The bronchial epithelium is the major barrier between the host and the provoking antigens in bronchial asthma. Recent studies have indicated that the epithelium is a truly stratified structure, with the superficial columnar cells depending on the underlying basal cells for anchorage. Only columnar cells are shed into bronchial lavage fluid. The epithelium is more fragile in asthma and more cells are lost in clusters. Desmosomes appear to be the major structural adhesion mechanism at the plane of cleavage between the columnar cells and the basal cells. The alpha 6- and beta 4-integrins, which contribute to hemidesmosomes and anchor cells to the underlying basement membrane, are expressed solely by basal cells. The apical aspects of the columnar cells are sealed by tight and intermediate junctions. There is constitutive expression of ICAM-1 and E-selectin in the vasculature of the bronchial mucosa, and ICAM is also present within the epithelium. These findings indicate that the bronchial epithelium is a complex structure that, as a mucosal surface, has constitutive expression of inflammatory cell adhesion molecules to serve normal leukocyte traffic.

The exchange of cross-talks between cells relies on soluble factors or direct cell-cell contact. Soluble factors increase the expression of cell surface molecules that activate adjacent cells by direct contact to produce cytokines. In the lung, dendritic cells are potent inducers of T-cell proliferation, and the interaction between the two leads to the production of high amounts of TNF alpha and TNF beta. Of the molecules involved in these biologic functions, LFA-3, CD11c, and the combination of beta 1 and beta 2 integrins are the most efficient. However, blocking TNF alpha or TNF beta production does not affect the alloreaction. The interaction between activated T cells and monocytes resulted in a large production of IL-1 beta. In this reaction, CD69, CD2, and the beta 2 integrins (CD11a, b, c, and CD18) and also other molecules such as a 25- to 35-kD glycoprotein play an important part. Finally, interaction between monocytes and fibroblasts leads to the production of large amounts of collagenase and PGE2 by fibroblasts. Cell-associated IL-1, particularly IL-1 alpha and membrane-bound TNF alpha, can also play a crucial role in the process of cell-cell interaction. This interaction may be controlled by inhibitors to IL-1 and TNF.

A multitude of glycoproteins expressed in cellular membranes have been identified by monoclonal antibodies. Besides mediating transient cell/cell contacts, these molecules unequivocally function as receptor structures capable of transmitting signals for cell growth and differentiation. They are the central determinators of local immune responses, and they allow an adjustment of the recirculating immunocompetent cells to their respective local microenvironments. Given that receptor/ligand interactions are characteristic of particular in vivo sites, knowledge of structural and functional features of adhesion receptors can provide new prospects for a more targeted clinical immune intervention.

The accumulation of leukocytes into tissues is a characteristic feature of inflammatory reactions. This process is triggered by chemical signals generated in a tissue in response to an inflammatory stimulus e.g., invading microbes, other foreign organisms, allergens, or damaged tissue cells. The mechanisms involved in neutrophil and eosinophil accumulation in vivo are complex and dependent on an initial interaction between the leukocytes and the microvascular endothelial cells. This response is regulated by the coordinated expression and/or activation of leukocyte and endothelial cell adhesion molecules. The precise mechanisms that control the selective accumulation of eosinophils, as opposed to neutrophils, in certain inflammatory reactions (e.g., in IgE-mediated allergic reactions) remain unclear. This may be explained partly by the generation of eosinophil-specific inflammatory mediators and activation of selective adhesion pathways such as the VLA-4/VCAM-1 interaction. Although the neutrophil and eosinophil have distinct roles in host defense, they have been implicated in the pathogenesis of a number of inflammatory disorders. Thus, a better understanding of the events mediating and regulating neutrophil and eosinophil accumulation in vivo will be of considerable value in the development of therapeutic strategies for inflammatory disease states.

Integrins are heterodimeric glycoproteins that mediate cell-to-matrix and some cell-to-cell interactions. Recent evidence underscores the important roles of these receptors in signaling machines that transduce positional information into complex changes in cell behavior. As such, integrins have been shown to play critical roles in cell growth, differentiation, and migration. Most cells express multiple members of this family, but the integrin repertoire of any given cell appears to be highly tissue- and cell-type-specific. We have used the homology-based polymerase chain reaction to identify known and novel integrin subunits in airway epithelial cells. With this technique we have identified three novel integrin subunits that participate in the formation of at least four novel integrin heterodimers. The best characterized of these, alpha v beta 6, is a receptor for the extracellular matrix protein fibronectin, and appears to be expressed only in terminally differentiated mucosal epithelial cells. The novel alpha subunit, alpha 9, forms a heterodimer with the known beta subunit, beta 1, in some epithelial cell lines. Elucidatation of the specific roles these receptors play in airway health and disease will likely provide unique insights into both the biology of integrins and the biology of the airway epithelium.

Several distinct cell adhesion molecule families have recently been identified and found to be important in the inflammatory response and for epithelial and endothelial homeostasis. The integrin family of adhesion molecules functions in both cell-matrix and cell-cell interactions, whereas the cadherins serve as important cell-cell receptors for maintenance of epithelial integrity. The leukocyte integrins, selectins, members of the immunoglobulin supergene family, and specific carbohydrates mediate adhesive interactions between leukocytes and endothelial cells. The mechanisms of leukocyte-epithelial adhesion are less well understood, but integrins and members of the immunoglobulin supergene family are also involved. The role of these molecules in pulmonary structure and inflammation is currently being actively explored. Further knowledge of these interactions, and the interplay of adhesion molecules, cytokines, and chemoattractants is likely to lead to novel therapeutic modalities in inflammatory diseases of the airway and lung parenchyma. In this overview, the families of adhesion molecules will be summarized, and their relevance for pulmonary structure and inflammation will be discussed.

T-lymphocytes with T-cell antigen receptor (TCR) comprising a gamma chain and a delta chain (gamma delta+ T cells) are believed to be involved in the immune reaction to mycobacterial antigens, and they have been found in increased proportions in sarcoid patients. We evaluated the proportions of gamma delta+ T-lymphocytes and of two major gamma delta+ subpopulations, the V delta 1+ and the V delta 2+ T-cell subsets, in 10 normal blood donors, in 15 patients with tuberculosis (TB), seven of whom had pleural effusion (PE), and in 12 patients with pulmonary sarcoidosis (PS), nine of whom underwent bronchoalveolar lavage (BAL). T-cell subsets were evaluated in peripheral blood (PBL) of all subjects and in PE from patients with TB and in BAL from patients with PS. Compared with normal blood donors, patients with TB had increased proportions of PBL CD3+ gamma delta+ T cells (6 +/- 1% versus 14 +/- 3% of CD3+ T cells, p < 0.05) because of the presence of four patients who had an increase (respectively, 18.3, 22.0, 24.2, and 35.4% of CD3+ T cells) of gamma delta+ T cells. In patients with TB and PE, gamma delta+ T cells were 7.9 +/- 2.7%, a value not different from that in the tubercular PBL and in normal PBL. Although patients with PS had proportions of PBL gamma delta+ T cells (9.2 +/- 3.4%) similar to those in normal PBL, two patients had increased (35 and 31%) PBL gamma delta+ T-lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent studies suggest that cytokines such as recombinant interferon-gamma (rIFN-gamma) may play a role in the treatment of certain respiratory conditions associated with infection and inflammation. This study was designed to determine if rIFN-gamma could be delivered effectively in a group of normal human volunteers. The effectiveness of the inhaled delivery system was demonstrated by the recovery of free IFN-gamma in bronchoalveolar lavage (BAL) fluid and macrophage (M phi) expression of IP-10, an IFN-gamma-inducible molecule, after therapy but not at baseline. IL-1 beta, but not IL-8, gene transcripts also showed evidence for up-regulation after rIFN-gamma therapy. Compared with baseline, inhaled rIFN-gamma did not significantly alter clinical symptom scores, spirometry, morning peak expiratory flow rate (PEFR), or the response to methacholine. Of interest, the evening PEFR increased significantly (p = 0.02), from 568 +/- 36 L/min at baseline to 584 +/- 33 L/min after inhaled rIFN-gamma. Although there was no significant change in total white cell count in BAL fluid, the cellular composition did demonstrate a significant decrease in percentage of alveolar M phi (p = 0.02) and an increase in percentage of lymphocytes (p = 0.02) after rIFN-gamma. There were no histologic differences seen in bronchial biopsy specimens, and there was no evidence for up-regulation of ICAM-1 or HLA-DR expression after rIFN-gamma. We conclude that, in normal persons, rIFN-gamma can be effectively delivered by inhalation. Future trials using inhaled rIFN-gamma appear to be warranted for certain pulmonary diseases.

A common side effect of radiotherapy is the development of fibrosis in the irradiated tissue. To study the mechanisms of this fibrogenic response, we developed a model system of whole-lung radiation in the rat and studied the evolution of injury by assessment of the cells and protein recovered by lavage. Once the pattern of injury was known, we attempted to modulate this reaction by administering the cytokine interferon-gamma (IFN-gamma). Rats received 15 Gy radiation to the whole thorax and were studied by lung lavage at intervals of 1 to 35 days after radiation. The effect of radiation was an initial (24 h) leak of protein, unaccompanied by cellular alterations, that resolved by 48 h. This was followed 2 wk later by a phase of inflammatory cell recruitment and more significant protein leak. A third phase of increase in inflammatory cells and further increase in protein flux was noted at Day 35. A significant cellular infiltrate was seen in lung sections obtained from animals treated in parallel experiments. IFN-gamma was given by osmotic pump from Day 0 to Day 35. This treatment significantly attenuated the PMN recruitment and protein leak (p < 0.002 and 0.01, respectively) at Days 25 and 35. Histologic sections demonstrated reduced alveolar cellularity and exudate at Day 25 (p < 0.05); however, significant numbers of inflammatory cells and exudate were present in irradiated and IFN-gamma-treated animals at Day 35. These data indicate that inflammatory cell recruitment may play a role in the lung injury following radiation. Furthermore, these preliminary data indicate that a cytokine blocks this reaction.

The potential role of neutrophil elastase in exacerbating pulmonary infection and tissue damage in cystic fibrosis (CF) has led to proposals for treatment of lung disease in CF with the elastase inhibitor, alpha 1-proteinase inhibitor (alpha 1PI). Reports that alpha 1PI is inactivated in the CF lung suggest that the effectiveness of alpha 1PI therapy depends on the quantity of elastase present and the extent of alpha 1PI inactivation, both of which are expected to vary with disease severity. In this study we assessed the elastase-alpha 1PI profile in sputum and plasma from CF patients with various degrees of pulmonary involvement. Levels of active elastase in sputum samples increased with severity of pulmonary disease (F ratio = 5.63, p < 0.01), as did sputum levels of alpha 1PI (F ratio = 4.88, p < 0.01). A positive correlation was observed between sputum levels of active elastase and alpha 1PI (r = 0.68, p < 0.005). Plasma alpha 1PI levels were also elevated in CF patients compared with control subjects (p < 0.005), indicating a compensatory increase in plasma and sputum levels of alpha 1PI in response to increased elastase load. Molar levels of total immunogenic neutrophil elastase were, on average, 12 times higher than alpha 1PI in CF sputum. These results suggest that the major contributor to the elevated levels of active elastase observed in the CF lung is an increase in elastase release rather than inactivation of alpha 1PI.

Positive end-expiratory pressure (PEEP) commonly decreases cardiac output. The major cause of this is believed to be decreased venous return due to increased right atrial pressure. We hypothesized that when the lungs were hyperinflated they could also restrict venous return by directly compressing the thoracic vena cavae. We measured the longitudinal distribution of pressure in the thoracic vena cavae of 10 dogs on and off 10 mm Hg PEEP, in the supine (S), prone (P), right lateral (RL), and left lateral decubitus (LL) positions. In the superior vena cava (SVC) both on and off PEEP, and in the inferior vena cava (IVC) off PEEP, pressure fell uniformly from the thoracic inlet to the right atrium. However, in the IVC on PEEP, intravascular pressure fell abruptly by up to 5 mm Hg. This pressure drop occurred in a discrete (1 to 2-cm) segment of the IVC, suggesting a localized increased in extravascular surface pressure. When this pressure inflection was present, changes in right atrial pressure had no effect on pressure in the IVC upstream of the inflection, consistent with a "vascular waterfall." These observations were most prominent in the LL, least common in the RL, and variably present in the P and S positions. Occlusion of the right bronchus intermedius prior to PEEP (preventing right lower, middle, and accessory lobe inflation) prevented the appearance of the pressure inflection during PEEP in the LL but not in the S or P positions. We conclude that PEEP impedes venous return partly by direct compression of the IVC, predominantly in positions in which the IVC is non-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal studies and clinical pediatric practice have shown that acute alkalosis attenuates hypoxic pulmonary vasoconstriction (HPV). However, increased intracellular pH appears to enhance pulmonary vasoreactivity. We therefore hypothesized that prolonged alkalosis augments HPV. This study compares the effects of acute and prolonged alkalosis on HPV in isolated perfused lungs of 1-month-old lambs (n = 5) and the hypoxic responses of 300- to 500-microns diameter segments of pulmonary arteries (n = 7) from mature cats at control pH and after 30 min of alkalosis. In isolated lamb lungs, normocarbic (5% CO2) hypoxia (4% O2) increased the total pressure gradient (delta PT) by 6.0 +/- 2.7 (SEM) mm Hg (p < or = 0.05). Acute hypocarbia (3% CO2) increased the perfusate pH to approximately 7.52 and significantly decreased the hypoxic delta PT to normocarbic, normoxic (28% O2) levels. Subsequent exposure to normoxia (while maintaining alkalosis) further decreased delta PT. However, re-exposure to hypoxia after 60 min of normoxic alkalosis significantly increased delta PT by 11.6 +/- 1.6 mm Hg (p < or = 0.05) to a level similar to that seen during normocarbic hypoxia. The increased hypoxic reactivity (i.e., change in pressure between normoxia and hypoxia) during prolonged alkalosis was due to enhanced HPV of the small vessels within the middle segment of the pulmonary circuit, as defined by an inflow-outflow occlusion technique (p < or = 0.05). The occlusion data also suggested that most of this increase occurred in small arteries. Moreover, the hypoxic response of isolated small arteries from the cat was increased almost threefold (p < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelial damage is a hallmark of acute lung injury. Endothelial mediators may increase pulmonary vascular tone and induce pulmonary arterial muscularization, thereby contributing to the pulmonary hypertension seen with acute lung injury. We measured plasma levels and net pulmonary clearance of endothelin-1, a potent endothelium-derived vasoconstrictor peptide and smooth muscle mitogen, in 26 patients with early acute lung injury, the adult respiratory distress syndrome, and pulmonary hypertension. Nineteen had another data collection at clinical improvement or worsening. Control subjects (n = 25) had no pulmonary hypertension or lung injury. Initial mixed venous and systemic arterial plasma endothelin-1 levels were elevated (4.6 +/- 0.6 SEM and 4.9 +/- 0.6 pg/ml, respectively) as compared with control subjects (0.9 +/- 0.1 and 0.6 +/- 0.1 pg/ml). The systemic arterial/venous endothelin-1 ratio was 1.1 +/- 0.1 (0.7 +/- 0.1 in control subjects), indicating a reduction in normal net pulmonary endothelin-1 clearance. With clinical improvement, as compared with clinical worsening, mean plasma endothelin-1 levels, arterial/venous ratio, and pulmonary arterial pressure fell significantly towards normal. Thus, patients with acute lung injury have marked early increases in circulating plasma endothelin-1 levels, associated with abnormal pulmonary endothelin-1 metabolism. These abnormalities reverse in patients who recover. Through its actions, endothelin-1 could contribute to the pulmonary hypertension seen in acute lung injury.

In order to determine whether endotoxemia induced generalized defects in vascular contraction and endothelium-dependent relaxation, we studied the effect of in vivo endotoxin administration in Sprague-Dawley rats and New Zealand White rabbits on endothelial and arterial smooth-muscle responses of isolated thoracic aorta in vitro. Endotoxin treatment significantly decreased contractile responses to phenylephrine (PE), angiotensin II (AII), serotonin (5-HT), and potassium chloride. This effect was not altered by indomethacin or endothelial denudation. Treatment of vessels with NG-nitro-L-arginine (NNLA), an inhibitor of arginine-dependent nitric oxide biosynthesis, or with methylene blue, an inhibitor of soluble guanylate cyclase, resulted in significant improvement of the contractile defect in endotoxin-treated vessels. The restorative effect of NNLA on contractile responses in endotoxin-treated aortic rings was similar in the presence or absence of an intact endothelium. Endothelium-dependent relaxation in response to acetylcholine, substance P, or the calcium ionophore A23187 was markedly impaired in vessels from endotoxin-treated rabbits, while endothelium-independent relaxation in response to nitroprusside was similar in both groups. These results suggest that endotoxemia both induces basal, nonendothelial nitric oxide synthesis and impairs the agonist-stimulated release of endothelium-derived relaxing factor (EDRF). These findings may have mechanistic importance in the hemodynamic derangements of endotoxemia.

The fluid that covers the surface of conducting airways (airway surface fluid, ASF) is a critical component of one of the first defense mechanisms of the lung against microbial and other environmental insults. Despite its physiologic importance, ASF is one of the only fluids in the human body whose composition remains poorly defined and understood. Attempts to analyze ASF have been hampered greatly by the fact that it exists only as a very thin layer covering the mucosal surface of airway epithelia. To overcome some of these limitations, we have applied ultramicroanalytic techniques to microsamples collected in human airways in vivo. In contrast to previous thinking from studies on sputum samples, ASF collected from healthy airways contains much less Na and Cl (approximately 45% less) and much more K (around 600% more) than extracellular fluid or plasma (ECF), which shows that steep ion gradients exist across normal airway epithelia. These differences also show that ASF composition must be regulated and maintained by active electrolyte transport processes of airway epithelia and that it is not merely the evaporated residue of isotonic secretions or extracellular fluid exudate. However, in patients with sustained airway irritation, infection, or cystic fibrosis, we find that ASF composition appears to become more isotonic with respect to plasma and much more hypotonic in patients with asthma.

Exposure to cold dry air induces rhinorrhea and other nasal symptoms in many persons. To evaluate whether this response involves a neurogenic component, we delivered a unilateral cold dry air (UniCDA) nasal challenge to volunteers with previously documented reactivity to cold dry air. We measured their nasal secretory responses bilaterally using small filter paper discs to absorb secretions from the nasal mucosa. UniCDA increased nasal secretion both ipsilateral (p < 0.001) and contralateral (p < 0.001) to the challenge when compared with control challenge. Topical atropine (0.225 mg), a muscarinic antagonist, inhibited ipsilateral secretion (p < 0.002) when given ipsilateral to UniCDA. When atropine was given contralateral to UniCDA, there was a trend toward reduction of contralateral secretion but no effect on ipsilateral secretion. Topical anesthesia with lidocaine given ipsilateral to UniCDA inhibited ipsilateral (p < 0.02) and contralateral (p < 0.05) secretion immediately after challenge. Topical anesthesia did not inhibit methacholine-induced nasal secretion. Thus, UniCDA stimulates reflex secretion both ipsilateral and contralateral to challenge which is inhibitable by interrupting either the efferent or the afferent arm of the reflex arc. This human in vivo model supports the importance of neural mechanisms in airway responsiveness to an environmental stimulus.

Abnormal inspiratory load compensation may be one factor leading to development of obstructive sleep apnea (OSA). Alternatively, abnormalities in ventilatory load compensation may be a consequence of the manifestations of OSA. This investigation was designed to determine if impairment of awake inspiratory load compensation exists in OSA and to determine if abnormalities in this parameter are reversible by nasal CPAP therapy. A new technique for assessment of awake inspiratory load compensation was devised to standardize the degree of ventilatory stimulation applied during load compensation assessment in each subject. This eliminates intersubject differences in degree of ventilatory stimulation during testing, which are inevitable with standard techniques and which have been shown to affect the measurement of load compensation. Inspiratory load compensation was assessed during resting room air ventilation and during steady state CO2 and exercise stimulation titrated to provide similar degrees of ventilatory stimulation in each subject. Impairment of awake inspiratory load compensation was found during all conditions in the patients with moderate to severe OSA studied compared with that in weight-matched control subjects. Normalization of awake inspiratory load compensation was observed after 4 wk of nasal CPAP therapy in five patients. These results indicate that impairment of awake inspiratory load compensation is a reversible consequence rather than a cause of OSA.

The peripheral chemoresponses of infant twin pairs were determined using a single-breath hyperoxic stimulus. A total of 43 twin pairs of comparable gestation and birth weight were studied during sleep at a mean (SD) age of 8 wk (1.4) while alternately breathing either air or 16% oxygen in nitrogen. Infants responded to a single breath of 100% oxygen by a reduction in ventilation; the mean (SEM) reduction in air was 273 ml/min (10.6) and in 16% oxygen 560 ml/min (18.4). Within-pair variances were compared in 14 monozygotic and 28 dizygotic pairs utilizing combined responses (air + 16% oxygen) computed for measurements made in behavioral quiet sleep and in 9 monozygotic and 20 dizygotic pairs for whom data were complete in polygraphically confirmed quiet sleep. The variance of responses within dizygotic twin pairs was greater than in monozygotic pairs when expressed in ml/min: F ratio 4.11 (p = 0.005) for all data and F ratio 7.67 (p = 0.003) in quiet sleep. Expressed in ml/min/kg the difference was less significant: F ratio 1.83 (p = 0.126) for all data and F ratio 3.46 (p = 0.039) in quiet sleep. Gender, birth weight, and birth order had no effect on these findings. This closer similarity of response in monozygotic twin pairs is explained by proposing a high degree of heritability for the response.

Pediatric obstructive sleep apnea (OSAS) is characterized by partial airway obstruction, alveolar hypoventilation, and elevated arterial CO2 (PaCO2). Thus, a reliable, practical method of estimating CO2 is needed for pediatric polysomnography. Therefore, we measured both transcutaneous CO2 (PtcCO2) and end-tidal CO2 (PETCO2) in 15 pediatric polysomnographic evaluations. Sleep state, the highest PtcCO2, and the highest PETCO2 were recorded for 5,159 thirty-second epochs. Although PtcCO2 and PETCO2 were available for 78.5 and 73.0% of epochs, respectively, at least one estimator was available for 92% of the epochs. One infant who would not tolerate a nasal sampling catheter had no PETCO2 data. For 13 of 14 studies there was a relatively constant difference between PtcCO2 and PETCO2. The difference between PtcCO2 and PETCO2 was within 4 mm Hg in 63.9% of 3,072 epochs. Across 14 studies, mean PtcCO2 exceeded mean PETCO2 by 2.8 +/- 3.0 mm Hg, and it was within 4 mm Hg in 10 studies. In three subjects, PETCO2 was intermittently or consistently less than PtcCO2 because of tachypnea, increased physiologic dead space, or severe partial airway obstruction; in one subject PtcCO2 exceeded PETCO2 for undetermined reasons during one electrode application. The results of this study indicate that PtcCO2, as well as PETCO2, should be measured during pediatric polysomnography. By utilizing both PtcCO2 and PETCO2 there was a 70% reduction in the number of epochs that could not be assessed for hypoventilation. For an individual subject or electrode application there was a constant, and usually close, relationship, between PtcCO2 and PETCO2.(ABSTRACT TRUNCATED AT 250 WORDS)

A method of recording cumulative nocturnal oxygen desaturation was utilized to develop a quantitative index of nocturnal hypoxemia (SIT index) to provide reference values and distributional properties for apneic and nonapneic sleep-disordered patients. The SIT indices were compared in patients with varying degrees of obstructive sleep apnea (OSA) as determined by traditional methods of counting apneas and hypopneas. We studied 298 patients who were divided into five groups based on the presence and frequency of apnea or sleep-related respiratory deterioration. SIT indices for patient groups and individual patients were compared with the respiratory disturbance index (apneas + hypopneas x 60/total sleep time = RDI) using scatter plots, Kruskal-Wallis analysis of variance, and Mann-Whitney U tests. The OSA and non-respiratory-impaired patient groups had mean SIT values that were significantly different (p < 0.05). Subjects with severe apnea differed (p < 0.05) from subjects with mild and moderate apnea at SIT index thresholds < baseline, < 90, < 80, and < 70% SaO2, but subjects with mild and moderate apnea did not differ statistically from each other at any threshold. In individual patients with similar RDI values, considerable variation in SIT index can be seen, and the reverse is also true. This suggests that using both RDI and SIT may provide complementary information in assessing the severity of OSA.

To clarify effects of aging on the load compensation response and the sensation of dyspnea, we examined 28 healthy male volunteers for ventilatory and P0.1 responses to hyperoxic progressive hypercapnia with and without inspiratory flow-resistive loading (17 cm H2O/L/s) while the intensity of dyspnea was simultaneously assessed by visual analogue scaling every 15 s. Of the 28 subjects, 14 were 61 to 79 yr of age and were classified as the older group; the others, 19 to 48 yr of age, were classified as the control group. Neither delta VE/delta PETCO2 nor delta P0.1/delta PETCO2 was different between the two groups without loading. In the control group, the delta P0.1/delta PETCO2 increased with loading (p < 0.01) without a change in the delta VE/delta PETCO2. In the older group, the delta P0.1/delta PETCO2 did not change with loading so that the delta VE/delta PETCO2 decreased with loading (p < 0.01). In the 28 subjects as a whole, the percent change in delta P0.1/delta PETCO2 with loading was inversely correlated with age (r = -0.53, p < 0.01). At PETCO2 levels of 45, 50, and 55 mm Hg, irrespective of loading, the dyspnea intensity was greater in the older group than in the control group, whereas the P0.1 expressed as its ratio to the predicted maximal inspiratory mouth pressure was not different between the two groups. We conclude that aging attenuates the compensatory response to inspiratory flow-resistive loading and it increases the intensity of dyspnea for a given level of PETCO2.

To investigate the importance of the inflammatory response in acute peripheral airway constriction, we measured peripheral airway responses to calcium chelators and acetylcholine in anesthetized Basenji-Greyhound (BG) dogs before, during, and after chronic corticosteroid treatment. A wedged bronchoscope technique was used to measure peripheral airway resistance before and after aerosol challenge with 4% Na2EDTA or acetylcholine (10 micrograms/ml) in contralateral lungs. After the initial measurements, five BG dogs received long-term treatment with methylprednisolone (2 mg/kg/d, subcutaneously), and five dogs were not treated and served as controls. Four weeks of methylprednisolone treatment almost totally abolished responses to Na2EDTA, but responses to acetylcholine did not change significantly. After discontinuing corticosteroid therapy, responses to Na2EDTA returned to levels found before corticosteroid treatment; responses to acetylcholine were significantly enhanced. We conclude that chronic corticosteroid treatment reduces acute response to calcium chelators and that withdrawal of corticosteroid therapy is associated with enhanced cholinergic responsiveness.

To investigate how treatment can affect airway dynamics and respiratory muscle strength in Parkinson's disease (PD), we assessed maximum effort inspiratory and expiratory mouth pressures (MIP and MEP), oscillatory impedance, and maximum expiratory and inspiratory flow-volume curves (MEFV and MIFV) in 10 patients (8 male and 2 female; mean age 51 +/- 5.3 yr, SD) after temporary interruption of antiparkinsonian therapy (off) and during continuous subcutaneous infusion of a direct stimulant of dopamine receptors, apomorphine (on). Treatment improved neurologic scores (off 25 +/- 5, on 9 +/- 5, modified Webster scale, p < 0.001), MEP (off 45 +/- 25, on 63 +/- 29 cm H2O, p = 0.003), and peak inspiratory flow (PIF; off 3.83 +/- 1.6, on 4.37 +/- 1.7 L/s, p = 0.028). Maximum inspiratory pressure was very low off treatment (-25 +/- 16 cm H2O) and improved moderately with apomorphine (-33 +/- 17 cm H2O) (p = 0.064). Total respiratory resistance during tidal breathing was normal in 9 patients both off and on treatment despite, in some cases, dramatic changes in MEFV and MIFV curves. These results suggest that abnormalities of the flow-volume curves may be due to problems in the rapid activation and coordination of contraction of upper airways and chest wall muscles during forced maneuvers, which is improved by apomorphine treatment.

The purpose of this study was to determine whether diaphragmatic fatigue occurs after high-intensity constant-load whole-body exercise to volitional exhaustion. Ten sedentary subjects with a maximal oxygen uptake of 2.52 +/- 0.47 L/min were studied. Subjects exercised on a bicycle ergometer at 80% of their maximal working capacity until volitional exhaustion. Minute ventilation during the last minute of exercise was 89.9 +/- 13.6 L/min, which represented 50 +/- 6% of the subjects' 12-s maximal voluntary ventilation. During the last minute of exercise, mean inspiratory esophageal pressure was 18.1 +/- 5.3 cm H2O, which represented only 15 +/- 4% of the subjects' maximal static inspiratory pressure. Bilateral transcutaneous supramaximal phrenic nerve stimulation was performed before and 10, 30, 45 and 60 min after exercise. Twitch diaphragmatic pressure (twitch Pdi) was significantly decreased after exercise in seven of the 10 subjects. For the group as a whole, twitch Pdi fell from 28.9 +/- 3.7 cm H2O during control to 23.9 +/- 5.1 cm H2O at 10 min after exercise (p < 0.005). The fall in twitch Pdi was due to a significant decrease in twitch esophageal pressure from 19.6 +/- 4.3 cm H2O during control to 15.5 +/- 4.9 cm H2O (p < 0.001). Twitch gastric pressure was not significantly different: 8.7 +/- 4.0 cm H2O, compared with 9.2 +/- 3.8 cm H2O during control. Twitch Pdi recovered to 93 +/- 7% of control values at 60 min after exercise. The fall in twitch Pdi after exercise indicates that diaphragmatic fatigue can occur following heavy endurance exercise in sedentary healthy persons.

In nonintubated patients, beta 2-agonist bronchodilators are equally effective when delivered by metered-dose inhalers (MDI) or nebulizers (NEB). The delivery of these drugs by MDI to intubated, mechanically ventilated patients has become a widespread practice. To compare the efficacy of the two delivery systems and establish optimal dosing, we prospectively randomized 10 mechanically ventilated patients, with increased airways resistance, to receive albuterol by either MDI or nebulizer in incrementally higher doses. After a 4-hr washout, patients were crossed-over to receive the drug by the alternative route of administration. Albuterol delivered by NEB to a total dose of 2.5 mg reduced the inspiratory flow-resistive pressure (peak-pause airway pressures) from 21.5 +/- 5.7 to 17.6 +/- 5.4 cm H2O (p < 0.01). Nebulized albuterol at cumulative doses of 7.5 mg led to further reductions in 8 of 10 patients (p < 0.1), but led to toxic side effects in 4 of them; in the remaining 6 patients toxicity occurred at a cumulative dose of 15.0 mg. By contrast, albuterol in cumulative doses reaching 100 puffs (9 mg) from an MDI administered into an endotracheal tube adapter did not significantly reduce resistive pressures, and produced no toxicity. We conclude that nebulized albuterol provides objective physiologic improvement, while albuterol administered by MDI through an endotracheal tube adapter has no effect in mechanically ventilated patients with airflow obstruction. Nebulizer treatments can and should be titrated to higher-than-conventional doses, using toxic side-effects and physiologic response to guide therapy.

Pneumocystis carinii pneumonia (PCP) remains the most common lethal opportunistic pulmonary infection in patients infected with the human immunodeficiency virus (HIV). Although the use of prophylactic inhaled pentamidine has effectively reduced the frequency of primary and recurrent episodes of PCP, the aerosolization of pentamidine may have altered the localization of active PCP, resulting in more upper lobe disease. The distribution of disease may have also affected the diagnostic accuracy of standard bronchoalveolar lavage of the middle lobe, with a reduction in sensitivity from about 90 to 65%. In retrospective surveys of patients from our institution, Steiger and Fahy found that pooled multiple-lobe radiographic site-directed bronchoalveolar lavage resulted in diagnostic sensitivities of 91 and 100%, respectively. We performed a follow-up prospective study of 38 consecutive patients on aerosolized pentamidine in whom we lavaged both the middle lobe and an upper lobe. We found that bilobar lavage including routine lavage of an upper lobe increases the diagnostic sensitivity of bronchoalveolar lavage alone to 95% compared with 65% if lavage is performed only in the middle lobe (p < 0.05). Radiographic studies demonstrate a concordant increase in exclusive or predominant upper lobe disease in patients on aerosolized pentamidine, but our results indicate that PCP is recovered more frequently from the upper lobe regardless of the radiographic appearance. We conclude that all patients on prophylactic inhaled pentamidine should undergo bilobar lavage with the inclusion of an upper lobe in the initial evaluation of possible PCP. The diagnostic sensitivity of 95% makes bilobar bronchoalveolar lavage an acceptable sole initial diagnostic modality without the need for initial transbronchial lung biopsy.

Inflammation may play a central role in the pathogenesis of HIV-related Pneumocystis carinii pneumonia (PCP). Serum levels of the amino-terminal propeptide of Type III procollagen (PIIINP) reflect inflammatory activity in granulation tissue and in chronic rheumatic and liver disorders. To investigate changes in PIIINP serum levels during an episode of HIV-related PCP, consecutive serum samples were taken from 48 HIV-infected patients with PCP in a randomized, placebo-controlled study of the effect of adjunctive methylprednisolone therapy (26 in corticosteroid [CS] group and 22 in control group). All patients were treated with co-trimoxazole. In the control group, PIIINP serum levels at day of initiation of therapy (Day 0) were significantly higher in patients requiring mechanical ventilation and/or dying during the course of the pneumonia, and serum levels of PIIINP higher than 5 ng/ml were associated with a higher mortality than levels below 5 ng/ml. The level of PIIINP increased from Day 0 to Day 5. There was a significant correlation between changes in PIIINP levels and changes in the alveolar-arterial oxygen gradient from Day 0 to Day 5. In the CS group, the PIIINP levels decreased while steroid was administered. At Days 21 to 28 there were no difference in the levels of PIIINP between the two groups. PIIINP serum levels may predict the clinical outcome of PCP. The antimicrobial therapy may exacerbate the inflammatory reaction in HIV-related PCP, leading to respiratory failure. CS prevents this increased inflammatory activity.

Bronchoalveolar lavage (BAL) and protected specimen brushing (PSB) are the most commonly used methods for diagnosing ventilator-associated (VA) pneumonia although they require bronchoscopy. Endotracheal aspiration (EA) is a simple and less costly technique than PSB or BAL. The purpose of our study was to investigate the diagnostic value of EA quantitative cultures and to compare the results obtained using EA with those obtained using PSB and BAL in mechanically ventilated patients with or without pneumonia. We prospectively studied 102 intubated patients divided into three diagnostic categories: Group I (definite pneumonia, n = 26), Group II (uncertain status, n = 48), and Group III (control group, n = 28). All patients received prior antibiotic treatment. EA, PSB, and BAL were obtained sequentially in all patients. When comparing Group I with Group III and using 10(5) cfu/ml as a threshold, we found that EA quantitative cultures represented a relatively sensitive (70%) and relatively specific (72%) method to diagnose VA pneumonia. The specificity of BAL and PSB (87% and 93%, respectively) was better than that of EA. The negative predictive value of EA cultures was higher (72%) when compared with that obtained using PSB (34%) (p < 0.05). EA quantitative cultures correlated with PSB and BAL quantitative cultures in patients with definite pneumonia. Although EA quantitative cultures are less specific than PSB and BAL for diagnosing VA pneumonia, our results suggest that the former approach may be used to treat these patients when bronchoscopic procedures are not available.