Pulmonary and systemic circulatory responses elicited by hyperosmotic solutions injected into the bronchial artery

In open chest anaesthetized dogs the haemodynamic effects of solutions of equal hyperosmolarity (viz. NaHCO3 8%, NaCl k.6%, and glucose 34.3%, solutions) given into the bronchial artery were studied. Administration of any of these solutions directly into the bronchial artery resulted in increased cardiac output, stroke volume, bronchial blood flow, and bronchial fraction of the cardiac output, and decreased heart rate and bronchial as well as pulmonary vascular resistances. When given into the pulmonary circulation, the same solutions evoked similar reactions of smaller magnitude. To exclude the effect of major surgical trauma and the open-chest condition, another experimental model closer to the physiological situation was also developed. In this preparation NaHCO3 failed to produce the above haemodynamic response even when given into the bronchial artery. After a one-hour bleeding period resulting in a drop of arterial blood pressure to 40 mmHg, while using the same preparation, the administration f NaHCO3 solution into the bronchial artery caused a significant rise in blood pressure in both the systemic and pulmonary arteries. In these experiments a correlation was found between arterial oxygen tension and the extent of change in blood pressure. The exact mechanism of action of the observed haemodynamic changes is still not clear. However, it is likely that receptors localized in the area of the bronchial circulation and sensitive to hypoxia might have played a role in the development of the haemodynamic effects described.     

Fetal circulatory responses to oxygen lack.

The knowledge on fetal and neonatal circulatory physiology accumulated by basic scientists and clinicians over the years has contributed considerably to the recent decline of perinatal morbidity and mortality. This review will summarize the peculiarities of the fetal circulation, the distribution of organ blood flow during normoxemia, and that during oxygen lack caused by various experimental perturbations. Furthermore, the relation between oxygen delivery and tissue metabolism during oxygen lack as well as evidence to support a new concept will be presented along with the principal cardiovascular mechanisms involved. Finally, blood flow and oxygen delivery to the principal fetal organs will be examined and discussed in relation to organ function. The fetal circulatory response to hypoxemia and asphyxia is a centralization of blood flow in favour of the brain, heart, and adrenals and at the expense of almost all peripheral organs, particularly of the lungs, carcass, skin and scalp. This response is qualitatively similar but quantitatively different under various experimental conditions. However, at the nadir of severe acute asphyxia the circulatory centralization cannot be maintained. Then there is circulatory decentralization, and the fetus will experience severe brain damage if not expire unless immediate resuscitation occurs. Future work in this field will have to concentrate on the important questions, what factors determine this collapse of circulatory compensating mechanisms in the fetus, how does it relate to neuronal damage, and how can the fetal brain be pharmacologically protected against the adverse effects of asphyxia.     

Genetic basis of murine responses to hyperoxia-induced lung injury

To evaluate the effect of genetic background on oxygen (O₂) toxicity, nine genetically diverse mouse strains (129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ) were exposed to more than 99% O₂ for 72 h. Immediately following the hyperoxic challenge, the mouse strains demonstrated distinct pathophysiologic responses. The BALB/cJ and CAST/Ei strains, which were the only strains to demonstrate mortality from the hyperoxic challenges, were also the only strains to display significant neutrophil infiltration into their lower respiratory tract. In addition, the O₂-challenged BALB/cJ and CAST/Ei mice were among six strains (A/J, BALB/cJ, CAST/Ei, BTBR+(T)/tf/tf, DBA/2J, and C3H/HeJ) that had significantly increased interleukin 6 concentrations in the whole lung lavage fluid and were among all but one strain that had large increases in lung permeability compared with air-exposed controls. In contrast, the DBA/2J strain was the only strain not to have any significant alterations in lung permeability following hyperoxic challenge. The expression of the extracellular matrix proteins, including collagens I, III, and IV, fibronectin I, and tenascin C, also varied markedly among the mouse strains, as did the activities of total superoxide dismutase (SOD) and manganese-SOD (Mn-SOD or SOD2). These data suggest that the response to O₂ depends, in part, on the genetic background and that some of the strains analyzed can be used to identify specific loci and genes underlying the response to O₂.     

Pulmonary and extrapulmonary acute lung injury: inflammatory and ultrastructural analyses.

To test whether pulmonary and extrapulmonary acute lung injury (ALI) of identical mechanical compromise would express diverse morphological patterns and immunological pathways. For this purpose, a model of pulmonary (p) and extrapulmonary (exp) ALI with similar functional changes was developed and pulmonary morphology (light and electron microscopy), cytokines levels, and neutrophilic infiltration in the bronchoalveolar lavage fluid (BALF), elastic and collagen fiber content in the alveolar septa, and neutrophil apoptosis in the lung parenchyma were analyzed. BALB/c mice were divided into four groups. In control groups, saline was intratracheally (it, 0.05 ml) instilled and intraperitoneally (ip, 0.5 ml) injected, respectively. In the ALIp and ALIexp groups, mice received E. coli lipopolysaccharide (10 microg it and 125 microg ip, respectively). The changes in lung resistive and viscoelastic pressures and in static elastance, alveolar collapse, and cell content in lung tissue were similar in the ALIp and ALIexp groups. The ALIp group presented a threefold increase in KC (murine function homolog to IL-8) and IL-10 levels in the BALF in relation to ALIexp, whereas IL-6 level showed a twofold increase in ALIp. Neutrophils in the BALF were more frequent in ALIp than in ALIexp. ALIp showed more extensive injury of alveolar epithelium, intact capillary endothelium, and apoptotic neutrophils, whereas the ALIexp group presented interstitial edema and intact type I and II cells and endothelial layer. In conclusion, given the same pulmonary mechanical dysfunction independently of the etiology of ALI, insult in pulmonary epithelium yielded more pronounced inflammatory responses, which induce ultrastructural morphological changes.     

Linking lung function and inflammatory responses in ventilator-induced lung injury

Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.     

Pulmonary lymphatics and edema accumulation after brief lung injury

In a past study of hyperoxia-induced lung injury, the extensive lymphatic filling could have resulted from lymphatic proliferation or simple lymphatic recruitment. This study sought to determine whether brief lung injury could produce similar changes, to show which lymphatic compartments fill with edema, and to compare their three-dimensional structure. Tracheostomized rats were ventilated at high tidal volume (12-16 ml) or low tidal volume (3-5 ml) or allowed to breathe spontaneously for 25 min. Light microscopy showed more perivascular, interlobular septal, and alveolar edema in the animals ventilated at high tidal volume (P < 0.0001). Scanning electron microscopy of lymphatic casts showed extensive filling of the perivascular lymphatics in the group ventilated at high tidal volume (P < 0.01), but lymphatic filling was greater in the nonventilated group than in the group that was ventilated at low tidal volume (P < 0.01). The three-dimensional structures of the cast interlobular and perivascular lymphatics were similar. There was little filling and no difference in pleural lymphatic casts among the three groups. More edema accumulated in the surrounding lymphatics of larger blood vessels than smaller blood vessels. Brief high-tidal-volume lung injury caused pulmonary edema similar to that caused by chronic hyperoxic lung injury, except it was largely restricted to perivascular and septal lymphatics and prelymphatic spaces.     

Pulmonary responses to phospholipase A2 in the perfused guinea pig lung

We examined the effect of phospholipase A2 (PLA2; Naja naja) challenge on pulmonary hemodynamics, airway constriction, and fluid filtration in isolated Ringer-perfused guinea pig lungs. Intratracheal PLA2 (10-100 U) produced dose-dependent increases in pulmonary arterial pressure, intratracheal pressure, and lung weight, although intravenous PLA2 administration had no effect on monitored variables. Morphological features indicative of airway constriction and pulmonary edema were observed by light microscopy. PLA2-induced increases in intratracheal pressure and/or lung weight were attenuated to varying degrees by pretreatment with indomethacin (1 microM, a cyclooxygenase inhibitor), ICI-198,615 (1 microM, a leukotriene D4 receptor antagonist), and WEB 2086 (1 microM, a platelet-activating factor antagonist). PLA2-induced increases in pulmonary arterial pressure and intratracheal pressure were also reduced in lungs removed from animals pretreated with dexamethasone (50 mg/kg ip for 2 days; a steroidal antiinflammatory agent). Pyrilamine (1 microM, a histamine1-receptor antagonist) and Takeda AA861 (1 microM, a delta 5-lipoxygenase inhibitor) did not produce significant inhibitory effects on PLA2-induced pathophysiological changes. Intratracheal instillation of high-dose platelet-activating factor (50 micrograms) or lysophosphatidylcholine (100 micrograms) produced gradual increases in intratracheal pressure and lung weight, but these changes were not as large as those induced by PLA2. Thus these studies suggest that resident cell populations associated with airways may play an important role in PLA2-induced pathophysiological changes in the perfused guinea pig lung. These PLA2-induced effects are most likely partially mediated by generation of eicosanoids and platelet-activating factor.     

Pulmonary microvascular responses to arachidonic acid in isolated perfused guinea pig lung

We examined the effects of arachidonic acid (AA) on pulmonary hemodynamics and fluid balance in Ringer- and blood-perfused guinea pig lungs during constant-flow conditions. Mean pulmonary arterial (Ppa), venous (Pv), and capillary pressures (Pcap, estimated by the double-occlusion method) were measured, and arterial (Ra) and venous resistances (Rv) were calculated. Bolus AA injection (500 micrograms) caused transient increases (peak response 1 min post-AA) in Ppa, Pcap, and Rv without affecting Ra in both Ringer- and blood-perfused lungs. The response was sustained in blood-perfused lungs. AA had no effect on the capillary filtration coefficient in either Ringer- or blood-perfused lungs. AA stimulated the release of thromboxane B2 and 6-ketoprostaglandin F1 alpha in both Ringer- and blood-perfused lungs, but the responses were sustained only in the blood-perfused lungs. Meclofenamate (1.5 X 10(-4) M), a cyclooxygenase inhibitor, abolished the AA-induced pulmonary hemodynamic responses in both Ringer- and blood-perfused lungs, whereas U-60257 (10 microM), a lipoxygenase inhibitor, attenuated the response only in the blood-perfused lungs. In conclusion, AA does not alter pulmonary vascular permeability to water in either Ringer- or blood-perfused lungs. AA mediates pulmonary venoconstriction and thus contributes to the rise in Pcap. The venoconstriction results from the generation of cyclooxygenase-derived metabolites from lung parenchymal cells and blood-formed elements. Lipoxygenase metabolites may also contribute to the vasoconstriction in the blood-perfused lungs.     

Acute increases in anastomotic bronchial systemic to pulmonary blood flow due to generalized lung injury

Since pulmonary blood flow to regions involved in adult respiratory disease syndrome (ARDS) is reduced by hypoxic vasoconstriction, compression by cuffs of edema, and local thromboses, we postulated that the bronchial circulation must enlarge to provide for the inflammatory response. We measured anastomotic bronchial systemic to pulmonary blood flow [QBr(s-p)] serially in a lung lobe in 31 open-chest dogs following a generalized lobar injury simulating ARDS. The pulmonary circulation of the weighed left lower lobe (LLL) was isolated and perfused (zone 2) with autologous blood in anesthetized dogs. QBr(s-p) was measured from the amount of blood which overflowed from this closed vascular circuit corrected by any changes in the lobe weight. The LLL was ventilated with 5% CO2 in air. The systemic blood pressure (volume infusion), gases, and acid-base status (right lung ventilation) were kept constant. We injured the LLL via the airway by instilling either 0.1 N HCl or a mixture of glucose and glucose oxidase or via the pulmonary vessels by injecting either alpha-naphthylthiourea or oleic acid into the LLL pulmonary artery. In both types of injury, there was a prompt rise in QBr(s-p) (mean rise = 247% compared with control), which was sustained for the 2 h of observation. The cause of this increase in flow was studied. Control instillation of normal saline into the airways or into the pulmonary vessels did not change QBr(s-p) nor did a similar increase in lobar fluid (weight) due to hydrostatic edema. Neither cardiac output nor systemic blood pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different types of circulatory responses to mental tasks

The present study investigated the circulatory responses to two mental tasks. Forty males and females performed a mental subtraction task and a color-word task. During each task, the systolic and diastolic blood pressure, mean arterial pressure, heart rate, stroke volume, cardiac output, and total peripheral resistance were measured as cardiovascular indices for a 5-min baseline, a 5-min task period, and a 10-min recovery period. As for the results, three hemodynamic reactivity patterns were verified: Pattern C, characterized by increased cardiac output and decreased total peripheral resistance; Pattern M, characterized by a moderate increase in both cardiac output and total peripheral resistance; and Pattern V, characterized by increased total peripheral resistance and decreased cardiac output. Also, four response types were found among all subjects: Type 1: cardiovascular responses showed the cardiac pattern for both tasks; Type 2: cardiovascular responses changed between the cardiac pattern and the mixed pattern with a change of tasks; Type 3: cardiovascular responses showed the mixed pattern for both tasks; Type 4: cardiovascular responses changed between the mixed pattern and the vascular pattern with a change of tasks. The comparison between types showed that Type 3 and Type 4 had an elevation in their blood pressure by an increased total peripheral resistance. On the other hand, Type 1 and Type 2 tended to have an increased blood pressure by a rise in their cardiac output. And Type 3 and Type 4 showed higher blood pressure and higher scores on the Type A behavior pattern questionnaire. In conclusion, at least four types of circulation response to the mental tasks existed, with Type 3 and Type 4 having higher blood pressure responses and tending to have an elevated blood pressure by a rise in their total peripheral resistance.     

Direct injury to the bronchial vasculature in anesthetized sheep.

Injury to the bronchial vasculature may contribute to liquid and solute leakage into the lung during noncardiac pulmonary edema. The purpose of this study was to measure changes in hemodynamics, pulmonary mechanics, extravascular lung water, and lung morphometry after selectively injuring the bronchial vasculature in anesthetized sheep. In two groups of seven sheep, we injected oleic acid (0.1 ml/kg) or normal saline directly into the bronchoesophageal artery. We measured systemic and pulmonary arterial pressures, cardiac output, oxygen saturation, pulmonary resistance and compliance, and lung volumes before and 1 and 4 h after injection. The lungs were removed for measurement of extravascular water, histology, and morphometry. Four hours after injection of oleic acid, cardiac output decreased but pulmonary arterial pressure did not change. In addition, pulmonary resistance increased and dynamic compliance and vital capacity decreased. Extravascular lung water was slightly but significantly greater in the oleic acid group. Histological examination showed interstitial edema and leukocytes in airway walls and sloughing of bronchial epithelium but little or no alveolar edema. Morphometric analysis showed significant thickening of airway walls. We conclude that direct injury to the bronchial vasculature increases lung resistance, decreases dynamic compliance, and increases extravascular lung water by the accumulation of an inflammatory infiltrate in airway walls.     

Initial ventilatory and circulatory responses to dynamic exercise are slowed in the elderly.

To elucidate the characteristics of ventilatory and circulatory responses at the onset of brief and light exercise in the elderly, 13 healthy, elderly men, aged 66.8 yr (mean), exerted bilateral leg extension-flexion movements for only 20 s with a weight around each ankle, with each weight being approximately 2.5% of their body mass. Similar movements were passively performed on the subjects by the experimenters. These results were compared with those of 13 healthy, young men (22.9 yr). Minute ventilation increased at the onset of voluntary exercise and passive movements in both groups but showed a slower increase in the elderly. Heart rate also increased in both groups but showed less change in the elderly. Mean blood pressure temporarily decreased in both groups but less in the elderly. The magnitude of relative change (gain) of heart rate in the elderly was significantly smaller than that in the young, whereas the increasing rate to reach one-half of the gain (response time) of ventilation in the elderly was significantly slower than that in the young. Similar tendencies were observed in the passive movements. It is concluded that the elderly show slower ventilatory response and attenuated circulatory response at the onset of dynamic voluntary exercise and passive movements.