吡非尼酮和尼达尼布抑制博来霉素诱导的小鼠肺纤维化药效比较

目的:比较不同时期给予吡非尼酮和尼达尼布对博来霉素诱导的小鼠肺纤维化的作用。方法:根据给药时间和给药时长,建立5类小鼠模型:炎症时期给药模型、纤维化早期预防给药模型、纤维化早期治疗模型、纤维化晚期治疗模型和全程给药模型,分别检测炎症指标和纤维化指标。结果:(1)抗炎抗氧化评估:吡非尼酮和尼达尼布均能降低炎症细胞数目,抑制炎症因子分泌。吡非尼酮对白细胞介素1β(IL-1β)和IL-4的抑制效果较好(P<0.01),尼达尼布对IL-6、IFN-γ的抑制作用较好(P<0.05)。吡非尼酮可显著提高超氧化物歧化酶(SOD)活性(P<0.01),而尼达尼布可显著降低丙二醛(MDA)和髓过氧化物酶(MPO)含量(P<0.01)。(2)肺组织胶原含量检测:在纤维化早期治疗模型、纤维化晚期治疗模型、全程给药模型中,尼达尼布对羟脯氨酸的抑制作用均优于吡非尼酮(P<0.05)。而吡非尼酮在纤维化早期预防给药模型中对羟脯氨酸的抑制作用较好(P<0.01)。(3)肺组织病理学评价:吡非尼酮和尼达尼布均可减少肺组织炎症浸润和纤维化面积,抑制效果对比结果同胶原检测结果一致。结论:在博来霉素诱导的小鼠肺纤维化模型中,吡非尼酮和尼达尼布均具有抗炎、抗氧化及抗肺纤维化作用,其中吡非尼酮在预防给药模型中作用效果更优,尼达尼布在早期、晚期和全程治疗模型中作用效果更优。     

Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat-Induced Pulmonary Fibrosis

Pirfenidone is known to slow the decline in vital capacity and increase survival in idiopathic pulmonary fibrosis (IPF). Besides, administration of glucocorticoids, e.g., prednisolone has been the conventional strategy to the treatment of patients with this disease, although their efficacy is under debate. Since multiple coactivated pathways are involved in the pathogenesis of IPF, combination therapy is a foundation strategy to cover many more synergetic mechanisms and increase response. The aim of the present study was to compare the therapeutic efficacy of prednisolone plus pirfenidone with pirfenidone alone in PQ-induced lung fibrosis. After development of PQ-induced lung fibrosis, pirfenidone, prednisolone, and their combination were administered for 14 consecutive days. Lung pathological lesions, along with increased hydroxyproline were determined in the paraquat group. Paraquat also caused oxidative stress and increasing the proinflammatory and profibrotic gene expression. Pirfenidone attenuated the PQ-induced pulmonary fibrosis from the analysis of antioxidant enzymes but prednisolone had no such effect. Co-treatment with pirfenidone and prednisolone suppressed lung hydroxyproline content, TGF-β1, and TNF-α; however, prednisolone alone could not suppress pulmonary fibrosis which was significantly suppressed only by pirfenidone. Pirfenidone also suppressed the increase in MMP-2 and TIMP-1 induced by PQ. All of these effects were exaggerated when pirfenidone coadministered with prednisolone. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of hydroxyproline content, oxidative stress and proinflammatory and profibrotic gene expression during the development of PQ-induced pulmonary fibrosis in rats and combination therapy with prednisolone can represent more potent therapeutic effects.     

灵菌红素对小鼠肺纤维化及其对Wnt/β-catenin信号通路的影响

目的观察灵菌红素对小鼠肺纤维化的改善作用,探讨Wnt/β-catenin信号通路的调控机制。方法C57BL/6小鼠随机分为对照组(Control group)、博来霉素组(Bleomycin group)和灵菌红素组(Peptide group),每组15只。除对照组外,其余各组小鼠气管内分别一次性注入100μL博莱霉素溶液(5mg/kg)以制备小鼠肺纤维化模型;造模完成后,治疗组分别腹腔注射300μg/kg灵菌红素或300 mg/kg吡非尼酮,连续28天。HE及Masson染色观察肺组织病理变化;测定肺组织羟脯氨酸含量;Western Blot检测肺组织中TGF-β1、α-SMA、Colla I、CollaⅢ及GSK-3β、p-GSK-3β、α-catenin蛋白的表达。结果灵菌红素明显改善小鼠肺组织病理损伤,降低肺组织中羟脯氨酸含量,下调TGF-β1、α-SMA、Colla I、CollaⅢ、p-GSK-3β及β-catenin蛋白表达水平,上调GSK-3蛋白表达水平。结论灵菌红素改善小鼠肺纤维化,与抑制Wnt/β-catenin信号通路活性相关。     

中介素抑制高肺血流性肺动脉高压大鼠肺组织胶原生成

 目的:研究中介素（IMD）对高肺血流性肺动脉高压大鼠肺组织胶原生成和沉积的调节作用及其机制。方法: 健康雄性SD大鼠20只,随机分为对照组（n=7）、分流组（n=7）和分流+IMD组（n=6）。对后2组大鼠行腹主动脉-下腔静脉分流术。8周后,对分流+IMD组大鼠,皮下埋微量渗透泵持续给予IMD 1.5 μg·kg-1·h-1。继续饲养2周后,比较各组大鼠肺动脉平均压（mPAP）、肺中、小动脉相对中膜厚度（RMT）,肺组织羟脯氨酸、Ⅰ和Ⅲ 型胶原、骨形成蛋白-2（BMP-2）含量和I、III型前胶原mRNA表达水平。结果: 与对照组相比,分流组大鼠mPAP明显上升,肺中、小动脉RMT明显增加,肺组织羟脯氨酸和Ⅰ、Ⅲ型胶原含量明显增多,Ⅰ、Ⅲ型前胶原mRNA表达上调,BMP-2含量明显增多。IMD则使分流大鼠肺动脉压力明显回降,肺血管结构改变缓解,胶原沉积减少,BMP-2含量降低,Ⅰ、Ⅲ 型前胶原mRNA表达下调。结论: IMD可通过抑制高肺血流大鼠肺组织胶原生成和沉积,缓解高肺血流性肺动脉高压和肺血管结构重构形成,该作用可能与BMP-2途径有关。     

Induction of unilateral pulmonary fibrosis in the rat by cadmium chloride

Intralobar instillation of cadmium chloride (CdCl2) into the left lungs of rats initiated a sequence of events that culminated in massive unilateral intraluminal fibrosis. Early events (days 1 and 2) after CdCl2 administration included infiltration of the treated lung with polymorphonuclear leukocytes, an increase in the number of alveolar macrophages, activation of the macrophages as assessed by the induction of cathepsin L mRNA, and the induction in liver of mRNA for the acute-phase response protein, alpha 1-acid glycoprotein. By days 5 to 7 in the treated lungs, mRNA for procollagen alpha 1(I) increased 20- to 60-fold, and mRNA for procollagen alpha 1(III) increased 4- to 14-fold. These increases were correlated with the almost complete filling of the alveolar spaces with fibroblasts and collagen. The contralateral lung exhibited no significant change in histology but showed a similar induction of collagen gene expression. These increases were tissue-specific, as the livers of these animals showed no change from the control levels of collagen gene expression. Procollagen messages in the treated and contralateral lungs were equally competent for translation into pro-alpha 1(I) and pro-alpha 2(I) polypeptides. Both the treated and contralateral lungs increased hydroxyproline content about 1.5- to 2-fold over 14 days. The contralateral lung, but not the treated lung, showed a 2-fold increase in lung volume. As a result, the collagen density (mg collagen/ml lung volume) doubled in the treated lung but remained constant in the contralateral lung. These data indicate that CdCl2 caused a rapid induction of pulmonary fibrosis in the treated lungs of rats and stimulated histologically normal growth of the contralateral lung.     

Respiratory mechanics and lung tissue remodeling in a hepatopulmonary syndrome rat model

Intrapulmonary vasodilation is a hallmark of the hepatopulmonary syndrome (HPS). However, its effects on respiratory mechanical properties and lung morphology are unknown. To determine these effects, 28 rats were randomly divided to control and experimental HPS groups (eHPS). The spontaneous breathing pattern, gas exchange, respiratory system mechanical properties, and lung and liver morphology of the rats were evaluated. Tidal volume, minute ventilation and mean inspiratory flow were significantly reduced in the eHPS group. Chest wall pressure dissipation against the resistive and viscoelastic components and elastic elastance were increased in the eHPS group. The lung resistive pressure dissipation was lower but the viscoelastic pressure was higher in the eHPS group. The airway volume proportion of collagen and elastic fibers was increased in the eHPS animals (16% and 51.7%; P<0.05 and P<0.001, respectively). The proportion of collagen volume in the vasculature increased 29% in the eHPS animals (P<0.01). HPS presents with respiratory system mechanical disarray as well as airway and vascular remodeling.     

Breathing pattern effects on pulmonary oxygen uptake

Pulmonary oxygen uptake has been analysed to determine the relative importance of breathing pattern parameters. Computer simulations of pulmonary oxygen transport were obtained with a multicompartment model of the lung, assuming an absence of shunts, constant cardiac output, and 21% inspired oxygen. Simulations of oxygen uptake in the lung for various breathing patterns showed that the parameters having the greatest effect on the arterial PO₂ are the tidal volume and breathing rate. At a constant tidal volume and breathing rate, that is a constant total ventilation, even extreme variations in the shape of the flow pattern produce relatively small changes in arterial Po₂. At a given inspired oxygen concentration, optimal strategies to provide sufficient gas exchange with mechanically aided ventilation in the absence of significant oedema or aetelectasis can be based primarily on changes in tidal volume and breathing rates.     

Endothelial Colony-Forming Cells Do Not Participate to Fibrogenesis in a Bleomycin-Induced Pulmonary Fibrosis Model in Nude Mice

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by fibroblast proliferation, extracellular matrix deposition, destruction of pulmonary alveolar architecture and vascular remodeling. Apart pirfenidone or nintendanib that only slow down the fibrotic process, there is no curative treatment other than lung transplantation. Because cell therapy approaches have been proposed in IPF, we hypothesized that injection of endothelial colony-forming cells (ECFCs), the vasculogenic subtype of endothelial progenitor cells, could modulate fibrosis in a Nude mouse model of bleomycin induced-pulmonary fibrosis. Mice were injected with ECFCs isolated from cord blood and from peripheral blood of adult IPF patients at two time-points: during the development of the fibrosis or once the fibrosis was constituted. We assessed morbidity, weight variation, collagen deposition, lung imaging by microCT, Fulton score and microvascular density. Neither ECFCs isolated from cord blood nor from IPF patients were able to modulate fibrosis or vascular density during fibrogenesis or when fibrosis was constituted. These findings indicate that human ECFCs do not promote an adaptive regenerative response in the lung upon fibrosis or angiogenic process in the setting of bleomycin-induced pulmonary fibrosis in Nude mice.     

Impact of respiratory pattern on lung mechanics and interstitial proteoglycans in spontaneously breathing anaesthetized healthy rats

Aim: The aim of this study was to investigate the effect of different pattern of spontaneous breathing on the respiratory mechanics and on the integrity of the pulmonary extracellular matrix. Methods: Experiments were performed on adult healthy rats in which different spontaneously breathing pattern was elicited through administration of two commonly used anaesthetic mixtures: pentobarbital/urethane (P/U) and ketamine/medetomidine (K/M). The animals (five per group) were randomized and left to spontaneously breath for 10 min (P/U‐sham; K/M‐sham) or for 4 h (P/U‐4 h; K/M‐4 h), targeting the anaesthesia level to obtain a tidal volume of about 8 mL kg^?1 body wt. At the end of the experiment, lung matrix integrity was assessed through determination of the glycosaminoglycans (GAGs) content in the lung parenchyma. Results: Compared with K/M, anaesthesia with P/U cocktail induced: (1) a higher respiratory rate and minute ventilation attained with lower P_aCO₂; (2) a higher pressure‐time‐product and work of breathing per minute; (3) a lower static lung compliance; (4) an increased activation of lung tissue metalloproteases; and (5) greater extraction of pulmonary interstitial GAGs. Conclusions: This study suggests that the breathing pattern induced by the different anaesthetic regimen may damage the pulmonary interstitium even during spontaneous breathing at physiological tidal volumes.     

Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis

Hermansky-Pudlak syndrome (HPS) is a rare disorder of oculocutaneous albinism, platelet dysfunction, and in some subtypes, fatal pulmonary fibrosis. There is no effective treatment for the pulmonary fibrosis except lung transplantation, but an initial trial using pirfenidone, an anti-fibrotic agent, showed promising results. The current, randomized, placebo-controlled, prospective, double-blind trial investigated the safety and efficacy of pirfenidone for mild to moderate HPS-1 and 4 pulmonary fibrosis. Subjects were evaluated every 4 months at the National Institutes of Health Clinical Center, and the primary outcome parameter was change in forced vital capacity using repeated measures analysis with random coefficients. Thirty-five subjects with HPS-1 pulmonary fibrosis were enrolled during a 4-year interval; 23 subjects received pirfenidone and 12 received placebo. Four subjects withdrew from the trial, 3 subjects died, and 10 serious adverse events were reported. Both groups experienced similar side effects, especially gastroesophageal reflux. Interim analysis of the primary outcome parameter, performed 12 months after 30 patients were enrolled, showed no statistical difference between the placebo and pirfenidone groups, and the study was stopped due to futility. There were no significant safety concerns. Other clinical trials are indicated to identify single or multiple drug regimens that may be effective in treatment for progressive HPS-1 pulmonary fibrosis.     

Pulmonary diffusing capacity for carbon monoxide by rebreathing in mechanically ventilated patients

Determination of pulmonary diffusing capacity is a routine method in pulmonary function laboratories for spontaneous breathing patients. However, it is not used in intensive care medicine for controlled ventilated patients with severe respiratory failure. We describe a rebreathing method for determination of pulmonary diffusing capacity for carbon monoxide (DCO) during mechanical ventilation based on an improved mathematical approach by Piiper and coworkers. The theoretical two-compartment model and the mathematical analysis are described. Factors (such as functional inhomogeneities, central blood volume, haemoglobin concentration, oxygen partial pressure, etc.) affecting this complex parameter of gas exchange are discussed. As the rebreathing technique for DCO seems to be influenced least by functional inhomogeneities in the diseased lung, it is advantageously qualified for measurements in intensive care patients. By adding an insoluble inert gas (for instance argon), functional residual capacity (FRC) can be determined at the same time. The method is well reproducible (+/- 3.8% for DCO and +/- 2.1% for FRC in duplicate determinations). During mechanical ventilation, the borderline towards pathological values determined by this method proved to be about 10 ml . min-1 . mmHg-1. First experimental and clinical results are presented which demonstrate DCO to be a qualified parameter for evaluating the pulmonary gas exchange function, indicating a progression of respiratory failure.     

The role of the vagus nerves in the respiratory and circulatory reactions to anaphylaxis in rabbits

1. Rabbits, previously sensitized to egg albumen, were anaesthetized and then rendered anaphylactic by a further injection of egg albumen; total lung conductance of flow, lung compliance, breathing rate, tidal volume, end-tidal CO(2)%, systemic arterial and right atrial blood pressures and heart rate were measured. Before induction of anaphylaxis, some rabbits were vagotomized, some had their vagi cooled to block differential conduction, and others were paralysed and artificially ventilated to minimize secondary changes in afferent activity from the lungs and in blood gas tensions.2. Lung conductance was reduced by anaphylaxis in spontaneously breathing and in artificially ventilated rabbits, and the effect was lessened by vagal cooling and greatly reduced by vagotomy; the hyperventilation of anaphylaxis took the form of an increase in tidal volume rather than in respiratory frequency during vagal cooling, and all changes in ventilation were abolished by vagotomy. These effects are therefore dependent on the integrity of vagal nervous pathways.3. Lung compliance was reduced by anaphylaxis to a similar degree in all groups of rabbits; all groups showed similar falls in end-tidal CO(2)%. These effects are therefore not dependent on the integrity of vagal conduction.4. Anaphylaxis reduced systemic arterial blood pressure, the response being smaller when the vagi were cooled or cut.5. It is concluded that anaphylaxis has direct actions on the pulmonary vascular bed, the distal airways or the alveoli. However, the changes in breathing, blood pressure and large airway calibre are mainly dependent on vagal reflex activity. By analogy with responses to injections of histamine and phenyl diguanide (Karczewski & Widdicombe, 1969b) it is concluded that anaphylaxis stimulates lung deflation and irritant receptors which mediate much of the reflex responses.     

Modeling Alveolar Volume Changes During Periodic Breathing in Heterogeneously Ventilated Lungs

A simplified model of periodic breathing, proposed by Whiteley et al. (Math. Med. Biol. 20:205–224, 2003), describes a non-uniform breathing pattern for a lung with an inhomogeneous gas distribution, such as that observed in some subjects suffering from respiratory disease. This model assumes a constant alveolar volume, and predicts incidence of irregular breathing caused by small, poorly ventilated regions of the lung. Presented here is an extension to this work which, by allowing variable lung volume, facilitates the investigation of pulmonary collapse in poorly ventilated compartments. A weakness of the original model is that a very small alveolar volume is required for periodic breathing to occur. The model presented within, which removes the assumption of constant compartment volume and allows alveolar volume to vary with time, predicts periodic breathing at higher, more realistic alveolar volumes. Furthermore, the predicted oscillations in ventilation match experimental data more closely. Thus the model that allows for alveolar collapse has improved upon these earlier results, and establishes a theoretical link between periodic breathing and atelectasis.     

The effect of disodium cromoglycate on pulmonary function in extrinsic bronchial asthma over 12 months

Fourteen patients with extrinsic type bronchial asthma had pulmonary ventilation, lung volume and gas transfer measurements at rest and on exercise, carried out during a control period and again at 2 weeks and 12 months whilst on disodium cromoglycate. A significant improvement in forced expiratory volume, vital capacity and the ratio of residual volume to total lung capacity and in the exercise gas transfer, was observed at 12 months. The improved pulmonary function measurements agree with the clinical assessment of the improvement obtained in these patients whilst on disodium cromoglycate.     

肺癌术后肺复张形态与肺功能相关性及其影响因素的研究

目的 用定量CT测量肺解剖容积联合肺功能检测分析肺复张形态和肺功能相关性及其影响因素。 方法 本试验是单中心回顾性研究。纳入符合标准的肺部术后患者,分别在术前和术后3个月使用定量CT计算肺解剖容积,同时测量肺功能指标包括FVC、FEV1和FEV1/FVC。然后分析肺容积与肺功能的相关性;根据肺复张指标,将患者分为非肺膨胀组和肺过度膨胀组,比较两组术前、术后肺容积变化和肺功能差异。 结果 共纳入40例患者,手术导致肺功能和肺容积都降低,其术前FVC (r=0.36, P=0.037 )、FEV1 （r=0.35, P=0.041）与肺容积呈正相关,术后3个月的FVC、FEV1与肺容积无显著相关 （P>0.05）。与非肺膨胀组相比较,肺过度膨胀组患者术前FEV1/FVC更低,且术后3月患者FEV1/FVC改善约5%;单因素分析表明个人吸烟史在肺过度膨胀组中更常见（P=0.045）。 结论 定量CT测量肺容积改变结合肺功能检查可用于早期识别术后肺过度膨胀形态,而吸烟史是肺肿瘤术后患者发生余肺过度膨胀的预测因素。     

Influence of ethanol on systemic and pulmonary hemodynamics in anesthetized dogs

Immediate circulatory reactions to acute intragastric ethanol administration were studied by a catheterization technique in spontaneously breathing dogs. Diluted ethanol was given in a dosage of 1 g/kg in test group I (n = 11), and 2 g/kg in group II (n = 10). The control group (n = 14) received only water. The highest blood ethanol concentration was 0.90 ± 0.07 mg/ml (mean ± SE) in group I, and 1.97 ± 0.10 mg/ml in group II. Heart rate and cardiac output increased (p < 0.001), but stroke volume, mean aortic blood pressure and right atrial blood pressure remained practically unchanged. Systemic vascular resistance decreased. Mean pulmonary arterial blood pressure increased markedly in both test groups (p < 0.001) while pulmonary arterial wedge pressure did not change. The pulmonary arterial resistance increased (p xyl 0.01). Changes in respiratory rate or volume and arterial pO₂ were negligible in group I, but respiratory minute volume decreased in group II. In conclusion, ethanol in concentrations 0.5 to 2.0 mg/ml increased resistance in the pulmonary arterial tree, indicating pulmonary arterial vasoconstriction, but reduced systemic vascular resistance, thus putting a concept of peripheral vasodilation in favour.     

Reference values for lung function tests in females. Regression equations with smoking variables

Prediction formulas for static and dynamic spirometry, gas distribution, static lung mechanics and transfer test were derived from measurements in healthy females. The measurements included total lung capacity, residual volume, airway resistance, static elastic recoil pressure of the lung, static compliance, closing volume, slope of the alveolar plateau (phase III), flow-volume variables (including mean transit time) during breathing of air or a helium/oxygen mixture, and conventional spirometric indices. The results from 86 smokers and 100 never-smokers were evaluated separately and combined. For all lung function tests, a single regression equation including time-related smoking variables, valid for both smokers and never-smokers, was obtained. For many lung function tests, a nonlinear age coefficient resulted in a significant reduction in variance compared with simple linear models. Heavy tobacco smoking influenced most lung function tests less than ageing from 20 to 70 years, but for airway resistance, volumic airway conductance, closing volume, phase III, FEV1/VC, volume of isoflow and mean transit time the opposite was found.     

Vagal influence on respiratory mechanics in newborn kittens

The aim of this study was to investigate the effects of pulmonary vagal innervation on respiratory mechanics of the newborn kitten. To this end, eight kittens in the first week of life were anaesthetized, tracheostomized and measurements of breathing pattern and respiratory mechanics compared between the intact and post-vagotomy condition. Airflow (V) and changes in lung volume (V) were measured with a pneumotachograph attached to the tracheal cannula; tracheal pressure (Ptr) was measured from a side-port of the cannula. Pressure in the oesophagus (Pes), representing the mean pleural pressure (Ppl), was recorded using a liquid filled catheter. By occluding the airway at end-inspiration, static respiratory system compliance (Crs), chest wall (Cw), and lung compliance (CL) were computed as the ratio of V over, respectively, Ptr, Pes and Ptr-Pes. The slope of the relationship between V and V during expiration represented the respiratory system time constant (tau rs), from which the resistance of the respiratory system was obtained (Rrs = tau rs/Crs). Dynamic lung compliance (Cdyn) and total pulmonary resistance (TPR) were obtained from the V, V and Ppl values during spontaneous breathing. After bilateral cervical vagotomy, most of the variables pertinent to respiratory mechanics did not change significantly, but Cw increased (35%) and TPR decreased (12%). The former probably resulted mainly from the deeper post-vagotomy breathing pattern, the latter from a loss in bronchomotor tone. Both the work per breath and the work per minute, computed as proposed by OTIS et al., tended to increase after vagotomy because of the deeper tidal volume, more than offsetting the changes in pulmonary mechanics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary function in systemic lupus erythematosus patients without respiratory symptoms.

Pulmonary function was studied in 22 patients with systemic lupus erythematosus without pulmonary clinical symptoms. The most striking features were: a) a restrictive functional pattern with hyperinflation, characterized by a decreased vital capacity and increased residual volume; b) alteration of the elastic properties of the lung, with increased pulmonary elastance; c) impairment of the alveolar-capillary gas transfer capacity, with very significant changes of the CO diffusion and arterio-alveolar gradients for O2 and CO2. No marked differences were found in functional disturbance among patients in the active or inactive phase of the disease.     

Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage pool deficiency and, in patients with HPS1 gene mutations, a progressive, fatal pulmonary fibrosis. We investigated the safety and efficacy of an antifibrotic agent, pirfenidone (800 mg, t.i.d.), in treating 21 adult Puerto Rican HPS patients, including 20 homozygous for the same HPS1 mutation. Patients were examined every 4 months for up to 44 months in a randomized, placebo-controlled trial, with rate of change in pulmonary function values as outcome parameters. Using the complete data set of 130 patient admissions, a repeated measures model showed that 11 pirfenidone-treated patients lost FVC at a rate 5% of predicted ( approximately 400 mL) per year slower than 10 placebo-treated patients (p=0.001). A random coefficients model showed no significant difference. However, using data restricted to patients with an initial FVC >50% of predicted, both models showed the pirfenidone group losing FVC (p<0.022), FEV(1) (p<0.0007), TLC (p<0.001), and DL(CO) (p<0.122) at a rate approximately 8%/year slower than the placebo group. Clinical and laboratory side effects were similar in the two groups. Pirfenidone appears to slow the progression of pulmonary fibrosis in HPS patients who have significant residual lung function.