxide and hyperoxia

Pulmonary hyperoxic injury manifests as widespread alveolar-epithelial and microvascular endothelial cell necrosis, resolution of which requires angiogenesis. We investigated the hypothesis that inhaled nitric oxide (iNO) and hyperoxia each decreases lung vascular endothelial growth factor (VEGF) expression but increases endostatin and that concurrent administration of both gases will show a greater effect. Piglets were randomized to breathe for 5 d room air (RA); RA + NO (RA + 50 ppm NO), O(2) (hyperoxia, F(I)O(2) >0.96), O(2) + NO, or O(2) + NO + REC (O(2) + NO plus recovery in 50% O(2) for 72 h. After the piglets were killed, we measured lung capillary leak, VEGF mRNA, VEGF, and endostatin protein in homogenates, plasma, and lavage. VEGF mRNA decreased significantly with O(2) and O(2) + NO compared with breathing RA (p < or = 0.05). VEGF protein declined in the experimental groups with a significant reduction in the recovery group compared with the RA group (p < or = 0.05). Similar but more dramatic, endostatin declined in all groups relative to the RA group (p < 0.001). Lavage fluid VEGF protein and lung capillary leak rose significantly with O(2) and O(2) + NO compared with RA, but endostatin was unchanged. At 72 h of recovery from hyperoxia, VEGF mRNA and lavage fluid VEGF but not lung VEGF protein had normalized. Hyperoxia and iNO suppresses lung endostatin expression, but iNO unlike hyperoxia alone does not alter lung VEGF production. Hyperoxia paradoxically raises lavageable VEGF levels. This latter effect and that on VEGF mRNA level but not protein is abrogated by recovery in reduced F(I)O(2) for 72 h.     

Endogenous production of nitric oxide in endotoxemic piglets

We sought to assess the relation between endotoxin-induced pulmonary hypertension and the production of nitric oxide (NO) in neonatal animals. Adult animals respond to endotoxin by increasing exhaled NO and plasma NO metabolites. The response of neonatal animals has not previously been reported. We administered 20 microg/kg of Escherichia coli lipopolysaccharide (LPS) to 12- to 18-day-old and to 5- to 7-week-old piglets. Pulmonary vascular resistance increased significantly in both age groups. Exhaled NO in the 12- to 18-day-old animals and in the 5- to 7-week-old piglets did not increase significantly. A similarly treated group of adult rats did show a significant increase in exhaled NO (2.6 +/- 1.0 to 109.5 +/- 54.3 ppb; p = 0.028). Plasma NO metabolite measurements followed the same pattern of no increase in both porcine groups, and a large increase in the rat group. However, immunostaining of lungs from 12- to 18-day-old piglets did reveal an increase in inducible NO synthase. These results suggest that piglets demonstrate a limited ability to modulate LPS-induced pulmonary hypertension by elevations in exhaled NO. They also demonstrate the differential response to LPS between species.     

Neonatal complications of preterm premature rupture of membranes. Pathophysiology and management

Midtrimester PROM is an infrequent, yet potentially disastrous complication of pregnancy. The most likely neonatal complication is preterm delivery with associated morbidity and mortality risks. Unique neonatal complications following PPROM include skeletal deformations and pulmonary hypoplasia related to prolonged oligohydramnios exposure. A systematic approach to an infant with respiratory insufficiency following PPROM delivery is possible with an understanding of the pathophysiology of pulmonary hypoplasia. Neonatal management should include immediate resuscitation including surfactant replacement, with careful attention to techniques of mechanical ventilation to avoid early volutrauma. Adjunctive therapies directed at pulmonary hypertension may now permit survival of some infants with less severe forms of pulmonary hypoplasia.     

Serum plasminogen and lung surfactant in the respiratory distress syndrome

Plasminogen, total protein, and surface-active material were measured in amniotic fluid in 112 pregnancies at 11-42 weeks' gestation. In 65 of these pregnancies, cord blood was also analyzed for serum plasminogen and total protein. Plasminogen was detected in 25 of 114 amniotic fluid samples, and 23 came from pregnancies of less than 37 weeks' gestation. Plasminogen was found in 15 of 32 amniotic fluid samples from pregnancies with complications, but only in 10 of 80 "uncomplicated" pregnancies. The mean cord serum plasminogen was relatively constant in births or abortuses of 17 to 30 weeks' gestation, but was present in increasing amounts in births of gestational ages from 30 to 40 weeks. The concentration of plasminogen in cord serum was directly related to the cord total protein (r = 0.7513, P less than 0.001). The cord plasminogen concentration was significantly higher in infants with a positive foam stability test (5.6 +/- 0.3 mg/100 ml) than in the combined group of infants with negative and intermediate tests (4.3 +/- 0.16, P less than 0.005). However, infants with a positive foam stability also had a significantly greater gestational age than infants with a negative or intermediate foam stability test. With one exception, infants with a low cord plasminogen (below 4 mg/100 ml) developed respiratory distress syndrome (RDS) only if amniotic fluid surfactant was low. The data suggest that low levels of serum plasminogen are correlated with severe lung disease only in the presence of surfactant deficiency.     

Early and Rapid Identification of COVID-19 Patients with Neutralizing Type I Interferon Auto-antibodies

Journal of Clinical Immunology - Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable...     

High-dose inhaled nitric oxide and hyperoxia increases lung collagen accumulation in piglets

Nitric oxide (NO), a pro-oxidant gas, is used with hyperoxia (O(2)) to treat neonatal pulmonary hypertension and recently bronchopulmonary dysplasia, but great concerns remain regarding NO's potential toxicity. Based on reports that exposure to oxidant gases results in pulmonary extracellular matrix injury associated with elevated lavage fluid levels of extracellular matrix components, we hypothesized that inhaled NO with or without hyperoxia will have the same effect. We measured alveolar septal width, lung collagen content, lavage fluid hydroxyproline, hyaluronan and laminin levels in neonatal piglets after 5 days' exposure to room air (RA), RA + 50 ppm NO (RA + NO), O(2) (FiO(2) > 0.96) or O(2) + NO. Matrix metalloproteinase (MMP) activity and MMP-2 mRNA were also measured. In recovery experiments, we measured lung collagen content in piglets exposed to RA + NO or O(2) + NO and then allowed to recover for 3 days. The results show that lung collagen increased 4-fold in the RA + NO piglets, the O(2) and O(2) + NO groups had only a 2-fold elevation relative to RA controls. Unlike the RA + NO piglets, the O(2) and O(2) + NO groups had more than 20-fold elevation in lung lavage fluid hydroxyproline compared to the RA group. O(2) and O(2) + NO also had increased lung MMP activity, extravascular water, and lavage fluid proteins. MMP-2 mRNA levels were unchanged. After 3 days' recovery in room air, the RA + NO groups' lung collagen had declined from 4-fold to 2-fold above the RA group values. The O(2) + NO group did not decline. Alveolar septal width increased significantly only in the O(2) and O(2) + NO groups. We conclude that 5 days' exposure to NO does not result in pulmonary matrix degradation but instead significantly increases lung collagen content. This effect appears potentially reversible. In contrast, hyperoxia exposure with or without NO results in pulmonary matrix degradation and increased lung collagen content. The observation that NO increased lung collagen content represents a new finding and suggests NO could potentially induce pulmonary fibrosis.     

Kr-81m ventilation imaging: clinical utility in suspected pulmonary embolism

The results of Kr-81m/Tc-99m ventilation-perfusion (VP) lung scintigraphy were correlated with the results of pulmonary angiography for 74 patients suspected of having pulmonary embolism (PE). Among patients having a diagnostic scan, the sensitivity and specificity of scintigraphy were 91% and 94%, respectively. Also, 157 consecutive cases of Kr-81m/Tc-99m VP lung scintigraphy were reviewed, and the frequency of an indeterminate scan was found to be 22%. A similar frequency was found for VP scintigraphy with xenon-133. Of eight patients who had indeterminate scans due to the presence of a single VP mismatch, four were demonstrated to have PE by angiography. Kr-81m is an excellent agent for VP scanning in cases of suspected PE, offering accuracy in diagnosis as well as favorable physical properties.