Intravenous iloprost in systemic sclerosis and its effect in cardiopulmonary function: a retrospective observational study.

OBJECTIVE: This study aims at evaluating the disease progression, specifically in terms of cardiopulmonary function, in a group of consecutively enrolled systemic sclerosis (SSc) patients treated with the approved iloprost regimen. PATIENTS AND METHODS: A retrospective observational study was performed on 68 SSc patients treated with 5-6 infusions of iloprost per month for 6 hours per day at a dosage of 0.5-2.0 ng/kg/min through a portable syringe pump. All patients were evaluated for modified Rodnan skin score, systolic pulmonary arterial pressure, tricuspid annular plane systolic excursion, diffusing capacity of the lungs for carbon monoxide, forced vital capacity, alveolar volume, diffusing capacity of the lungs for carbon monoxide/alveolar volume, pro-brain natriuretic peptide (pBNP), New York Heart Association class, and the presence or absence of digital ulcers (DUs). RESULTS: After a follow-up period of 9.9±2.9 years, all patients improved in frequency and severity of the Raynaud phenomenon and showed a stabilization or improvement of cardiopulmonary parameters. The pulmonary arterial pressure and pBNP improved significantly from baseline (30.91±6.4 mmHg vs. 27.36±7.1 mmHg, and 97.20±69.3 pg/ml vs. 66.65±44.3 pg/ml, respectively; p<0.0001 for both). A significant improvement was observed in the modified Rodnan skin score in 57 patients who continued the treatment during the entire follow-up (5.09±5.7 vs. 3.30±4.2, p<0.0001). CONCLUSIONS: Despite the retrospective design and the lack of a control group, the regular and continued administration of iloprost maintained the stability of the cardiopulmonary and cutaneous parameters in SSc. It significantly reduced pBNP levels, a prognostic cardiac biomarker of SSc. Future research should be addressed to demonstrate a stronger causality of this effect.

Nedocromil sodium inhibits the increase in airway reactivity induced by platelet activating factor in humans.

To investigate the effect of nedocromil sodium on changes in airway reactivity to methacholine induced by platelet activating factor, we studied 12 nonasthmatic, nonatopic subjects (24 to 41 years) in a double-blind trial. The FEV1 and airflow at 30 percent of vital capacity from a partial forced expiration (V30p) were used to assess changes in airway caliber. Two concentration-response curves to doubling concentrations of MCh (from 0.3 mg/ml) were performed 48 h apart. The concentrations of MCh causing a 20 percent fall in FEV1 (PC20FEV1) or a 40 percent fall in V30p (PC40V30p) were calculated. After the first MCh challenge, subjects were matched by airway reactivity and randomly assigned to nedocromil sodium (two puffs qid 2 mg/puff) or placebo treatment. Two days after the second MCh challenge, PAF was inhaled, and changes in airway caliber were recorded. Administration of either nedocromil sodium or placebo was ended at this time and airway response to MCh was assessed two days after PAF. The two concentration-response curves to MCh obtained before PAF exposure were superimposable. The PAF caused a dose-related bronchoconstriction in both groups; the maximal fall in V30p was 27.6 +/- 6.6 percent (mean +/- SE) in the nedocromil sodium group and 37.4 +/- 4.6 percent in the placebo group. Two days after PAF, the PC20FEV1 did not change in subjects who received nedocromil sodium (4.86 vs 4.32 mg/ml; geometric mean), but it fell from 6.59 to 1.12 mg/ml (p less than 0.05) in placebo-treated subjects. These results indicate that nedocromil sodium inhibits PAF-induced increase in airway reactivity.

Antigen challenge of sensitized rats increases airway responsiveness to methacholine.

We measured airway responsiveness to methacholine (MCh) of highly inbred rats before and after six inhalational challenges with antigen. Ten Brown-Norway rats (130-216 g) that were actively sensitized to ovalbumin (OA) received six challenges with OA at 5-day intervals beginning 19 days after sensitization. An aerosol of OA (5% wt/vol) was inhaled for 1, 2, 5, and 10 min or until pulmonary resistance (RL) increased by at least 50%. Challenges with aerosolized MCh were performed immediately before and 14 days after sensitization, 2 days after the 3rd OA exposure, and 2, 7, 12, and 17 days after the 6th OA challenge. Four unsensitized rats underwent inhalational challenges with MCh over an equivalent time period. Responsiveness to MCh was calculated as the concentration of MCh required to increase RL to 200% of the control value (EC200RL). Seven out of 10 rats in the experimental group reacted to the first OA challenge with an immediate increase in RL of greater than 50% of control (range 70-550%). Three animals were unreactive to OA. Base-line EC200RL for all rats undergoing sensitization was 2.13 mg/ml (geometric mean), and it did not change significantly after sensitization (2.05 mg/ml). However, EC200RL of the rats that reacted to OA (n = 7) decreased significantly after 3 (1.11 mg/ml; P less than 0.005) and 6 OA exposures (0.96 mg/ml; P less than 0.005). The increase in responsiveness to inhaled MCh was present 17 days after the last OA exposure (EC200RL = 1.40 mg/ml; P less than 0.05). EC200RL of neither the unreactive sensitized rats (n = 3) nor the control rats (n = 4) changed after OA challenges.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of elastase-induced emphysema on airway responsiveness to methacholine in rats.

We examined the effects of elastase-induced emphysema on lung volumes, pulmonary mechanics, and airway responses to inhaled methacholine (MCh) of nine male Brown Norway rats. Measurements were made before and weekly for 4 wk after elastase in five rats. In four rats measurements were made before and at 3 wk after elastase; in these same animals the effects of changes in end-expiratory lung volume on the airway responses to MCh were evaluated before and after elastase. Airway responses were determined from peak pulmonary resistance (RL) calculated after 30-s aerosolizations of saline and doubling concentrations of MCh from 1 to 64 mg/ml. Porcine pancreatic elastase (1 IU/g) was administered intratracheally. Before elastase RL rose from 0.20 +/- 0.02 cmH2O.ml-1.s (mean +/- SE; n = 9) to 0.57 +/- 0.06 after MCh (64 mg/ml). A plateau was observed in the concentration-response curve. Static compliance and the maximum increase in RL (delta RL64) were significantly correlated (r = 0.799, P less than 0.01). Three weeks after elastase the maximal airway response to MCh was enhanced and no plateau was observed; delta RL64 was 0.78 +/- 0.07 cmH2O.ml-1.s, significantly higher than control delta RL64 (0.36 +/- 0.7, P less than 0.05). Before elastase, increase of end-expiratory lung volume to functional residual capacity + 1.56 ml (+/- 0.08 ml) significantly reduced RL at 64 mg MCh/ml from 0.62 +/- 0.05 cmH2O.ml-1.s to 0.50 +/- 0.03, P less than 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)

Transepithelial prostacyclin gradient in isolated canine trachea.

Cyclooxygenase products of arachidonic acid, potential modulators of airway smooth muscle, have recently been described in bronchoalveolar lavage from canine lungs. To evaluate the possibility that airway epithelium represents a barrier to movement of prostacyclin (PGI2), an important bronchodilator synthesized by isolated airway, we measured the concentrations of 6-oxoprostaglandin F1 alpha (6-oxo-PGF1 alpha), the stable degradation product of PGI2, on the mucosal and serosal sides of isolated canine tracheal segments (CTS) mounted in Ussing chambers. 6-oxo-PGF1 alpha was measured by radioimmunoassay after purification by high-performance liquid chromatography. The concentration of 6-oxo-PGF1 alpha was significantly higher on the serosal than the mucosal side of CTS (1,262 +/- 252 vs. 390 +/- 168 pg.min-1.g-1, n = 8, P less than 0.05). A significant correlation was present between 6-oxo-PGF1 alpha measured on both sides of each CTS (r = 0.778, n = 26, P less than 0.01). 6-oxo-PGF1 alpha production from CTS stripped of mucosa was significantly greater than from isolated mucosa. Radiochromatograms obtained after incubation with [3H]arachidonic acid and calcium ionophore A23187 confirmed PGI2 as the predominant cyclooxygenase product of the submucosa, whereas the mucosa produced only small amounts of PGI2 in proportion to other cyclooxygenase products. PGI2 (10(-8) to 10(-6) M) applied to the mucosal surface of closed tracheal segments precontracted with histamine resulted in no significant relaxation, whereas serosal application showed a concentration-dependent effect. Radiolabeled 6-oxo-PGF1 alpha did not cross the isolated epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamics of the collateral pathways of canine lungs after flow interruption.

After interruption of a constant flow (Vcoll) delivered through a bronchoscope into a wedged segment of lung, the pressure at the tip of the bronchoscope (Pb) often decays in a pattern seemingly indicative of two time constants. We tested the hypothesis that the initial more rapid component of the decay is associated with pressure equilibration across the bronchial resistance (Rb), separating bronchoscope tip from alveolus, and that the slower component is associated with pressure equilibration across the collateral pathways separating the wedged segment from surrounding regions. In eight open-chest mongrel dogs, we affixed an alveolar capsule to the segment subtended by the wedged bronchoscope and measured alveolar pressure (PA) and Pb during delivery of Vcoll into the segment and after its sudden interruption. Under both control conditions and after delivery of aerosolized histamine (1.0 or 10 mg/ml), we were unable to demonstrate a gradient between Pb and PA either during constant flow or after flow interruption. Whenever the decay of Pb was not monoexponential, neither was that of PA. Thus there was no evidence of an appreciable Rb, and the rapid component of the decay must be attributable to other factors. In a second protocol, we examined whether behavior departing from monoexponential decay was attributable to the presence of multicompartment behavior within the wedged segment or rather reflected the behavior of a single homogeneous but nonlinear compartment. In five closed-chest dogs, we systematically varied the initial Pb by changing Vcoll and recorded nonexponential pressure decay after flow interruption.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclooxygenase products mediate the cutaneous vasodilation induced by endothelin-1 in humans.

Intradermal injection of endothelin-1 (ET-1) causes vasoconstriction (pallor) at the injection site, surrounded by a larger area of vasodilation (flare) in humans. Some of the vasomotor responses to ET-1 are thought to be mediated by prostaglandins. In the present study, we investigated the involvement of cyclooxygenase-derived products of arachidonic acid metabolism on the cutaneous vasomotor responses to ET-1. Ten normal subjects (25-44 years) were studied after treatment with either indomethacin (50 mg t.i.d.) or placebo according to a double blind cross-over design. Five doses of ET-1 (5 x 10(-5) to 5 x 10(-1) pmol) were injected intradermally 2 h after the last dose of indomethacin or placebo. Pallor and flare areas measured by planimetry 15 min after the injection were analyzed to evaluate cutaneous vasomotor responses to ET-1. ET-1 induced dose-dependent pallor and flare responses that were significant at the dose of 5 x 10(-3) pmol or greater. Indomethacin did not affect the ET-1-induced pallor but significantly shifted to the right the flare dose-response curve to ET-1. The inhibition of the flare response to 5 x 10(-1) pmol ET-1 was 58.9 +/- 8.5%. These results indicate that the cutaneous vasodilation induced by intradermal injection of ET-1 is mediated by the release of vasodilating cyclooxygenase products.

The effect of inhaled furosemide and acetazolamide on bronchoconstriction induced by deep inspiration in asthma.

In some asthmatics deep inspiration causes a sustained bronchoconstration, which is dependent on Ca2+ uptake. Inhaled diuretics protect against bronchoconstriction induced by a variety of indirect stimuli, by inhibiting the ionic fluxes involving Ca2+ uptake across the cell membrane of airway epithelium. The aim of this study was therefore to investigate the protective effect of inhaled furosemide on the bronchoconstriction induced by deep inspiration in asthma and to compare it with the effect of acetazolamide, an inhibitor of carbonic anhydrase devoid of effect on ion cotransport but possessing inhibitory effects on chloride ion influx and Na+/K+ exchange. The study was carried out on three different study days according to a randomized, double-blind, placebo-controlled, crossover design. Nine non smoking asthmatic subjects first performed a series of 9 controlled deep inspirations to TLC followed by forced expirations to RV within 20 min, which caused a decrease of FEV1 > 20% from baseline. Two hours later, the subjects inhaled either furosemide (40 mg), or acetazolamide (500 mg), or saline (placebo) in random order, and then two more deep-inspiration challenges were performed after 30 and 140 mins. The progressive percent decrement of FEV1 caused by deep-inspiration challenge was taken as an index of bronchoconstriction. Bronchoconstriction was significantly blunted at 30 mins, but not 140 mins, after inhaling furosemide (p < 0.01) or acetazolamide (p < 0.05) compared to control. We interpret these results as due to a modulation of ionic fluxes across the smooth muscle cell membrane afforded by inhaled furosemide and acetazolamide.

Inhaled platelet-activating factor increases airway sensitivity but not maximal airway narrowing to methacholine in normal subjects.

To examine the effect of inhaled platelet-activating factor (PAF) on airway sensitivity and on maximal airway narrowing, we measured airway response to doubling concentrations of methacholine (MCh) 48 h before and 48 h after inhalation of 10, 50 and 100 micrograms of PAF in six nonatopic, nonasthmatic subjects. The forced expiratory volume in one second (FEV1) and airflow at 30 percent of vital capacity (V30) from partial forced expiration were used to assess changes in airway calibre. Inhalation of PAF caused only minor changes in FEV1. In contrast, inhalation of 100 micrograms of PAF caused a significant fall in V30 from 2.64 +/- 0.35 to 1.35 +/- 0.43 l.min-1 (p < 0.05). Two days after PAF inhalation a leftward shift of the concentration-response curve to MCh was observed. The MCh concentration causing a 20% fall in FEV1 (PC20FEV1) was 11.25 +/- 1.78 and 2.38 +/- 1.29 mg.ml-1 (geometric mean +/- GSEM; p < 0.05) before and after PAF inhalation, respectively. PAF did not affect the maximal airway response to MCh. The maximum percentage fall in FEV1 was 36.2 +/- 1.9% at baseline and 37.6 +/- 1.8% after PAF inhalation. Likewise, maximum percentage change in V30 was 72.8 +/- 3.7% at baseline and 73.6 +/- 3.4% after PAF inhalation. The results of this study show that PAF inhalation increases airway sensitivity without altering the maximal bronchoconstrictive response to MCh in normal subjects.

Late airway responses to antigen challenge in sensitized inbred rats.

We studied the magnitude and the time course of changes in pulmonary resistance (RL) after aerosol challenge with chicken ovalbumin (OA) of 15 sensitized, highly inbred Brown-Norway (BN) rats. Animals were actively sensitized and 2 wk later were challenged through the airways. Airway responses of sensitized animals were compared to those of 6 control animals challenged with sufficient methacholine (MCh) to at least double RL and to 4 unsensitized control rats challenged with OA. Ten of 15 rats in the experimental group displayed an early response (ER), defined as an increase in RL of at least 50% within 1 h of challenge. A late response (LR) was considered to have occurred when the value of RL exceeded the mean plus 2 standard deviations of all the measurements taken from 1 h after challenge to the end of the experiment. Two rats died less than 240 min after OA challenge with RL greater than 200% baseline. The remaining 13 were studied for a total duration that ranged from 390 to 720 min and of these animals 10 demonstrated LRs. Maximal RL during the LR after OA was 287 +/- 49% (SE) baseline (range, 129 to 760) versus 115 +/- 15% (75 to 176) for control animals after MCh (p less than 0.01) and 52 +/- 3% (51 to 142; p less than 0.01) for unsensitized control animals after OA. There was no correlation between the magnitude of ER and LR; 3 LRs occurred in the absence of detectable ERs. The median time to the peak of the LR was 450 min; median duration of LRs was 90 min (range, 30 to 135 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in upper and lower airway resistance after inhalation of antigen in sensitized rats.

To assess the contribution of upper and lower airways to the changes in pulmonary resistance after inhalation of antigen by sensitized rats, we measured changes in upper airway resistance (Ru) and lower pulmonary resistance (Rlo) after inhalation of ovalbumin (OA) in anesthetized, spontaneously breathing, sensitized BN rats. Aerosols of antigen were inhaled through the nose and through a tracheostomy in random order; there was a 1-h recovery interval between challenges. After inhalation of OA through the nose, Ru increased from 0.441 +/- 0.057 (mean +/- 1 SE) to 1.342 +/- 0.504 cm H2O X ml-1 X s (n = 6; p less than 0.05) and Rlo increased from 0.099 +/- 0.017 to 0.269 +/- 0.08 cm H2O X ml-1 X s (p less than 0.05). Changes in Ru and Rlo were strongly correlated (r = 0.938; p less than 0.001). After OA was inhaled through the tracheostomy, Rlo increased from 0.089 +/- 0.021 to 0.152 +/- 0.041 cm H2O X ml-1 X s (p less than 0.05). However, Ru did not change significantly. Pretreatment of the lower airways with inhaled atropine did not affect the magnitude of the changes in Ru after inhalation of OA through the nose but significantly attenuated the response of the lower airways. We conclude that when sensitized, spontaneously breathing rats inhale antigen through the nose, the predominant reaction occurs in the upper airways; changes in upper airway resistance do not result from reflexes originating in the lower airways; lower airway responses are mediated in part by cholinergic mechanisms.

Regulation of airway neurogenic inflammation by neutral endopeptidase.

Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases.

Relationship between in vivo airway reactivity and in vitro responsiveness of tracheal smooth muscle in inbred rats.

We evaluated the in vivo and in vitro airway responses to cholinergic stimulation in two highly inbred strains of rats. Five Fisher and six Lewis rats inhaled aerosols of doubling concentrations of methacholine (MCh). Pulmonary resistance (RL) was measured before and after each MCh inhalation. The concentration of MCh required to double RL (EC200RL MCh) was calculated. Spirally cut tracheal strips were suspended in an organ bath and the isometric tension was recorded. Cumulative concentration-response curves to carbachol were obtained using concentrations ranging from 10(-9) to 10(-3) M in half-log increments. The maximum tension (Tmax) developed and the negative log of the molar concentration required to induce 50% of Tmax (pD2) were calculated. The geometric mean of ED200RL MCh for the Fisher group was significantly lower than that for the Lewis group (0.68 and 2.66 mg/ml, respectively; p less than 0.05). No significant difference was found for Tmax (0.67 +/- 0.11 vs. 0.50 +/- 0.11 g) and pD2 value (6.24 +/- 0.08 vs. 6.21 +/- 0.22 -log M), indicating a similar contraction of tracheal smooth muscle. We therefore conclude that (1) in vivo airway responsiveness is strain-related and genetically determined in the rat; (2) that there is no correlation between in vivo and in vitro airway response to cholinergic stimulation and (3) that intrinsic properties of airway smooth muscle do not account for the differences observed in airway responsiveness in vivo.

Regional variability in the response of collateral resistance to histamine in the dog: effects of cyclooxygenase inhibition.

The aim of the study was to examine the role of cyclooxygenase metabolites in determining the variability in histamine responsiveness of the collateral channels of different lung segments of the dog. Using the wedged bronchoscope technique we measured the change in collateral resistance (Rcoll) to aerosolized histamine in two different lung segments of 5 anaesthetized, paralyzed, intubated, mongrel dogs. The same lung segments were examined twice under baseline conditions, and twice after indomethacin (INDO) pretreatment. Rcoll measurements were obtained under control conditions, after saline aerosol, and then after increasing concentrations of histamine (range 0.1 microgram/ml-10.0 mg/ml) were ultrasonically nebulized into the wedged segment. The concentration of histamine that elicited a 50% increase in Rcoll was calculated by log linear interpolation. In addition we performed bronchoalveolar lavage (BAL) in the wedged segment at the completion of the concentration-response curves, and assayed the BAL fluid for TXB2, PGE2, and 6-oxo-PGF1 alpha. The geometric mean ratio of histamine responsiveness between lung segments of each animal was 42.5-fold under control conditions and fell to 9.1-fold after INDO (P less than 0.05). While the concentration of TXB2 fell in the BAL after INDO, concentrations of PGE2 and 6-oxo-PGF1 alpha did not. Moreover, there was no correlation between levels of prostanoids and either responsiveness or variability in responsiveness of the collateral channels. Hence while cyclooxygenase blockade altered the regional variability in histamine responsiveness in the collateral channels, this change was not reflected in the levels of prostanoids in the BAL fluid.

The site of airway responses to methacholine or antigen inhalation challenge.

We evaluated changes in upper airway and lower pulmonary resistance after methacholine or ovalbumin challenge in inbred rats. Methacholine or antigen were inhaled through the intact upper airway and through a tracheostomy, in two groups of normal sensitized animals. Methacholine challenge resulted in both upper airway and lower pulmonary resistance increase regardless of the inhalation route. Lower airway ovalbumin challenge caused an increase in lower pulmonary resistance with no change in upper airway resistance. By contrast ovalbumin inhalation through the nose provoked a striking increase in upper airway resistance. Atropine pretreatment of lower airways reduced lower pulmonary response to antigen. We conclude that: 1) the increase in upper airway resistance following methacholine challenge occurs through a reflex mechanism; 2) upper airway constriction following antigen challenge through the nose results from a local mechanism; 3) the site of airway constriction depends on local mechanisms and vagal reflexes.

Neutral endopeptidase inhibitor thiorphan increases airway narrowing to inhaled sodium metabisulfite in normal subjects.

Possible mechanisms involved in inhaled sodium metabisulfite (MBS)-induced bronchoconstriction include cholinergic reflex and release of tachykinins from sensory nerve endings. Tachykinins are potent bronchoconstrictors cleaved and inactivated by neutral endopeptidase (NEP) in the airways. To investigate the role of tachykinins in airway response to MBS, we assessed the effect of NEP-inhibitor thiorphan on airway response to MBS in nine nonatopic, nonasthmatic subjects. Two inhalational challenges with doubling doses of MBS (0.03 to 16 mumol) were performed 3 d apart. Ten minutes before MBS challenge, subjects randomly inhaled either thiorphan (1.25 mg) or placebo according to a double-blind cross-over design. Airflow at 30% of vital capacity (V30p) from partial expiratory flow-volume curves was measured at baseline, 10 min after thiorphan or placebo, and 2 min after each MBS dose. The dose of MBS causing 40% fall in V30p (PD40V30p) was calculated. Neither thiorphan nor placebo affected baseline airway caliber. Thiorphan caused a leftward shift of the dose-response curve to MBS. After placebo a measurable PD40V30p was obtained in four of nine subjects. In these subjects PD40V30p fell significantly after thiorphan inhalation. Four of five subjects who did not exhibit PD40V30p after placebo showed measurable PD40V30p after thiorphan. Percent fall in V30p caused by highest dose of MBS was significantly greater after thiorphan compared with placebo (55.9 +/- 4.6% versus 30.8 +/- 5.6%; mean +/- SE; p < 0.001). Results of this study demonstrate that the NEP-inhibitor thiorphan increases MBS-induced bronchoconstriction in normal subjects, suggesting that tachykinins are involved in airway responses to inhaled MBS.

Endothelin potently constricts rat airways in vivo.

We investigated the effects of aerosolized endothelin (ET) on pulmonary mechanics of anesthetized spontaneously breathing rats. ET inhalation caused a concentration-dependent increase in pulmonary resistance (RL). In control condition RL was 0.17 +/- 0.04 cmH2O/ml/s (mean +/- SE; n = 6) and increased to 1.45 +/- 0.28 cmH2O/ml/s (p less than 0.05) after ET 4 x 10(-5) M. The pulmonary responses to ET lasted up to 60 minutes. These results suggest a role for endothelin in the regulation of airway smooth muscle tone.

Behavior of morphometric indices in pancreatic elastase-induced emphysema in rats.

Two morphometric indices, the destructive index (DI), a measure of alveolar wall destruction, and the proportion of destroyed alveolar attachments to the airways (AA), have been proposed as measures of early lung destruction in human smokers. The aim of this study was to compare DI and AA to the usual measure of airspace enlargement--the mean linear intercept (Lm)--in experimental emphysema. Porcine pancreatic elastase was administered intratracheally to 2 groups of Brown Norway rats (high-dose, n = 8, 1 IU/g body weight; low-dose, n = 4, 0.7 IU/g; control, n = 7). Total lung capacity (TLC), functional residual capacity (FRC) and pressure-volume curves were measured 3 weeks after administration of elastase. Lung elasticity was assessed by chord compliance (Cst). Administration of high-dose, but not low-dose, elastase led to significant increases in FRC and TLC. Cst significantly increased after high-dose elastase compared to controls (p less than 0.01). Lm increased after both low-dose and high-dose elastase compared to controls (p less than 0.01); DI and AA were increased only after high-dose elastase. Significant correlations were found between each morphometric index and Cst; the highest correlation was with AA. Behavior of the morphometric indices in this model differed from that reported in human smokers: Lm was a more sensitive measure of destruction than DI, reflecting a process marked by predominance of airspace enlargement over alveolar septal breaks. These differences from human smokers may result from a differing underlying pathogenesis of lung destruction.