Loss Of Alveoli Research Articles

Alterations at the Synthesis and Degradation of E-cadherin in the Human Lungs with Emphysema

Pulmonary emphysema leads to a cascade of events starting with enlarged alveoli, loss of alveoli and, subsequently to the damage and disruption of pulmonary epithelium. The integrity of the pulmonary epithelium, which is constituted by pneumocytes linked to each other through E-cadherin proteins, is important for respiration. The aim of the present study was to detect the content and destruction of E-cadherin protein and to investigate the contribution of E-cadherin to pulmonary emphysema pathogenesis. The structural changes, reparative capacity of the pulmonary epithelium, amount of E-cadherin protein and, the immunoreactivity of neural precursor cell expressed developmentally down-regulated protein 9 (NEDD9) were evaluated in emphysematous (n=7) and non-emphysematous (n=6) areas of lung samples taken from patients with chronic obstructive pulmonary disease. Emphysematous areas are characterized by enlarged alveoli, disrupted alveolar walls and epithelium, increased type 2 pneumocytes and NEDD9 immunoreactivity, and reduced E-cadherin proteins. Our data shows that E-cadherin levels are decreased in emphysematous areas due to its degradation by NEDD9. Decreased E-cadherin levels also lead to the disintegration of the pulmonary epithelium by causing the presence of weakness intercellular connections or the absence of intercellular connections. The repair of the pulmonary epithelium could not complete due to the reduced E-cadherin, because type 2 pneumocytes could not differentiate into type 1 pneumocytes. In conclusion, the reduced E-cadherin levels lead to emphysematous alterations in human lungs and contributes to pulmonary emphysema pathogenesis.

191 - Dose-response Effect of Glutathione added in Parenteral Nutrition on Lung Oxidative Stress and Alveolarization in Newborn Guinea Pig

Peroxides contaminating parenteral nutrition (PN) are associated with oxidized redox potential of glutathione in blood of preterm newborns ( Methods At day 3 of life, through a jugular catheter, guinea pigs (N=55) received PN (dextrose, amino acids, lipids, vitamins, electrolytes) enriched in glutathione (0, 50, 120, 165, 270, 370, 650 μg GSSG/kg/d). A control group (no manipulation, fed by mouth) served as reference. After 4 days, lungs were taken for determination of GSH, GSSG, redox potential (capillary electrophoresis) and alveolarization index (AI) (number of intercepts between a 1 mm line and histological structures). Data (mean ± sem) from animals on PN were compared by ANOVA, p Results The low AI observed with low doses (μg/kg/d) of GSSG (0-120: 26±1) was corrected with higher level (165-650: 30±1, p Conclusion Addition of glutathione into PN allows detoxification of peroxides (lower GSSG), preventing oxidation of redox and loss of alveoli. Our team is funded to start a clinical study soon.

Stereological monitoring of mouse lung alveolarization from the early postnatal period to adulthood.

Postnatal lung maturation generates a large number of small alveoli, with concomitant thinning of alveolar septal walls, generating a large gas exchange surface area but minimizing the distance traversed by the gases. This demand for a large and thin gas exchange surface area is not met in disorders of lung development, such as bronchopulmonary dysplasia (BPD) histopathologically characterized by fewer, larger alveoli and thickened alveolar septal walls. Diseases such as BPD are often modeled in the laboratory mouse to better understand disease pathogenesis or to develop new interventional approaches. To date, there have been no stereology-based longitudinal studies on postnatal mouse lung development that report dynamic changes in alveoli number or alveolar septal wall thickness during lung maturation. To this end, changes in lung structure were quantified over the first 22 mo of postnatal life of C57BL/6J mice. Alveolar density peaked at postnatal day (P)39 and remained unchanged at 9 mo (P274) but was reduced by 22 mo (P669). Alveoli continued to be generated, initially at an accelerated rate between P5 and P14, and at a slower rate thereafter. Between P274 and P669, loss of alveoli was noted, without any reduction in lung volume. A progressive thinning of the alveolar septal wall was noted between P5 and P28. Pronounced sex differences were observed in alveoli number in adult (but not juvenile) mice, when comparing male and female mouse lungs. This sex difference was attributed exclusively to the larger volume of male mouse lungs.

Lung remodeling in aging surfactant protein D deficient mice

Pulmonary surfactant, a mixture of lipids and proteins at the air–liquid interface of alveoli, prevents the lungs from collapsing due to surface tension. One constituent is surfactant-associated protein-D (SP-D), a protein involved in surfactant homeostasis and innate immunity. Mice deficient in SP-D (SP-D (−/−)) has been described as developing a characteristic phenotype which affects the surfactant system (including changes in the intra-cellular and intra-alveolar surfactant pool, alveolar epithelial type II cells and alveolar macrophages), lung architecture and its inflammatory state (development of an emphysema-like pathology, inflammatory cell infiltration). Furthermore, it has been described that these mice develop sub-pleural fibrosis and a thickening of alveolar septal walls. The aim of the present study was to systematically investigate the long term progression of this phenotype with special focus on parenchymal remodeling, whether there are progressive emphysematous changes and whether there is progressive septal wall thickening which might indicate the development of pulmonary fibrosis. By means of design-based stereology and light microscopy, lungs of wild type (wt) and SP-D (−/−) mice of four age groups (3, 6, 12 and ∼18 months) were investigated. The data do not suggest a relevant spontaneous pro-fibrotic remodeling or a destructive process in the aging SP-D (−/−) mice. We demonstrated neither a significant destructive emphysema nor significant thickening of alveolar septal walls, but the data suggest an increase in the number weighted mean alveolar volume in aging SP-D (−/−) mice without loss of alveoli or alveolar epithelial surface area per lung. This increase may reflect over-distension due to altered mechanical properties of alveoli. In the light of our findings and data from the literature, the question arises as to whether a lack of SP-D promotes structural changes in the lung which have been described as being associated with aging lungs. Furthermore, data from wt mice point to an ongoing alveolarization during adult life in C57Bl/6NCrl mice. Our data may promote further studies on the morphological development of the aging lung and the role of SP-D in this process.

Effect of recombinant human keratinocyte growth factor in inducing Ras–Raf–Erk pathway-mediated cell proliferation in emphysematous mice lung

Context: Pulmonary emphysema is resulted due to destruction of the structure of the alveoli. Recently, exogenous recombinant human Keratinocyte growth factor (rHuKGF) has been reported to induce the regeneration of gas exchange structures. However, the molecular mechanisms governing this process are so far unknown.Objective: The objective of this study was to investigate the effect of rHuKGF in the lungs of emphysema-challenged mice on Ras–Raf–Erk (Erk, extracellular signal-regulated kinase) mediated signaling pathway that regulates alveolar epithelial cell proliferation.Methods: Three experimental groups (i.e. emphysema, therapy and control group) were prepared. Lungs of mice were therapeutically treated at three occasions by oropharyngeal instillation of 10 mg rHuKGF per kg body weight after induction of emphysema by porcine pancreatic elastase (PPE). Subsequently, lung tissues from each mouse were collected for histopathology and molecular biology studies.Results and discussion: Histopathology photomicrographs and Destructive Index analysis have shown that elastase induced airspace enlargement and loss of alveoli were recovered in therapy group. Moreover, proliferating cell nuclear antigen (PCNA) at mRNA and protein expression level was markedly increased in therapy group than emphysema group. Upon validation at mRNA level, expressions of FGF-7, FGF-R, Ras, c-Raf, Erk-1, Erk-2, c-Myc and were significantly increased, whereas Elk-1 was notably decreased in therapy group when compared with emphysema group and were well comparable with the control group.Conclusion: Therapeutic supplementation of rHuKGF rectifies the deregulated Ras–Raf–Erk pathway in emphysema condition, resulting in alveolar epithelium regeneration. Hence, rHuKGF may prove to be a potential drug in the treatment of emphysema.

Ascorbylperoxide from parenteral nutrition induces an increase of redox potential of glutathione and loss of alveoli in newborn guinea pig lungs

BackgroundBronchopulmonary dysplasia is one of the main complications associated with extreme prematurity. Oxidative stress is suspected to be a trigger event of this lung disease, which is characterized by impaired alveolar development. Peroxides, mainly ascorbylperoxide and H2O2, are known contaminant of parenteral nutrition. We hypothesize that these oxidant molecules induce bronchopulmonary dysplasia development. The aim was to determine if the infusion of ascorbylperoxide, whether in presence or absence of H2O2, is associated with oxidative stress, apoptosis and loss of alveoli in the lungs of newborn guinea pigs. MethodThree-day-old guinea pigs received parenteral solutions containing 0, 20, 60 or 180 µM ascorbylperoxide in the presence or not of 350 µM H2O2 (concentrations similar to those measured in parenteral nutrition). After 4 days, the lungs were collected for determination of glutathione's redox potential, caspase-3 activation (an apoptosis marker), alveolarization index (by histology), activation of Nrf2 and NFκB (biological markers of oxidative stress), and IL-6 and PGJ2 levels (markers of NFκB activation). Groups were compared by ANOVA, p < 0.05. ResultsLoss of alveoli was associated with ascorbylperoxide in a dose-dependent manner, without an influence of H2O2. The dose-dependent activation of caspase-3 by ascorbylperoxide was lower in the presence of H2O2. Ascorbylperoxide induced an increase of redox potential in a dose-dependent manner, which reached a plateau in presence of H2O2. Nrf2 and NFκB were activated by H2O2 but not by ascorbylperoxide. ConclusionResults suggest that ascorbylperoxide, generated in parenteral nutrition, is involved in the development of bronchopulmonary dysplasia, independently of the increase of the redox potential. This study underlines the importance of developing a safer formulation of parenteral nutrition.

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastase-induced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with <0.6% residual elastase activity, provided no protection from elastase-induced emphysema. Covalently combining an endogenous peptide from the target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy.

Keratinocyte Growth Factor induces alveolisation in emphysematous mouse lungs via TGFβ-1

Rationale: Emphysema is characterized by destruction of alveoli and extracellular matrix (ECM) with ensuing airspace enlargement. Induction of alveolar and ECM regeneration is still a major challenge in emphysema therapy. Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10mg rHuKGF per kg body weight after induction of emphysema by porcine pancreatic elastase (PPE). Results: Airflow limitation associated with emphysema was largely reverse. PPE induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. The therapeutically effect of rHuKGF related with induced proliferation of epithelium, endothelium and fibroblasts as well as increased expression and activation of TGFβ-1, p-Smad2, PAI-1, and elastin as assessed by quantitative RT-PCR, Western blotting and immuno histochemistry. Thus rHuKGF induced activation of TGFβ-1 from primary mouse AE2 cells, LA-4 cells but not in MLF cultured alone. Recombinant TGFβ-1 but not rHuKGF induced elastin gene expression in MLF. Blockade of TGFβ-signaling by neutralizing antibody abolished these effects. Conclusions: These data indicate that therapeutic application of rHuKGF has the potential to induce alveolar maintenance and ECM in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to activation of TGFβ-1.

Palifermin Induces Alveolar Maintenance Programs in Emphysematous Mice

Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy. To investigate whether therapeutic application of palifermin (DeltaN23-KGF) is able to induce a regenerative response in distal lung parenchyma after induction of pulmonary emphysema. Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg DeltaN23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase. Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase-induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. DeltaN23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanced differentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-beta1, TGF-beta2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. DeltaN23-KGF induced the expression of TGF-beta1 in and release of active TGF-beta1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-beta1 but not DeltaN23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of DeltaN23-KGF in LA-4/MLF cocultures. Our data demonstrate that therapeutic application of DeltaN23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-beta1.

Adrenomedullin Promotes Lung Angiogenesis, Alveolar Development, and Repair

Bronchopulmonary dysplasia (BPD) and emphysema are significant global health problems at the extreme stages of life. Both are characterized by alveolar simplification and abnormal distal airspace enlargement due to arrested development or loss of alveoli, respectively. Both lack effective treatments. Mechanisms that inhibit distal lung growth are poorly understood. Adrenomedullin (AM), a recently discovered potent vasodilator, promotes angiogenesis and has protective effects on the cardiovascular and respiratory system. Its role in the developing lung is unknown. We hypothesized that AM promotes lung angiogenesis and alveolar development. Accordingly, we report that lung mRNA expression of AM increases during normal alveolar development. In vivo, intranasal administration of the AM antagonist, AM22-52 decreases lung capillary density (12.4 +/- 1.5 versus 18 +/- 1.5 in control animals; P < 0.05) and impairs alveolar development (mean linear intercept, 52.3 +/- 1.5 versus 43.8 +/- 1.8 [P < 0.05] and septal counts 62.0 +/- 2.7 versus 90.4 +/- 3.5 [P < 0.05]) in neonatal rats, resulting in larger and fewer alveoli, reminiscent of BPD. This was associated with decreased lung endothelial nitric oxide synthase and vascular endothelial growth factor-A mRNA expression. In experimental oxygen-induced BPD, a model of arrested lung vascular and alveolar growth, AM attenuates arrested lung angiogenesis (vessel density, 6.9 +/- 1.1 versus 16.2 +/- 1.3, P < 0.05) and alveolar development (mean linear intercept, 51.9 +/- 3.2 versus 44.4 +/- 0.7, septal counts 47.6 +/- 3.4 versus 67.7 +/- 4.0, P < 0.05), an effect in part mediated by inhibition of apoptosis. AM also prevents pulmonary hypertension in this model, as assessed by decreased right ventricular hypertrophy and pulmonary artery medial wall thickness. Our findings suggest a role for AM during normal alveolar development. AM may have therapeutic potential in diseases associated with alveolar injury.

Airway Delivery of Mesenchymal Stem Cells Prevents Arrested Alveolar Growth in Neonatal Lung Injury in Rats

Bronchopulmonary dysplasia (BPD) and emphysema are characterized by arrested alveolar development or loss of alveoli; both are significant global health problems and currently lack effective therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) prevent adult lung injury, but their therapeutic potential in neonatal lung disease is unknown. We hypothesized that intratracheal delivery of BMSCs would prevent alveolar destruction in experimental BPD. In vitro, BMSC differentiation and migration were assessed using co-culture assays and a modified Boyden chamber. In vivo, the therapeutic potential of BMSCs was assessed in a chronic hyperoxia-induced model of BPD in newborn rats. In vitro, BMSCs developed immunophenotypic and ultrastructural characteristics of type II alveolar epithelial cells (AEC2) (surfactant protein C expression and lamellar bodies) when co-cultured with lung tissue, but not with culture medium alone or liver. Migration assays revealed preferential attraction of BMSCs toward oxygen-damaged lung versus normal lung. In vivo, chronic hyperoxia in newborn rats led to air space enlargement and loss of lung capillaries, and this was associated with a decrease in circulating and resident lung BMSCs. Intratracheal delivery of BMSCs on Postnatal Day 4 improved survival and exercise tolerance while attenuating alveolar and lung vascular injury and pulmonary hypertension. Engrafted BMSCs coexpressed the AEC2-specific marker surfactant protein C. However, engraftment was disproportionately low for cell replacement to account for the therapeutic benefit, suggesting a paracrine-mediated mechanism. In vitro, BMSC-derived conditioned medium prevented O(2)-induced AEC2 apoptosis, accelerated AEC2 wound healing, and enhanced endothelial cord formation. BMSCs prevent arrested alveolar and vascular growth in part through paracrine activity. Stem cell-based therapies may offer new therapeutic avenues for lung diseases that currently lack efficient treatments.

Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia and emphysema are significant global health problems at the extreme stages of life. Both are characterized by arrested alveolar development or loss of alveoli, respectively. Both lack effective treatment strategies. Knowledge about the genetic control of branching morphogenesis in mammals derives from investigations of the respiratory system in Drosophila, but mechanisms that regulate alveolar development remain poorly understood. Even less is known about regulation of the growth and development of the pulmonary vasculature. Understanding how alveoli and the underlying capillary network develop, and how these mechanisms are disrupted in disease states, are critical for developing effective therapies for lung diseases characterized by impaired alveolar structure. Recent observations have challenged old notions that the development of the blood vessels in the lung passively follows that of the airways. Rather, increasing evidence suggests that lung blood vessels actively promote alveolar growth during development and contribute to the maintenance of alveolar structures throughout postnatal life. Our working hypothesis is that disruption of angiogenesis impairs alveolarization, and that preservation of vascular growth and endothelial survival promotes growth and sustains the architecture of the distal airspace. Furthermore, the explosion of interest in stem cell biology suggests potential roles for endothelial progenitor cells in the pathogenesis or treatment of lung vascular disease. In this Pulmonary Perspective, we review recent data on the importance of the lung circulation, specifically examining the relationship between dysmorphic vascular growth and impaired alveolarization, and speculate on how these new insights may lead to novel therapeutic strategies for bronchopulmonary dysplasia.

Toward therapeutic pulmonary alveolar regeneration in humans.

In humans, age results in loss of pulmonary alveoli; menopause accelerates loss of diffusing capacity, an index of alveolar surface area; and disease (e.g., chronic obstructive pulmonary disease) results in loss of alveoli. Thus, an important goal for investigators is to generate knowledge that allows induction of pulmonary alveolar regeneration in humans. Our enthusiasm for this goal and our assessment of its feasibility are based on work in several laboratories over the last decade that has disproved the notion that pulmonary alveoli are incapable of regeneration, and on the growing evidence that signals that regulate programs of alveolar turnover (loss and regeneration) are conserved from rodents to humans. We review animal models of alveolar loss and regeneration and their conservation during evolution, and hence their relevance to humans.

Lung growth and repair

For many years, the structure of the lung was thought to be static in the absence of disease. Over the past 10 years, the numbers of studies and reports aimed at understanding the molecular basis for the formation and loss of alveoli have accelerated, propelled by the notion that alveoli are, in

Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice.

Lung tissue elastic recoil and the dimension and number of pulmonary gas-exchange units (alveoli) are major determinants of gas-exchange function. Loss of gas-exchange function accelerates after menopause in the healthy aged and is progressively lost in individuals with chronic obstructive pulmonary disease (COPD). The latter, a disease of midlife and later, though more common in men than in women, is a disease to which women smokers and never smokers may be more susceptible than men; it is characterized by diminished lung tissue elastic recoil and presently irremediable alveolar loss. Ovariectomy in sexually immature rats diminishes the formation of alveoli, and estrogen prevents the diminution. In the present work, we found that estrogen receptor-alpha and estrogen receptor-beta, the only recognized mammalian estrogen receptors, are required for the formation of a full complement of alveoli in female mice. However, only the absence of estrogen receptor-beta diminishes lung elastic tissue recoil. Furthermore, ovariectomy in adult mice results, within 3 wk, in loss of alveoli and of alveolar surface area without a change of lung volume. Estrogen replacement, after alveolar loss, induces alveolar regeneration, reversing the architectural effects of ovariectomy. These studies 1) reveal estrogen receptors regulate alveolar size and number in a nonredundant manner, 2) show estrogen is required for maintenance of already formed alveoli and induces alveolar regeneration after their loss in adult ovariectomized mice, and 3) offer the possibility estrogen can slow alveolar loss and induce alveolar regeneration in women with COPD.

Matrix proteoglycans and remodelling of interstitial lung tissue in lymphangioleiomyomatosis.

The interstitial lung disease lymphangioleiomyomatosis (LAM) is characterized by diffuse proliferation of smooth muscle cells (SMCs), which in many patients show TSC2 (tuberin) gene mutations, in addition to thickening of interstitial tissues, loss of alveoli, and the development of cystic spaces. While SMC proliferation is the defining feature of LAM, a significant proportion of LAM lung tissue consists of expanded interstitial connective tissue that is negative for smooth muscle actin and TSC2 mutations. The importance of this actin-negative interstitial tissue to the pathophysiology of LAM is not clear. The present study has determined the contribution of this interstitial tissue to LAM lung volume by morphometric analysis and has examined its cell and matrix proteoglycan composition by immunohistochemistry. Lung tissue from nine LAM patients and four control subjects was examined. LAM lung contained twice as much interstitial tissue as control lung (27% versus 13% of total lung volume), with SMCs accounting for less than 25% of the interstitial volume. Areas of interstitial tissue stained strongly for the matrix proteoglycans versican and biglycan. Decorin was prominent in association with collagen bundles. SMCs did not stain, or stained lightly, for proteoglycans. Versican and biglycan deposits were closely associated with actin-negative interstitial fibroblasts identified by prolyl 4-hydroxylase immuno-staining. Comparatively normal alveolar walls in LAM lung also stained strongly for versican and had a reduced elastin content. Thickened interstitial regions contained significant amounts of elastin (approximately 13% of interstitial volume) but with fibres in disorganized patterns. Elastic fibres were absent from areas that stained strongly for versican and biglycan. These areas also showed weak staining for elastin binding protein (EBP), consistent with proteoglycan-induced shedding of EBP and inhibition of elastic fibre formation. These findings point to a significant contribution from matrix proteoglycans to the expanded and remodelled interstitial lung tissue of LAM patients.

Can Exogenously Administered Hyaluronan Improve Respiratory Function in Patients With Pulmonary Emphysema?

While most attempts at developing a treatment for pulmonary emphysema have focused on the use of elastase inhibitors to reduce elastic fiber damage and the loss of alveoli, this laboratory has developed a method of preventing such injury by the intratracheal administration of hyaluronan (HA). Animals treated with HA prior to the induction of experimental emphysema develop significantly less disease than untreated controls. The protective effect of HA may be related to its ability to bind to lung elastic fibers, thereby preventing their breakdown by elastases. Although clinical trials involving nebulized HA are not expected to yield a measurable treatment effect for at least several years, it is proposed that the special ability of this polysaccharide to retain water may increase the elasticity of lung elastic fibers, producing a relatively rapid improvement in pulmonary mechanics. Such an outcome might speed the development of this potential treatment for pulmonary emphysema.

Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice.

Increased production of EGF or TGF-alpha by the respiratory epithelial cells has been associated with the pathogenesis of various forms of lung injury. Growth factors and cytokines are thought to act locally, via paracrine and autocrine mechanisms, to stimulate cell proliferation and matrix deposition by interstitial lung cells resulting in pulmonary fibrosis. To test whether TGF-alpha mediates pulmonary fibrotic responses, we have generated transgenic mice expressing human TGF-alpha under control of regulatory regions of the human surfactant protein C (SP-C) gene. Human TGF-alpha mRNA was expressed in pulmonary epithelial cells in the lungs of the transgenic mice. Adult mice bearing the SP-C-TGF-alpha transgene developed severe pulmonary fibrosis. Fibrotic lesions were observed in peribronchial, peribronchiolar, and perivascular regions, as well as subjacent to pleural surfaces. Lesions consisted of fibrous tissue that included groups of epithelial cells expressing endogenous SP-C mRNA, consistent with their identification as distal respiratory epithelial cells. Peripheral fibrotic regions consisted of thickened pleura associated with extensive collagen deposition. Alveolar architecture was disrupted in the transgenic mice with loss of alveoli in the lung parenchyma. Pulmonary epithelial cell expression of TGF-alpha in transgenic mice disrupts alveolar morphogenesis and produces fibrotic lesions mediated by paracrine signaling between respiratory epithelial and interstitial cells of the lung.