TUMOR NECROSIS FACTOR- AND LUNG INJURY BY ISCHEMIA AND REPERFUSION

Khimenko et al. (p. 2005) examined the role of tumor necrosis factor- (TNF-) in pulmonary ischemia-reperfusion injury. In isolated rat lungs, reperfusion after 90 min of ischemia led to an increased capillary filtration coefficient (K_fc), a measure of lung injury, and the appearance of TNF- in the perfusate. The increase in K_fc was prevented by pretreatment of the rats with an anti-TNF- antibody. Addition of TNF- to the perfusate did not increase K_fc in the absence of ischemia but exacerbated the response to ischemia and reperfusion. The results suggest that TNF- plays an important role in the ischemia-reperfusion injury process. The paper is discussed in an Invited Editorial by Al-Mehdi and Fisher (p. 2003).

	IS MAXIMAL AIRWAY RESPONSIVENESS A VALID CONCEPT?

Normal subjects, when challenged with bronchoconstrictor aerosols, often reach a maximal response, which does not increase even when high concentrations of agonists are used. In contrast, asthmatic patients with hyperresponsive airways often show progressive bronchoconstriction with increasing agonist concentrations. Brown and Mitzner (p. 2012) examined this phenomenon by using high-resolution computed tomography to visualize canine airways narrowed by conventional methacholine aerosol challenge or by local atomization of methacholine in individual airways. In both cases, the response was progressive, without evidence of a dose-response plateau. The apparent plateau seen in clinical testing may reflect limitations in the delivery of high concentrations of agonists via aerosol and the effects of progressive airway constriction on aerosol penetration and deposition.

	VASCULAR RESPONSES TO HYPERCAPNIA AND ACIDOSIS

Sweeney et al. (p. 2040) examined the response of isolated rat pulmonary arterial and aortic rings to isohydric hypercapnia or normocapnic acidosis and the role of the endothelium in these responses. The vessels were precontracted with phenylephrine. Pulmonary arterial ring tension was not significantly affected by isohydric hypercapnia with or without an intact endothelium. Normocapnic acidosis caused an endothelium-independent relaxation of the pulmonary arterial rings. Isohydric hypercapnia produced an endothelium-dependent relaxation of the aortic rings. Normocapnic acidosis relaxed the aortic rings, and removal of the endothelium augmented the relaxation. Thus the studies point to the potential importance of the endothelium in understanding the role of hypercapnia and acidosis on pulmonary vascular tone.

	OVARIAN CYCLE INFLUENCES SYMPATHETIC RESPONSES TO EXERCISE

Does cellular metabolism influence the ovarian cycle and contribute to gender-related differences in the exercise pressor reflex? Ettinger et al. (p. 2075) report that muscle sympathetic nerve activity (MSNA) in response to static handgrip at 30% maximum voluntary contraction was greater during the menstrual than follicular phase of the cycle. During ischemic rhythmic handgrip exercise, a cycle phase effect was not observed for MSNA or for intracellular metabolism assessed by nuclear magnetic resonance. This suggests that blood flow is necessary for the phase effect and that factors other than cellular by-product concentrations contribute to the effects of ovarian cycle phase on MSNA.

	UNEVEN VENTILATION AND AEROSOL DISPERSION

The primary function of the lungs is O₂ and CO₂ exchange. The most important process that can interfere with this is nonuniform distribution of ventilation and blood flow. Although gas molecules such as O₂ and CO₂ are much lighter than 0.5-µm aerosol particles, both gases and aerosols have long been used to estimate ventilatory inhomogeneity. Brown et al. (p. 2112) have used a gas (xenon) and an aerosol (0.5- µm triphenyl phosphate) together to determine the extent to which aerosol distribution is influenced by the factors causing xenon-detected ventilatory inhomogeneity. Aerosol dispersion was not related to xenon parameters in normal subjects, but strong correlations were seen in patients with cystic fibrosis, in whom heterogeneity was, as expected, much greater. Aerosols can be designed in a wide range of sizes mimicking various foreign inhalants, and it would be interesting to compare aerosol- and gas-dispersion indexes over a range of particle sizes.

	ROLE OF RESPIRATORY ALKALOSIS IN HYPOXIC VENTILATORY ACCLIMATIZATION

Tansley and colleagues (p. 2125) have used a unique hypoxic-exposure system with precise control of end-tidal PCO₂ to investigate the role of respiratory alkalosis in two key features of acclimatization to hypoxia, namely, the increased hypoxic ventilatory response and the continued hyperventilation with acute hyperoxia. Both of these indexes of acclimatization occurred over 48 h of exposure to moderate hypoxia, whether the end-tidal PCO₂ was held constant or allowed to fall. The data suggest that ventilatory acclimatization occurs whether or not respiratory alkalosis accompanies hypoxic exposure.

	REDUCED ABDOMINAL CONTRIBUTION TO VT DURING HYPERCAPNIA IN REM SLEEP

The erratic tachypneic breathing pattern typical of rapid-eye-movement (REM) sleep has been further investigated in humans during CO₂ breathing by Schäfer and Schläfke (p. 2213). These authors identified a shortened expiratory duration (TE) as a primary cause of the tachypneic pattern during normocapnia; tidal volume (VT) was reduced due to decreased rib cage excursion. During CO₂ breathing, REM sleep caused further shortening of TE and a greater reduction of VT secondary to reduced abdominal excursion. These findings implicate reduced diaphragmatic activity as a major cause of reduced VT during CO₂ breathing in REM sleep.

	LEPTIN AND LUNG DEVELOPMENT

Genetically obese (ob/ob) mice exhibit respiratory abnormalities that are similar to those found in obese humans. Leptin, a protein product of the ob gene, is a potent satiety factor that reduces food intake and prevents body weight gain when administered to ob/ob mice. Tankersley et al. (p. 2261) examined the pattern of breathing and lung compliance in ob/ob mice treated daily with recombinant leptin or with inert vehicle. Leptin replacement controlled body weight and prevented the development of the rapid breathing and reduced lung compliance that are characteristic of the obese phenotype. The results suggest a physiological role for leptin in the normal development of respiratory structure and function.

	REGIONAL ALVEOLAR VENTILATION AND BLOOD FLOW AFTER PULMONARY EMBOLISM

In methodologically linked companion papers, Altemeier et al. (p. 2337 and p. 2344) examine the ability of inhaled and perfused microspheres to measure regional ventilation and blood flow, respectively, before and after pulmonary vascular embolization. Comparisons to simultaneous measurement with the multiple inert-gas elimination technique revealed that the microsphere approach does not capture all of the heterogeneity, presumably because of limited spatial resolution. On the other hand, the general pattern of the gas-exchange response to embolism could be identified with microspheres, confirming that ventilation-perfusion mismatch and redistribution of blood flow, in particular, explain the hypoxemia of experimental pulmonary arterial obstruction.