Fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic disorder of HO in humans. Episodic disease flare-ups are precipitated by soft tissue injury, and immobility is cumulative. Recently, a recurrent mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved target for drug development in the transforming growth factor (TGF)-beta/BMP signalling pathway, and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for ACVR1/ALK2. Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups. Effective therapies for FOP, and possibly for other common conditions of HO, may potentially be based on future interventions that block ACVR1/ALK2 signalling.

A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia.

BACKGROUND: Experimental and clinical data suggest that fetal endoscopic tracheal occlusion to induce lung growth may improve the outcome of severe congenital diaphragmatic hernia. We performed a randomized, controlled trial comparing fetal tracheal occlusion with standard postnatal care. METHODS: Women carrying fetuses that were between 22 and 27 weeks of gestation and that had severe, left-sided congenital diaphragmatic hernia (liver herniation and a lung-to-head ratio below 1.4), with no other detectable anomalies, were randomly assigned to fetal endoscopic tracheal occlusion or standard care. The primary outcome was survival at the age of 90 days; the secondary outcomes were measures of maternal and neonatal morbidity. RESULTS: Of 28 women who met the entry criteria, 24 agreed to randomization. Enrollment was stopped after 24 patients had been enrolled because of the unexpectedly high survival rate with standard care and the conclusion of the data safety monitoring board that further recruitment would not result in significant differences between the groups. Eight of 11 fetuses (73 percent) in the tracheal-occlusion group and 10 of 13 (77 percent) in the group that received standard care survived to 90 days of age (P=1.00). The severity of the congenital diaphragmatic hernia at randomization, as measured by the lung-to-head ratio, was inversely related to survival in both groups. Premature rupture of the membranes and preterm delivery were more common in the group receiving the intervention than in the group receiving standard care (mean [+/-SD] gestational age at delivery, 30.8+/-2.0 weeks vs. 37.0+/-1.5 weeks; P<0.001). The rates of neonatal morbidity did not differ between the groups. CONCLUSIONS: Tracheal occlusion did not improve survival or morbidity rates in this cohort of fetuses with congenital diaphragmatic hernia.

Pseudomonas pneumonia in infants: an autopsy study.

Pseudomonas pneumonia is an uncommon but serious infection in infants, occurring mainly in infants of low birth weight. In this retrospective clinicopathologic correlation study, we reviewed the clinical records and analyzed postmortem lung pathology in 8 infants with pneumonia due to P. aeruginosa. From the histopathology, 2 different pneumonic patterns emerged: a distinctive paucicellular coagulative confluent bronchopneumonia with perivascular bacillary infiltration (7 cases) and a more usual cellular pneumonia without evidence of perivascular organisms (1 case). Clinically, infants with the first type could be considered immunocompromised and had a precipitous course characterized by signs of sepsis, whereas the infant with the second type (who likely had a more normal immune system) had a relatively protracted course with respiratory failure. We conclude that (1) the pattern of pneumonic inflammation correlates with the immune state of infants, similar to what has been reported in adults; (2) among immunocompromised infants, histopathologic signs of bacteremia are prevalent; and (3) the clinical signs do not correlate with the severity of the pathology at autopsy and may reflect sepsis rather than pneumonia. We speculate that the histopathology in this population reflects the virulence of the organism, as well as the immune status of the host.

Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia.

OBJECTIVE: We describe a case of chronic pulmonary hypertension in a 7-wk-old infant with congenital diaphragmatic hernia and an oral teratoma. Our patient was dependent on low-dose inhaled nitric oxide and was still very unstable with systemic right ventricular pressures leading to frequent oxygen desaturations. We administered sildenafil therapy to stabilize the infant with discontinuation of inhaled nitric oxide. We describe successful discontinuation of the inhaled therapy as well as a period of stabilization and improvement with continued sildenafil administration. DESIGN: Case report. SETTING: Intensive care nursery in tertiary academic center. PATIENT: A 7-wk-old infant with congenital diaphragmatic hernia who was mechanically ventilated from birth. INTERVENTION: Oral sildenafil 0.3 mg/kg/dose every 12 hrs. MEASUREMENTS AND RESULTS: Right ventricular pressure (from tricuspid valve regurgitant flow) to systemic systolic arterial pressure was measured by echocardiogram. Right ventricular to systemic pressure ratio was marginally improved with the initiation of sildenafil therapy. Inhaled nitric oxide was successfully discontinued, and the patient clinically stabilized temporarily, but he ultimately succumbed to his pulmonary hypertension. CONCLUSION: Sildenafil may be a useful therapy for chronic pulmonary hypertension in congenital diaphragmatic hernia, but further studies of safety and efficacy need to be performed.

General anesthesia treatment of propriospinal myoclonus in a patient with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva, a rare and severely disabling genetic condition, is characterized clinically by progressive ossification of skeletal muscle and connective tissue and congenital malformations of the great toes. Recurrent episodes of heterotopic ossification (flare-ups) lead to increasing loss of mobility as joints become progressively affected. We report the case of a young woman with fibrodysplasia ossificans progressiva who had recurrent, debilitating myoclonus that was refractory to conventional therapies but was relieved for prolonged periods after general anesthesia was administered.

CNS demyelination in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of progressive heterotopic ossification (HO) caused by a recurrent activating mutation of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. FOP is characterized by progressive HO, which is associated with inflammation in the setting of dysregulated BMP signaling, however, a variety of atypical neurologic symptoms are also reported by FOP patients. The main objective of this study is to investigate the potential underlying mechanism that is responsible for the observed atypical neurologic symptoms. We evaluated two mouse models of dysregulated BMP signaling for potential CNS pathology through non-invasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 is over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of a recurrent FOP mutation of ACVR1/ALK2. We also retrospectively examined MRI scans of four FOP patients. We consistently observed demyelinated lesions and focal inflammatory changes of the CNS in both mouse models but not in wild-type controls, and also found CNS white matter lesions in each of the four FOP patients examined. These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP.

Neurological symptoms in individuals with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP), a rare, disabling condition caused by gain-of-function mutations of a bone morphogenetic protein (BMP) type I receptor, leads to episodes of heterotopic ossification and resultant immobility. Neurological problems have not been associated with FOP, but neurological symptoms are commonly reported by FOP patients. To determine the prevalence of neurological symptoms and their characteristics in individuals with FOP, we conducted a survey of the 470 patient members of the International FOP Association (IFOPA) using a questionnaire about neurological symptoms. There were 168 responses (105 females, 63 males; age 1.5-68 years) from 30 countries representing 36 % of IFOPA members. Chronic neurological symptoms were reported by 86 (51 %). Prevalence of neuropathic pain (NP) was significantly increased (P < 0.001) compared to the general population, and tenfold more common in females (15 %) than males (1.6 %). Of those with NP, 94 % reported other sensory abnormalities. Prevalence of recurrent severe headaches (HA) (26 %) was similar to that in the general population, but prevalence in females with FOP (36 %) was almost fourfold greater than in males. Prevalence of NP, HA, and other sensory abnormalities was substantially higher in post-pubertal females; 33 % reported symptoms worsened during menstrual periods. Worsening of neurological symptoms during FOP flare-ups was reported by 23 %. Three patients with FOP (1.8 %) reported myoclonus, a prevalence much greater than reported in the general population (P < 0.001). Our worldwide survey indicates that neurological symptoms are common in FOP. We speculate that these symptoms are related to effects of dysregulated BMP signaling on the central and/or peripheral nervous systems.

Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva, a rare genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification in humans. However, little is known about the lifespan or causes of mortality in these patients. We undertook this study to determine the lifespan and causes of mortality in individuals who had fibrodysplasia ossificans progressiva. METHODS: We reviewed comprehensive mortality reports from two large registries of patients with fibrodysplasia ossificans progressiva. Together, these registries comprise >90% of all known patients with this condition in the world. We noted the sex, dates of birth and death, and the cause of death for each individual. We verified the cause of death with extensive medical records, when available. We also collected date of birth, current age, and sex information for each living patient member of the International Fibrodysplasia Ossificans Progressiva Association. RESULTS: Sixty deaths (thirty male and thirty female patients) were reported in the fibrodysplasia ossificans progressiva community during a thirty-three-year-period. For all sixty patients, the median age at the time of death was forty years (range, three to seventy-seven years). Data were sufficient to establish the cause of death in forty-eight (80%) of the sixty individuals. The median age at the time of death for the forty-eight patients (twenty-four male and twenty-four female patients) with an established cause of death was also forty years. The median lifespan estimated from the 371 individuals in the international fibrodysplasia ossificans progressiva community who were alive and the sixty who had died was fifty-six years (95% confidence interval, fifty-one to sixty years). The most common causes of death in patients with fibrodysplasia ossificans progressiva were cardiorespiratory failure from thoracic insufficiency syndrome (54%; median age, forty-two years) and pneumonia (15%; median age, forty years). CONCLUSIONS: Fibrodysplasia ossificans progressiva is not only an extremely disabling disease but also a condition of considerably shortened lifespan. The most common cause of death in patients with fibrodysplasia ossificans progressiva is cardiorespiratory failure from thoracic insufficiency syndrome.

Congenital diaphragmatic hernia prevents absorption of distal air space fluid in late-gestation rat fetuses.

We hypothesized that congenital diaphragmatic hernia (CDH) may decrease distal air space fluid absorption due to immaturity of alveolar epithelial cells from a loss of the normal epithelial Na+ transport, as assessed by amiloride and epithelial Na+ channel (ENaC) and Na-K-ATPase expression, as well as failure to respond to endogenous epinephrine as assessed by propranolol. Timed-pregnant dams were gavage fed 100 mg of nitrofen at 9.5-day gestation to induce CDH in the fetuses, and distal air space fluid absorption experiments were carried out on 22-day gestation (term) fetuses. Controls were nitrofen-exposed fetuses without CDH. Absorption of distal air space fluid was measured from the increase in 131I-albumin concentration in an isosmolar, physiological solution instilled into the developing lungs. In controls, distal air space fluid absorption was rapid and mediated by beta-adrenoceptors as demonstrated by reversal to fluid secretion after propranolol. Normal lung fluid absorption was also partially inhibited by amiloride. In contrast, CDH fetuses continued to show lung fluid secretion, and this secretion was not affected by either propranolol or amiloride. CDH lungs showed a 67% reduction in alpha-ENaC and beta-ENaC expression, but no change in alpha1-Na-K-ATPase expression. These studies demonstrate: 1) CDH delays lung maturation with impaired distal air space fluid absorption secondary to inadequate Na+ uptake by the distal lung epithelium that results in fluid-filled lungs at birth with reduced capacity to establish postnatal breathing, and 2) the main stimulus to lung fluid absorption in near-term control fetuses, elevated endogenous epinephrine levels, is not functional in CDH fetuses.

Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva.

BACKGROUND: Little is known about diagnostic errors for a disease worldwide. Such errors could alter the disease's natural history, especially if unwarranted interventions cause irreversible harm. Fibrodysplasia ossificans progressiva (FOP), a rare, autosomal dominant genetic disease characterized by episodes of permanent heterotopic ossification of soft tissues, occurs worldwide without racial, ethnic, or geographic predilection. There is no effective treatment, and soft-tissue trauma (eg, biopsies, surgical procedures, intramuscular injections, or mandibular blocks for dental procedures) and viral illnesses are likely to induce episodes of rapidly progressive heterotopic ossification, with resultant permanent loss of motion in the affected area. Accurate diagnoses can be made on the basis of the clinical findings of tumor-like swellings on the head, neck, back, or shoulders and characteristic short great toes with hallux valgus-like malformations and missing interphalangeal joints. On the basis of conversations with numerous individuals with FOP, we suspected that diagnostic errors with FOP are common and often associated with inappropriate and harmful diagnostic and therapeutic procedures. OBJECTIVE: To document the frequency of diagnostic errors with FOP and complications resulting from misdiagnoses. DESIGN: A questionnaire requesting detailed demographic, diagnostic, and treatment information was sent to all 269 patient-members of the International FOP Association; the sampling frame included > 90% of all known FOP patients worldwide. We received 138 replies (51% response) from 25 countries. The age range was 2 to 71 years; there were 78 female subjects and 60 male subjects. In addition, to assess the availability and adequacy of information about FOP, we reviewed 184 English-language textbooks in relevant specialties published in the past 20 years. RESULTS: Incorrect diagnoses were given initially to 87% of individuals with FOP. This astonishing rate of diagnostic errors occurred worldwide, regardless of ethnicity, geographic background, or misdiagnosing physician's specialty. The most common incorrect diagnosis was cancer (32%). The mean period from the onset of symptoms to correct diagnosis was 4.1 years, and the median number of physicians consulted before the correct diagnosis of FOP was 6. For 67% of patients, unnecessary invasive procedures (biopsies) were performed; 68% received inappropriate therapies. Forty-nine percent of all patients reported permanent loss of mobility resulting from invasive medical interventions that caused posttraumatic ossification. Notably, only 8% of the 184 textbooks that were reviewed contained adequate descriptions of FOP, including the caution that trauma can accelerate the process of heterotopic ossification. CONCLUSIONS: Diagnostic errors and inappropriate medical procedures, which may lead to permanent harm, can alter the natural history of a disease. In FOP, the astonishing rates of diagnostic errors and inappropriate invasive medical procedures likely result from lack of physician awareness because of failure of information transfer.

Changes in fetal lung distension alter expression of vascular endothelial growth factor and its isoforms in developing rat lung.

Vascular endothelial growth factor A (VEGF-A) is essential for normal pulmonary vascular and parenchymal development. Changes in fetal lung distension profoundly affect lung growth and maturation, including vascular development. To define developmental lung expression of VEGF-A and its receptors and investigate effects of changes in fetal lung distension, we studied fetal rats at embryonic day (ED) 16, 19, and 22, postnatal rats at postnatal day (PD) 5, 10, and 21, and adult rats. We used reverse transcriptase PCR to measure mRNA expression for VEGF-A isoforms (VEGF-A(120), (-144), (-164), and (-188)) and VEGF-A receptors, Flt-1 and Flk-1. With advancing development, mRNA content increased only for VEGF-A(188) (p < 0.05) and for Flt-1 (p < 0.02) and Flk-1 (p < 0.005). As a percentage of total VEGF-A mRNA, VEGF-A(188) (15% at ED 16) increased to become the dominant isoform at PD 21 (40%, p < 0.005) and adulthood; in contrast, there were decreases in both VEGF-A(144) (p < 0.05) and (-120) (p < 0.005). VEGF-A protein was expressed in alveolar epithelium (type I and II cells) and interstitium. Increasing fetal lung distension by tracheal occlusion (TO) accelerated the normal maturational pattern of VEGF-A isoforms and increased VEGF-A protein; decreasing fetal lung distension by congenital diaphragmatic hernia (CDH) retarded the normal developmental pattern and decreased VEGF-A protein. Neither TO nor CDH consistently affected Flt-1 or Flk-1 mRNA content. These results show that mechanical factors significantly affect lung VEGF-A expression and suggest that VEGF-A mediates previously described changes in lung vascular and parenchymal development caused by CDH and by TO.

Congenital diaphragmatic hernia, tracheal occlusion, thyroid transcription factor-1, and fetal pulmonary epithelial maturation.

Congenital diaphragmatic hernia (CDH) occurs in approximately 1:2,500 human births and has high morbidity and mortality rates, primarily due to pulmonary hypoplasia and pulmonary hypertension. Tracheal occlusion (TO), in experimental animals, distends lungs and increases lung growth and alveolar type I cell maturation but decreases surfactant components and reduces alveolar type II cell density. We examined effects of CDH and CDH+TO on lung growth and maturation in fetal rats. To induce CDH, we administered nitrofen (100 mg) to dams at 9.5 days of gestation. We compared lungs from fetuses with CDH, CDH+TO, and those exposed to nitrofen without CDH. CDH decreased lung wet weight bilaterally (P < 0.0001) and DNA content in lung ipsilateral to CDH (P < 0.05). CDH+TO significantly increased lung wet weights bilaterally; DNA content was intermediate between CDH and NC. To evaluate effects on the distal pulmonary epithelium, we examined surfactant mRNA and protein levels, type I and II cell-specific markers (RTI(40) and RTII(70), respectively), and transcriptional regulator thyroid transcription factor-1 (TTF-1). Decreased lung distension (due to CDH) increased SP-C mRNA and TTF-1 protein expression and reduced RTI(40) (P < 0.05 for all). Increased lung distension (due to CDH+TO) reduced expression of SP mRNAs and pro-SP-C and TTF-1 proteins and enhanced expression of RTI(40) (mRNA and protein; P < 0.05 for all). We conclude that CDH+TO partially reverses effects of CDH; it corrects the pulmonary hypoplasia and restores type I cell differentiation but adversely affects SP expression in type II cells. These effects may be mediated through changes in TTF-1 expression.

Ontogeny of poly(ADP-ribose) polymerase-1 in lung and developmental implications.

Poly(ADP-ribose) polymerase 1 (PARP-1) is the predominant NAD-dependent modifying enzyme in DNA repair, transcription, and apoptosis; its involvement in development has not been defined. Here, we report expression and cellular localization of PARP-1 in developing rat and human fetal lung, in vivo and in explant culture, and effects of inhibiting PARP-1 activity on lung surfactant protein (SP) expression. PARP-1 was expressed as 113-kD (p113) and 85-kD (p85) fragment in both rat and human lung. In rat lung, p113 content by Western was maximal at Embryonic Days 16-18, decreased sharply by Embryonic Day 20, and continued to decrease postnatally. p85 level was constant in the fetus and decreased postnatally. In human fetal lung, both PARP-1 mRNA expression and protein content changed little between 15 and 24 wk. Immunohistochemistry for PARP-1 in Embryonic Day 18 rat lung showed predominantly nuclear staining in most cells. In later gestation and postnatally, PARP-1 staining was primarily cytoplasmic and progressively restricted to a subset of cells, mainly bronchial epithelial and smooth muscle cells. Cell subfractionation showed that p113 localized to nucleus and p85 to cytoplasm. Inhibition of PARP-1 activity by 5-iodo-6-amino-1,2-benzopyrone in fetal rat lung explant culture did not affect SP-A and -B mRNA, but significantly increased SP-C mRNA. These findings indicate that in lung (i) PARP-1 is abundantly expressed during fetal development; (ii) p113 and p85 levels are differentially regulated; (iii) PARP-1 undergoes complex developmental changes in cellular and subcellular expression, including extensive cytoplasmic localization; and (iv) inhibition of PARP-1 activity differentially affects expression of SPs.

Maternally administered dexamethasone transiently increases apoptosis in lungs of fetal rats.

In late gestation, morphological maturation of fetal lung includes septal thinning of potential airspaces, a process accelerated by exogenous glucocorticoids. Apoptosis occurs in normal fetal lung. Glucocorticoids increase apoptosis in several tissues. The authors hypothesized that exogenous glucocorticoids would increase apoptosis in fetal lung, primarily in the interstitium. They administered dexamethasone (DEX), 1 mg/kg, or vehicle (Control) to pregnant rats at 19 days of gestation. Fetuses were delivered at 3, 7, 12, or 24 hours post injection. DEX decreased fetal body weight and lung weight, DNA, and protein 12 hours post injection. Using the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) reaction to label apoptotic cells in lung, they calculated an apoptotic index (AI, apoptotic cells/1000 total cells) for each fetus. Average DEX AI (3.6+/-2.6, mean+/-SD) was greater than Control (1.7+/-0.5) (P<.02). All DEX AIs were greater than Control AIs at 3, 7, and 12 hours, but were similar to Controls at 24 hours post injection. Apoptotic cells appeared to be interstitial, based on colocalization with vimentin staining. Presence of apoptotic cells was confirmed by electron microscopy and detection of the nucleosomal ladder pattern on DNA electrophoresis. The authors conclude that maternal administration of dexamethasone increases apoptosis in fetal lung, primarily in the interstitium. They speculate that apoptosis may contribute to morphological fetal lung maturation induced by endogenous glucocorticoids.

Fetoscopic temporary tracheal occlusion for congenital diaphragmatic hernia: prelude to a randomized, controlled trial.

OBJECTIVE: As previously reported, high postnatal mortality seen in fetuses with congenital diaphragmatic hernia (CDH) with liver herniation and low lung-to-head ratio (LHR) appears to be improved in fetuses who undergo fetoscopic temporary tracheal occlusion (TO). To test whether further evolution of this technique produces results that justify a randomized controlled trial comparing prenatal intervention to postnatal care, the authors analyzed 11 additional cases and the cumulative experience with 19 cases. METHODS: The authors analyzed retrospectively the outcome of 11 new and 8 previously reported cases of fetoscopic temporary tracheal occlusion. Various factors were studied including maternal morbidity, antenatal outcome, physiologic lung response, and neonatal course. RESULTS: Temporary TO can be accomplished using 3 5-mm radially expanding uterine ports without hysterotomy. Obstetric morbidity included mild pulmonary edema in 6 cases, chorioamniotic separation and premature rupture of membranes in 12 patients, and preterm labor and delivery in all patients. Thirteen of 19 (68%) neonates survived for 90 days after delivery; one died in utero, and 5 died after birth. Late mortality included one death caused by sepsis and 2 by complications associated with tracheostomies. Morbidity from gastroesophageal reflux requiring Nissen fundoplication, tracheal injury requiring repair or tracheostomy, and recurrent hernias after diaphragmatic repair were characteristic in longterm survivors. CONCLUSIONS: Fetoscopic temporary TO may improve outcome in poor-prognosis fetuses with CDH. However, complications related to tracheal dissection, premature delivery and late morbidity are significant. This experience has led to simpler techniques for fetoscopic tracheal occlusion and to an National Institutes of Health-sponsored randomized controlled trial comparing fetoscopic tracheal occlusion with optimal postnatal care.

Tracheal occlusion stimulates cell cycle progression and type I cell differentiation in lungs of fetal rats.

Fetal tracheal occlusion (TO) has been reported to stimulate lung growth but decreases number and maturation of type II cells, effects that vary with gestational age and duration of TO. We examined effects of a novel method of TO (unipolar microcautery to seal the trachea) produced at 19.5-20 days (d) of gestation in fetal rats; fetuses were delivered at term, 22 d. Controls were sham operated and unoperated littermates. TO increased wet lung weight but not dry lung weight or lung DNA and protein. To evaluate further the effects of TO, we examined the cell cycle regulators, cyclins D1 and A, in fetal lungs. Cyclin D1 increased with TO (P < 0.005). TO also increased expression of the type I epithelial cell marker RTI40 (mRNA and protein). TO decreased mRNA for surfactant proteins (SP)-A and -C but did not affect protein levels of SP-A and -B and of RTII70, a type II epithelial cell marker. We conclude that TO by microcautery, even of short duration, has diverse pulmonary effects including stimulating increased levels of cyclin D1 with probable cell cycle progression, type I cell differentiation, and possibly inhibiting type II cell function.

Distal air space epithelial fluid clearance in near-term rat fetuses is fast and requires endogenous catecholamines.

Knowledge about the conversion of the epithelium in the distal air spaces of the lung from secretion to absorption is imperative to the understanding of postnatal lung development; little such information is available in rats. Distal air space fluid clearance was therefore measured in 21- to 22-day gestation rat fetuses and newborn (40 h) rats. Distal air space fluid clearance was measured from the increase in (131)I-albumin concentration in an isosmolar, physiological solution instilled into the developing lungs. There was no net fluid movement across the distal air space epithelium in the lungs of 21-day gestation fetuses. Twenty-four hours later, distal air space fluid was cleared at a rapid rate in the 22-day gestation fetuses. Within the first 40 h after birth, the rate rapidly declined to adult levels. The high distal air space fluid clearance at 22 days gestation and at 40 h after birth was mediated by beta-adrenergic receptors as demonstrated by elevated plasma epinephrine levels and inhibition by propranolol. Interestingly, the elevated distal air space fluid clearance in the 22-day gestation fetuses was only minimally amiloride sensitive; however, amiloride sensitivity increased over the first 40 h after birth. In conclusion, these studies demonstrate that 1) rapid rates of net alveolar fluid clearance occur late in gestation in the rat and 2) this clearance is driven by elevations of endogenous epinephrine.

Infant pulmonary function in a randomized trial of fetal tracheal occlusion for severe congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) carries a high mortality risk secondary to pulmonary hypoplasia and respiratory failure. In experimental animals, fetal tracheal occlusion (TO) induces lung growth and morphologic maturation. We measured indicators of pulmonary function in 20 infants who were enrolled in a randomized trial of fetal TO as treatment for severe CDH [nine with conventional treatment (controls); 11 with TO]. We hypothesized that TO would improve lung function. At birth, the TO group had a lower mean gestational age (30.8 +/- 2.0 versus 37.4 +/- 1.0 wk; p=0.0002). All infants required assisted ventilation. Mortality did not differ between groups (64 versus 78%, TO and control, respectively; p=0.64). We measured respiratory mechanics at four study points: 1) first 24 h, 2) before CDH operative repair (5.9 +/- 2.2 d), 3) immediately after repair (7.0 +/- 2.2 d), and 4) before elective extubation (32.5 +/- 16.1 d). We calculated perioperative oxygenation index and alveolar-arterial oxygen difference to assess efficiency of pulmonary gas exchange. Data were analyzed by univariate and repeated measures techniques. Respiratory system compliance (Crs) was low. The rate of increase in Crs over the four study points was greater in the TO group than in control subjects. Crs in the TO group was significantly greater at study 2 (0.28 +/- 0.12 versus 0.17 +/- 0.04 mL.cm H2O(-1).kg(-1); p=0.02) and study 4 (0.93 +/- 0.45 versus 0.51 +/- 0.16 mL.cmH2O(-1).kg(-1); p=0.02). oxygenation index did not differ between groups, but alveolar-arterial oxygen difference was lower in the TO infants. We conclude that fetal TO for severe CDH results in modest improvements in neonatal pulmonary function that are of questionable clinical significance.

Effects of oligohydramnios on lung growth and maturation in the fetal rat.

Oligohydramnios (OH) retards fetal lung growth by producing less lung distension than normal. To examine effects of decreased distension on fetal lung development, we produced OH in rats by puncture of uterus and fetal membranes at 16 days of gestation; fetuses were delivered at 21 or 22 days of gestation. Controls were position-matched littermates in the opposite uterine horn. OH lungs had lower weights and less DNA, protein, and water, but no differences in saturated phosphatidylcholine, surfactant proteins (SP)-A and -B, and mRNA for SP-A, -B, -C, and -D. To evaluate effects on epithelial differentiation, we used RTI(40) and RTII(70), proteins specific in lung to luminal surfaces of alveolar type I and II cells, respectively. At 22 days of gestation, OH lungs had less RTI(40) mRNA (P < 0.05) and protein (P < 0.001), but RTII(70) did not differ from controls. With OH, type I cells (in proportion to type II cells) covered less distal air space perimeter (P < 0.01). We conclude that OH, which retards lung growth, has little effect on surfactant and impedes formation of type I cells relative to type II cells.