The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance between the pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors pro-inflammatory mediators dictating the development of chronic diffuse lung disease. This review focuses on the mediators that influence this imbalance.

Background: Nitric oxide (NO) is a very reactive agent with potentially toxic oxidation products such as nitrogen dioxide (NO2). Therefore, during NO inhalation a constant inspired concentration and accurate measurement of NO and NO2 concentrations are essential. The objective of this study was to test the NO concentrations at various positions along the inspiratory limb of the breathing circuit using a recently developed system to administer NO in phase with inspiratory flow during mechanical ventilation (Servo 300 NO-A, Siemens, Sweden). Furthermore, we tested whether an active heating system would interfere with inspired NO concentrations. Results: A sharp decline in the NO concentration was found between the respirator's inspiratory outlet and more distal points along the inspiratory limb of the circuit. This finding was most evident when an active heating system was mounted between those points. Conclusions: The concentrations of NO and NO2 should be measured as near to the patient as possible, as significant fluctuations of these concentrations might be found along the inspiratory limb of the respiratory circuit especially when an active heating system is used.

Background The importance of nitric oxide (NO) in hypoxic pulmonary hypertension has been demonstrated using nitric oxide synthase (NOS) knockout mice. In that model NO from endothelial NOS (eNOS) plays a central role in modulating pulmonary vascular tone and attenuating hypoxic pulmonary hypertension. However, the normal regulation of NOS expression in mice following hypoxia is uncertain. Because genetically engineered mice are often utilized in studies of NO, we conducted the present study to determine how hypoxia alters NOS expression in wild-type mice. Method Mice were exposed to sea level, ambient conditions (5280 feet) or severe altitude (17,000 feet) for 6 weeks from birth, and hemodynamics and lung NOS expression were assessed. Results Hypoxic mice developed severe pulmonary hypertension (right ventricular systolic pressure [RVsP] 60 mmHg) as compared with normoxic mice (27 mmHg). Using quantitative reverse-transcription PCR, it was found that expressions of eNOS and inducible NOS (iNOS) increased 1.5-fold and 3.5-fold, respectively, in the lung. In addition, the level of lung eNOS protein was increased, neuronal NOS (nNOS) protein was unchanged, and iNOS was below the limit of detection. Immunohistochemistry demonstrated no change in lung iNOS or nNOS staining in either central or peripheral areas, but suggested increased eNOS in the periphery following hypoxia. Conclusion In mice, hypoxia is associated with increases in lung eNOS, possibly in iNOS, but not in nNOS; this suggests that the pattern of lung NOS expression following hypoxia must be considered in studies using genetically engineered mice.

Background: Recent investigations have shown that leukocyte activation is involved in the pathogenesis of ventilator-associated lung injury. This study was designed to investigate whether the inflammatory responses and deterioration of oxygenation in ventilator-associated lung injury are attenuated by high-frequency oscillatory ventilation (HFO). We analyzed the effects of HFO compared with conventional mechanical ventilation (CMV) on the activation of pulmonary macrophages and neutrophils in 10 female rabbits. Results: After surfactant depletion, the rabbits were ventilated by CMV or HFO at the same mean airway pressure. Surfactant-depletion followed by 4 h mechanical ventilation hindered pulmonary oxygenation in both groups. Impairment of oxygenation was less severe in the HFO group than in the CMV group. In the HFO group the infiltration of granulocytes into alveolar spaces occurred more readily than in the CMV group. Compared with CMV, HFO resulted in greater attenuation of β2-integrin expression, not only on granulocytes, but also on macrophages. Conclusions: In the surfactant-depleted lung, the activation of leukocytes was attenuated by HFO. Reduced inflammatory response correlated with decreased impairment of oxygenation. HFO may reduce lung injury via the attenuation of pulmonary inflammation.

GC-MS chromatograms of silylated samples from the photooxidation of toluene in the presence of NOx showing the secondary origin of nitrophenols. This dataset is associated with the following publication: Khan, F., M. Jaoui, K. Rudziński, K. Kwapiszewska, A. Martinez-Romero, D. Gil-Casanova, M. Lewandowski, T. Kleindienst, J. Offenberg, J.D. Krug, J. Surratt, and R. Szmigielski. Cytotoxicity and Oxidative Stress Induced by Atmospheric Mono-Nitrophenols in Human Lung Cells. ENVIRONMENTAL POLLUTION. Elsevier Science Ltd, New York, NY, USA, 301(15): 119010, (2022).

Introduction The use of low-dose dobutamine to maintain hemodynamic stability in pulmonary hypertension may have a detrimental effect on gas exchange. The aim of this study was to investigate whether inhaled nitric oxide (INO), dobutamine and a combination of the two have beneficial effects in patients with end-stage airway lung disease and pulmonary hypertension. Method Hemodynamic evaluation was assessed 10 min after the administration of each drug and of their combination, in 28 candidates for lung transplantation. Results Administration of INO caused a reduction in mean pulmonary arterial pressure (MPAP), an increase in PaO2 with a significant reduction in venous admixture effect (Qs/Qt).Dobutamine administration caused an increase in cardiac index and MPAP, with a decrease in PaO2 as a result of a higher Qs/Qt. Administration of a combination of the two drugs caused an increase in the cardiac index without MPAP modification and an increase in PaO2 and Qs/Qt. Conclusion Dobutamine and INO have complementary effects on pulmonary circulation. Their association may be beneficial in the treatment of patients with mild to moderate pulmonary hypertension.

Equipment review: Pulmonary uptake and modes of administration of inhaled nitric oxide in mechanically-ventilated patients

Background: The aim of this prospective study was to assess whether the presence of septic shock could influence the dose response to inhaled nitric oxide (NO) in NO-responding patients with adult respiratory distress syndrome (ARDS). Results: Eight patients with ARDS and without septic shock (PaO2 = 95 ± 16 mmHg, PEEP = 0, FiO2 = 1.0), and eight patients with ARDS and septic shock (PaO2 = 88 ± 11 mmHg, PEEP = 0, FiO2 = 1.0) receiving exclusively norepinephrine were studied. All responded to 15 ppm inhaled NO with an increase in PaO2 of at least 40 mmHg, at FiO2 1.0 and PEEP 10 cmH2O. Inspiratory intratracheal NO concentrations were recorded continuously using a fast response time chemiluminescence apparatus. Seven inspiratory NO concentrations were randomly administered: 0.15, 0.45, 1.5, 4.5, 15, 45 and 150 ppm. In both groups, NO induced a dose-dependent decrease in mean pulmonary artery pressure (MPAP), pulmonary vascular resistance index (PVRI), and venous admixture (QVA/QT), and a dose-dependent increase in PaO2/FiO2 (P ≤ 0.012). Dose-response of MPAP and PVRI were similar in both groups with a plateau effect at 4.5 ppm. Dose-response of PaO2/FiO2 was influenced by the presence of septic shock. No plateau effect was observed in patients with septic shock and PaO2/FiO2 increased by 173 ± 37% at 150 ppm. In patients without septic shock, an 82 ± 26% increase in PaO2/FiO2 was observed with a plateau effect obtained at 15 ppm. In both groups, dose-response curves demonstrated a marked interindividual variability and in five patients pulmonary vascular effect and improvement in arterial oxygenation were dissociated. Conclusion: For similar NOinduced decreases in MPAP and PVRI in both groups, the increase in arterial oxygenation was more marked in patients with septic shock.

Background: This study was designed to evaluate the effect of nitric oxide (NO) on the management of neonates with severe persistent pulmonary hypertension refractory to high-frequency oscillatory ventilation. Methods: The birth weight and the gestational age of infants were 3125.5 ± 794 g (mean ± SD) and 39 ± 2.4 weeks, respectively. All neonates were ventilated for an average of 137.5 min (range 90-180 min) prior to NO therapy. The mean oxygenation index (OI) of all neonates prior to NO was 46.3 ± 5 (mean ± SEM). NO was initially administered at 20 parts per million (ppm) for at least 2 h and increased gradually by 2 ppm to a maximum of 80 ppm. Results: Eighteen infants (75%) responded and six (25%) did not respond to the treatment. Three neonates died in the responding group, while all the non-responders died (P = 0.0001). The survival rate was 62.5% among all neonates. NO significantly decreased OI (P < 0.0001) and improved the arterial/alveolar (a/A) oxygen ratio (P < 0.0001) within the first 2 h of NO therapy in 61.1% of the responders. However, the OI and the a/A oxygen ratio remained almost the same throughout the treatment in the non-responders and the non-survivors. Conclusion: Inhaled NO at 20 ppm, following adequate ventilation for 2 h without significant response, could be used to identify the majority of the non-responders in order to seek other alternatives.

Chronic airway inflammation is one of the main features of asthma. Release of mediators from infiltrating inflammatory cells in the airway mucosa has been proposed to contribute directly or indirectly to changes in airway structure and function. The airway smooth muscle, which has been regarded as a contractile component of the airways responding to various mediators and neurotransmitters, has recently been recognised as a rich source of pro-inflammatory cytokines, chemokines and growth factors. In this review, we discuss the role of airway smooth muscle cells in the regulation and perpetuation of airway inflammation that contribute to the pathogenesis of asthma.