Pulmonary elastic fibers in normal human development and in pathological conditions

Normal human pulmonary elastic fiber development and development in some pathological conditions were examined using elastic stains by light microscopy, electron microscopy, and immunohistochemistry. In normal development elastic fibers, composed mainly of microfibrils, first appeared around primitive bronchioles at 10 weeks of gestation. As they matured, their appearance became more amorphous, and they extended into the peripheral alveolar walls. Development of elastic fibers was retarded in the hypoplastic lungs of the oligohydramnios syndrome, diaphragmatic hernia, and hydrops fetalis. Elastic development was also retarded in congenital pulmonary lymphangiectasia and in focal areas of lungs with pulmonary dysplasia. Distribution of well-developed elastic fibers was found around the dilated bronchioles and alveoli in cases of congenital cystic adenomatoid malformation and extralobar pulmonary sequestration. Elastic fibers were distributed irregularly and unevenly in the lungs of bronchopulmonary dysplasia and ventilated cases of Wilson Mikity syndrome. In addition, four very immature infants who had progressively deteriorating respiratory function showed an almost total lack of elastic fibers in their alveolar walls.     

Persistent Pulmonary Hypertension of the Newborn due to Alveolar Capillary Dysplasia

Three unrelated female term infants died when less than 1 month old from intractable pulmonary hypertension associated with deficient capillaries in airspace walls, anomalous small pulmonary veins in bronchiolar-arterial rays, and medial thickening in small pulmonary arteries together with peripheral muscularization. This complex uascular abnormality in the lungs has been termed alveolar capillary dysplasia and/or misalignment of lung uessels in seven previously reported cases. Each infant also showed abnormally immature parenchymal development in the lungs, as was noted in four of the seven prior cases. One had phocomelia; four of the seven prior cases had a variety of congenital anomalies. The primary pulmonary uascular anomaly is likely to be a failure of fetal lung uascularization dating from the second trimester and to be due to action of an unknown teratogen. Centroacinar veins may represent bronchial veins that do not normally develop beyond the ends of cartilaginous bronchi. Pulmonary arterial occlusive changes are interpreted, as reactive to obstruction at the level of pulmonary arterioles.     

Cystic lung disease in Down's syndrome: a report of two cases

Previously unreported lung disease found at autopsy in 2 young infants with Down's syndrome and congenital heart disease (complete atrioventricular canal malformation with left-to-right shunt) is described. The perinatal and neonatal period was unremarkable, and there was no history of mechanical ventilation or administration of high concentration of oxygen for extended periods. In 1 of the cases respiratory symptoms and hyperinflation with focal cystic changes in the lung fields on chest X-ray were noted at 5-7 months of age. Pathologically there was cystic dilatation of alveoli with focal cuboidal metaplasia of alveolar epithelium and mild to moderate focal alveolar septal fibrosis. Wilson-Mikity syndrome, congenital pulmonary lymphagiectasia, bronchopulmonary dysplasia, and idiopathic interstitial fibrosis of lungs were ruled out on clinical and/or pathologic grounds. Factors such as compression of bronchi by enlarged pulmonary arteries or cardiac chambers, peribronchiolar accumulation of fluid, pulmonary hypoplasia occurring in Down's syndrome, and episodes of pulmonary arterial hypoperfusion associated with severe congenital heart disease may be related to the pathogenesis of the lesion.     

Cystic Lung Disease in Down's Syndrome: A Report of two Cases

Previously unreported lung disease found at autopsy in 2 young infants with Down's syndrome and congenital heart disease (complete atrioventricular canal malformation with left-to-right shunt) is described. The perinatal and neonatal period was unremarkable, and there was no history of mechanical ventilation or administration of high concentrations of oxygen for extended periods. In 1 of the cases respiratory symptoms and hyperinflation with focal cystic changes in the lung fields on chest X-ray were noted at 5-7 months of age. Pathologically there was cystic dilatation of alveoli with focal cuboidal metaplasia of alveolar epithelium and mild to moderate focal alveolar septal fibrosis. Wilson-Mikity syndrome, congenital pulmonary lymphangiectasia, bronchopulmonary dysplasia, and idiopathic interstitial fibrosis of lungs were ruled out on clinical and/or pathologic grounds. Factors such as compression of bronchi by enlarged pulmonary arteries or cardiac chambers, peribronchiolar accumulation of fluid, pulmonary hypoplasia occurring in Down's syndrome, and episodes of pulmonary arterial hypoperfusion associated with severe congenital heart disease may be related to the pathogenesis of the lesion.     

Disordered pulmonary myofibroblast distribution and elastin expression in preterm infants with Ureaplasma urealyticum pneumonitis.

Respiratory colonization of preterm infants with Ureaplasma urealyticum is a significant risk factor for bronchopulmonary dysplasia, a chronic lung disease characterized by arrest of alveolar development, variable interstitial fibrosis, and disordered elastic fibers in the distal airspaces. As indicated in previous studies, moderate to severe fibrosis is a hallmark of pathology in the Ureaplasma-infected preterm lung. To further characterize the preterm lung's response to Ureaplasma, lung specimens from 4 gestational controls (GC), 12 other pneumonia and 5 Ureaplasma-infected infants were analyzed by immunohistochemistry for alpha-smooth muscle actin (alphaSMA) and transforming growth factor beta1 (TGFbeta1), Hart's elastin staining, and in situ hybridization for tropoelastin (TE) expression. Cells positive for alphaSMA were observed in thickened, extensive bundles surrounding terminal airspaces in Ureaplasma and other pneumonia cases compared to individual myofibroblasts in GC. The myofibroblast pattern correlated with the severity of fibrosis, but not duration of ventilation. Transforming growth factor beta1 immunostaining was primarily localized to alveolar macrophages and was increased in Ureaplasma more than in other pneumonia cases. Elastic fibers and TE-expressing cells were spatially limited to emerging septal tips in GC. In pneumonia cases, increased deposition of elastic fibers was observed surrounding terminal airspaces, but TE expression was similar to GC. In Ureaplasma specimens, accumulation of elastic fibers correlated with duration of ventilation, and TE expression was extensive throughout the walls of terminal airspaces. These findings suggest that Ureaplasma is associated with alveolar macrophage TGFbeta1 immunostaining and myofibroblast proliferation contributing to abnormal septation, interstitial fibrosis, and a prolonged and strong elastogenic response in the preterm lung.     

Primary pulmonary hypoplasia: report of a case with polyhydramnios.

We describe a case of extreme primary pulmonary hypoplasia. No other congenital anomalies and none of the conditions known to be associated with pulmonary hypoplasia were present. Pregnancy had been complicated by substantial polyhydramnios. The hypoplasia was due to a marked deficiency of the respiratory parenchyma in the presence of normal upper airways and bronchi. Virtually no parenchymal development had occurred and there were very few bronchioles, alveolar ducts, and alveoli. The changes differ from those seen in pulmonary hypoplasia secondary to congenital diaphragmatic hernia, bilateral renal agenesis, anomalies of the urinary outflow tracts, and malformations of the thoracic cavity, in which the pulmonary hypoplasia appears to be compressive in nature. While neither the etiology or pathogenesis of the pulmonary hypoplasia are apparent in this case, the presence of substantial polyhydramnios during pregnancy suggests the possibility that the developing lungs may offer an important surface area for reabsorption and recycling of constituents of amniotic fluid.     

Changes in pulmonary circulation in severe bronchopulmonary dysplasia.

Eight patients with severe bronchopulmonary dysplasia underwent cardiac catheterisation. Seven had a pulmonary vascular resistance greater than 3 mm Hg.l-1 min.m2 (mean 8.9, range 2.2-13.8). All had raised intrapulmonary shunts (mean 25.6%, range 5.4-50%, normal less than 5%). Two had a high alveolar dead space, and two had unsuspected congenital heart disease. Epoprostenol (prostacyclin), but not 100% oxygen, caused a significant fall in pulmonary vascular resistance. Death was associated with a high pulmonary vascular resistance and a high shunt. Morphometric studies in three cases showed normal numbers of airways, but increased thickness of bronchial muscle. The numbers of alveoli were reduced and the walls thickened. There was increased medial thickness in small pulmonary arteries with distal extension of muscle. In the oldest child some vessels were obliterated by fibrosis. We speculate that measurements of pulmonary vascular resistance and shunt may have prognostic value; that a trial of pulmonary vasodilators other than oxygen might be worthwhile in patients with poor prognosis; and that abnormalities of the pulmonary circulation contribute to the difficulties of managing patients with bronchopulmonary dysplasia.     

Rhabdomyomatous Dysplasia of the Lung: A Case Report with Review of the Literature

The occurrence of rhabdomyomatous dysplasia of the lung in a macerated term baby with multiple congenital anomalies is described. The hypoplastic right lung revealed abundant striated muscle in the alveolar septa and bronchial walls of the middle and lower lobes. A brief review of the literature is followed by a discussion of the pathogenesis of this rare pulmonary malformation.     

Rhabdomyomatous dysplasia of the lung: a case report with review of the literature

The occurrence of rhabdomyomatous dysplasia of the lung in a macerated term baby with multiple congenital anomalies is described. The hypoplastic right lung revealed abundant striated muscle in the alveolar septa and bronchial walls of the middle and lower lobes. A brief review of the literature is followed by a discussion of the pathogenesis of this rare pulmonary malformation.     

Rhabdomyomatous Dysplasia of the Lung

This article deals with the presence of nontumoral striated muscle fibers in the lungs of 3 neonates. These cells were diffusely distributed in one lung (case 1) or in both (case 2), orfocally localized to the lung parenchyma adjacent to the liver in a case with a large right diaphragmatic hernia (case 3). The striated muscle fibers were located in the walls of small bronchi and bronchioli or in the alveolar interstitium. Other major lung malformations found simultaneously were absence of lobation, hypoplastic lungs, and hypoplastic pulmonary vessels. The origin of striated muscle fibers in the neonatal lung has been attributed to anomalous differentiation of mesoblastic cells (as in cases 1 and 2). The presence of striated muscle cells in the lower margin of a hypoplastic lung associated with a right diaphragmatic hernia (case 3) suggests that intrapulmonary inclusion of diaphragmatic muscle fibers might be a source as well. Striated muscle fibers in the lung are commonly associated with major malformations involving heart and lungs, suggesting a much wider morphogenetic error.     

Rhabdomyomatous dysplasia of the lung

This article deals with the presence of nontumoral striated muscle fibers in the lungs of 3 neonates. These cells were diffusely distributed in one lung (case 1) or in both (case 2), or focally localized to the lung parenchyma adjacent to the liver in a case with a large right diaphragmatic hernia (case 3). The striated muscle fibers were located in the walls of small bronchi and bronchioli or in the alveolar interstitium. Other major lung malformations found simultaneously were absence of lobation, hypoplastic lungs, and hypoplastic pulmonary vessels. The origin of striated muscle fibers in the neonatal lung has been attributed to anomalous differentiation of mesoblastic cells (as in cases 1 and 2). The presence of striated muscle cells in the lower margin of a hypoplastic lung associated with a right diaphragmatic hernia (case 3) suggests that intrapulmonary inclusion of diaphragmatic muscle fibers might be a source as well. Striated muscle fibers in the lung are commonly associated with major malformations involving heart and lungs, suggesting a much wider morphogenetic error.     

Congenital alveolar capillary dysplasia and associated gastrointestinal anomalies

Congenital alveolar capillary dysplasia is a rare cause of irreversible pulmonary hypertension with 100% mortality. We present three cases of congenital alveolar capillary dysplasia with associated gastrointestinal abnormalities. Three full-term neonates presented with pulmonary hypertension needing ventilatory support by oscillation. Of the three, two neonates subsequently needed extracorporeal membrane oxygenation. Abdominal distension associated with bilious aspirates was the gastrointestinal manifestation. One child had duodenal atresia and anorectal anomaly, one with intestinal malrotation and the other with a rare combination of intestinal malrotaion and total colonic Hirschsprung's disease. All three infants succumbed to pulmonary hypertension at mean age 34 days. The etiopathogenesis and pathology of this condition are discussed with a comprehensive review of the literature.     

Alveolar capillary dysplasia as a cause of failure in treatment of a neonate with pulmonary persistent hypertension of the newborn - case report

A patient with severe persistent pulmonary hypertension of the newborn (PPHN) due to alveolar capillary dysplasia, congenital (ACD), is presented. In the treatment, apart from standard methods, high frequency oscillatory ventilation (HFOV), inhaled nitric oxide and activated C protein have been applied. In spite of treatment the patient died and post-mortem diagnosis was based on lung histopathology examination. ACD occurs very rarely and is a congenital disease. Diagnosis is by pulmonary tissue histopathology examination. Pathological structure of the lungs leads to severe dysfunction of gas exchange as well as increasing pulmonary hypertension. No effective treatment is known and all so far described cases have ended up with death. The described case and literature data lead the authors to the following conclusions: 1. in case of PPHN resistant to treatment, ACD diagnosis should be taken into consideration, 2. histopathological examination determines the diagnosis, 3. limited capabilities of diagnosis are the reason for applying non-standard and expensive treatment methods which so far are doomed to failure, 4. in case of a patient with severe, persistent pulmonary hypertension and unclear aetiology, not reacting to nitrous oxide treatment, a diagnostic lung biopsy should be considered.     

Congenital Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins Associated with Hypoplastic LeftHeart Syndrome

Three full-term infants died in the first month of life with hypoplastic left heart syndrome (HLH) and persistent pulmonary hypertension (PPH). At postmortem examination, they were found to have alveolar capillary dysplasia with misalignment of pulmonary veins (ACD with MPV). The association of HLH syndrome, and ACD with MPV with intestinal malrotation and/or obstruction, is unique. Decreased blood flow in the ascending aorta in fetuses with left outflow tract obstruction might cause vasoconstriction of pulmonary arterioles to maintain cerebral perfusion. Vasoconstriction early during embryogenesis might lead to decreased growth and development of alveolar capillaries and pulmonary veins. This results in pulmonary hypertension, and the arterial blood is forced to bypass the deficient capillary bed and can drain only via the anomalous bronchial veins. Received October 26, 1999; accepted March 2, 2000.     

Changes in Pulmonary Tissue of Patients with Congenital Heart Disease and Down Syndrome: A Morphological and Histochemical Study

Pulmonary tissues obtained from 12 individuals suffering from congenital heart disease associated with Down syndrome were examined by light and transmission electron microscopy and compared with those of 29 cases without the syndrome. Alkaline phosphatase (ALPase) activity, which is known to play an important role in the secretion of pulmonary surfactant, was histochemically examined and compared. The major changes found in the pulmonary tissues examined from pulmonary hypertensive patients were increase in the number of type I1 alveolar cells and in ALPase activity. ALPase activity was positive in the plasma membrane of type I1 cells and in the limiting membrane of the osmiophilic bodies contained within them. These changes were more conspicuous and detected at an earlier age in the pulmonary hypertensive individuals with Down syndrome than in those without the syndrome. These observations indicate that the acinar region in pulmonary tissue is affected at an earlier stage, and that changes in the production and secretion of pulmonary surfactant occur, in patients with Down syndrome. Early surgical treatment is recommended for them.     

Neonatal Pulmonary Hypoplasia: An Autopsy Study of 25 Cases

Pulmonary hypoplasia (PH) is defined as defective or incomplete development of lungs that are immature for gestational age. A prospective study was done to establish practical criteria for the diagnosis of pulmonary hypoplasia and to determine the relative frequency of pulmonary hypoplasia and its associated congenital malformations. Postmortem, formalin-inflated, routinely processed lungs were examined for fresh lung weight, fixed lung volume, radial alveolar count, and tissue maturity. Of these, lung volume was found to be the least useful. However, no single parameter was adequate for diagnosis in every case. Using the remaining three in conjunction, reliable diagnostic criteria were established. In this series of 113 cases, 22% had pulmonary hypoplasia as the primary cause of death, of which one-third had no associated congenital malformations to account for the development of pulmonary hypoplasia. It was found that premature rupture of membranes (PROM) for as short as 5 days could lead to fatal PH. It is concluded that PH is a common problem in neonatal autopsies and can be diagnosed in the average laboratory. Recognizing PH is important because once it has developed, intrauterine intervention in cases of oligohydramnios and postnatal treatment with surfactant inhalation cannot influence the outcome. It remains to be seen whether early fluid replacement in PROM will prevent development of PH.     

Fetal lung growth in laryngeal atresia and tracheal agenesis

Three cases of airway obstruction in fetuses born at 21, 32 and 40 weeks gestation are reported. The first had laryngeal atresia, cystic dysplastic kidneys, oligohydramnios and immense fluid-filled lungs. The second had upper tracheal agenesis, a tracheo-oesophageal fistula, a cystic dysplastic horseshoe kidney, oligohydramnios and normal-sized lungs. The third had a pin-hole mucosal tract through an otherwise atretic larynx, normal kidneys, no oligohydramnios and normal-sized lungs. Lung weight:body weight ratios, radial alveolar or radial canalicular counts and point-counting of sections of lungs in cases 1 and 2 show that laryngeal or tracheal obstruction may prevent or reduce the pulmonary hypoplasia associated with renal dysplasia, and in cases 2 and 3, that grossly enlarged, hyperplastic lungs may not be seen unless obstruction is complete.     

Fetal lung growth in laryngeal atresia and tracheal agenesis

Abstract Three cases of airway obstruction in fetuses born at 21, 32 and 40 weeks gestation are reported. The first had laryngeal atresia, cystic dysplastic kidneys, oligohydramnios and immense fluid-filled lungs. The second had upper tracheal agenesis, a tracheo-oesophageal fistula, a cystic dysplastic horseshoe kidney, oligohydramnios and normal-sized lungs. The third had a pin-hole mucosal tract through an otherwise atretic larynx, normal kidneys, no oligohydramnios and normal-sized lungs. Lung weight:body weight ratios, radial alveolar or radial canalicular counts and point-counting of sections of lungs in cases 1 and 2 show that laryngeal or tracheal obstruction may prevent or reduce the pulmonary hypoplasia associated with renal dysplasia, and in cases 2 and 3, that grossly enlarged, hyperplastic lungs may not be seen unless obstruction is complete.     

Different expression of surfactant protein B mature peptide and proprotein at 21 weeks'' gestation in human fetal pulmonary epithelial cells

AIM: The aim of this study is to evaluate the maturation of pulmonary epithelial cells in human fetal lungs at 21 weeks' gestation. METHODS: Eight fetuses at 21 weeks' gestation were evaluated. The maturation of pulmonary epithelial cells was assessed by immunohistochemical examination for surfactant proteins and by electron microscopy. RESULTS: Surfactant protein B mature peptide was detected slightly in the epithelial lining of the bronchioles, but was totally absent in the terminal airways. Surfactant protein B proprotein was clearly detected in the epithelial lining of both bronchioles and terminal airways. Transmission electron microscopy of terminal airway cells showed abundant glycogen granules and few intracellular organelles. CONCLUSIONS: The production of mature surfactant protein B in terminal airways is scarce at 21 weeks' gestation, which is associated with the immature mechanism of proprotein processing in the cytoplasm.     

Secondary surfactant deficiencies.]

Preterm babies born before the 33rd week of gestation often exhibit primary surfactant deficiency responsible for the respiratory distress syndrome or hyaline membrane disease. In that situation, there is a limited and insufficient production of surfactant by type II alveolar cells of the lung due to immaturity. Secondary surfactant deficiencies occur in patients with prior normal surfactant synthesis and can be related to sepsis, hypoxia, ventilator induced lung injury or surfactant inhibition by a variety of substances reaching the alveolar spaces. They occur in full-term newborns with meconium aspiration syndrome, acute respiratory distress syndrome and congenital diaphragmatic hernia. In children and adults, acute respiratory distress syndrome and respiratory syncytial virus bronchiolitis can be responsible. In prematures they occur after the initial primary deficiency during pulmonary hemorrhage, pneumonia and bronchopulmonary dysplasia. Treatment with exogenous surfactant may be beneficial. There is a need for randomized controlled studies for evaluation of this treatment. Next generation of surfactants containing recombinant surfactant protein or synthetic peptides appear as promising agents in these situations of secondary surfactant deficiencies.