Facial erythema in patients with atopic dermatitis treated with Dupilumab - a descriptive study of morphology and Aetiology.

BACKGROUND: The development of dermatitis on face and neck, which was not described in phase 3 clinical trials, has been reported in the literature in patients treated with dupilumab. Little is known regarding the causes or defining features of the facial dermatitis. OBJECTIVES: We conducted surveys of consecutive patients with AD on dupilumab to describe its clinical features, morphology and aetiology. METHODS: A multi-centre prospective cohort study was conducted from 1 January 2020, to 31 December 31 2020. A total of 162 patients under dupilumab treatment were asked to complete a questionnaire and patients were evaluated by dermatologists. RESULTS: Of all 162 patients, 137 (84.6%) patients reported pre-existing facial dermatitis prior to dupilumab therapy. One hundred and twenty-one (88.3%) patients with pre-existing facial dermatitis reported improvement of their facial dermatitis with dupilumab therapy, nine (6.6%) patients reported no change after the treatment and seven (4.3%) patients of them got worse after the treatment (exacerbation group). Of 25 patients who reported no pre-existing active facial dermatitis, six (24%) patients reported new-onset facial erythema after the starting dupilumab therapy (new-onset group). A large proportion of the patients in both the exacerbation (86%) and new-onset groups (67%) had a history of facial TCS use. Both groups showed similar clinical manifestations and distribution with few differences. CONCLUSIONS: The vast majority of patients treated with dupilumab in academic institutions from Korea and the United States experienced improvement in their facial dermatitis with dupilumab therapy. A small proportion of patients had new onset and exacerbation. Although the mechanisms of this adverse event remain unclear, steroid withdrawal should be considered as a diagnosis of the erythema in some patients.

Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function.

Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT.

Implementation of a medical student-run telemedicine program for medications for opioid use disorder during the COVID-19 pandemic.

OBJECTIVES: The COVID-19 pandemic led to the closure of the IDEA syringe services program medical student-run free clinic in Miami, Florida. In an effort to continue to serve the community of people who inject drugs and practice compassionate and non-judgmental care, the students transitioned the clinic to a model of TeleMOUD (medications for opioid use disorder). We describe development and implementation of a medical student-run telemedicine clinic through an academic medical center-operated syringe services program. METHODS: Students advertised TeleMOUD services at the syringe service program on social media and created an online sign-up form. They coordinated appointments and interviewed patients by phone or videoconference where they assessed patients for opioid use disorder. Supervising attending physicians also interviewed patients and prescribed buprenorphine when appropriate. Students assisted patients in obtaining medication from the pharmacy and provided support and guidance during home buprenorphine induction. RESULTS: Over the first 9 weeks in operation, 31 appointments were requested, and 22 initial telehealth appointments were completed by a team of students and attending physicians. Fifteen appointments were for MOUD and 7 for other health issues. All patients seeking MOUD were prescribed buprenorphine and 12/15 successfully picked up medications from the pharmacy. The mean time between appointment request and prescription pick-up was 9.5 days. CONCLUSIONS: TeleMOUD is feasible and successful in providing people who inject drugs with low barrier access to life-saving MOUD during the COVID-19 pandemic. This model also provided medical students with experience treating addiction during a time when they were restricted from most clinical activities.

The levels of CD4+CD25+ regulatory T cells in patients with allergic rhinitis.

BACKGROUND: The involvement of CD4+CD25+ regulatory T cells (CD4+CD25+ TRegs) in allergic diseases was reported previously. However, it remains unclear whether CD4+CD25+ TRegs are involved in allergic rhinitis (AR). METHODS: Fresh whole blood from 20 patients with AR and 16 healthy donors was used to investigate the frequency of CD4+CD25+ and CD4+CD25hi Treg cells using flow cytometry. In addition, serum total IgE (IU/mL) levels were determined using enzyme-linked immunosorbent assays. RESULTS: Patients with AR had fewer CD4+CD25+ Treg cells (2.80 ± 1.36% vs. 3.94 ± 0.97%, P < 0.01) and CD4+CD25hi TRegs (1.53 ± 0·62% vs. 2.00 ± 0.52%, P < 0.05) than control subjects. The number of CD4+CD25+ and CD4+CD25hi TRegs was correlated negatively with total immunoglobulin E levels (r = -0.79, P < 0.01 and r = -0.61, P < 0.01, respectively). CONCLUSION: Deficient regulatory T cells might play a role in the development of AR.

Optimization of Swine Breeding Programs Using Genomic Selection with ZPLAN.

The objective of this study was to evaluate the present conventional selection program of a swine nucleus farm and compare it with a new selection strategy employing genomic enhanced breeding value (GEBV) as the selection criteria. The ZPLAN+ software was employed to calculate and compare the genetic gain, total cost, return and profit of each selection strategy. The first strategy reflected the current conventional breeding program, which was a progeny test system (CS). The second strategy was a selection scheme based strictly on genomic information (GS1). The third scenario was the same as GS1, but the selection by GEBV was further supplemented by the performance test (GS2). The last scenario was a mixture of genomic information and progeny tests (GS3). The results showed that the accuracy of the selection index of young boars of GS1 was 26% higher than that of CS. On the other hand, both GS2 and GS3 gave 31% higher accuracy than CS for young boars. The annual monetary genetic gain of GS1, GS2 and GS3 was 10%, 12%, and 11% higher, respectively, than that of CS. As expected, the discounted costs of genomic selection strategies were higher than those of CS. The costs of GS1, GS2 and GS3 were 35%, 73%, and 89% higher than those of CS, respectively, assuming a genotyping cost of $120. As a result, the discounted profit per animal of GS1 and GS2 was 8% and 2% higher, respectively, than that of CS while GS3 was 6% lower. Comparison among genomic breeding scenarios revealed that GS1 was more profitable than GS2 and GS3. The genomic selection schemes, especially GS1 and GS2, were clearly superior to the conventional scheme in terms of monetary genetic gain and profit.

Two-year experience of using the measles, mumps and rubella vaccine as intralesional immunotherapy for warts.

BACKGROUND: The currently available treatments for warts, including cryosurgery, laser surgery, electrosurgery, and topical keratolytic applications, are often very painful and can induce disfiguring scars. Recently, intralesional immunotherapy with skin test antigens and vaccines has been shown to be effective in the management of warts. AIMS: To evaluate the efficacy of a new intralesional immunotherapy for warts, using the measles, mumps and rubella (MMR) vaccine. METHODS: A retrospective study was performed, and we enrolled 136 patients with various types of warts into the study, which was for a duration of 2 years. Patients were treated for a total of six times at 2-week intervals. The treatment response was classified as one of three levels, based on reduction in the size and number of warts, and patients with complete response (CR) were checked for recurrence. Clinical evaluations were carried out using photographs and medical records. RESULTS: Over half (51.5%) of patients experienced > 50% reduction in the size and number of warts, and 46.7% who had distant warts (in different locations) showed good response. Common warts showed significantly higher treatment response than other types of warts (P < 0.05). However, other clinical variables did not have any effect on efficacy. Almost all the patients reported mild pain during the injection, but other side effects were rarely observed. Only 5.6% of patients who experienced CR had recurrence of warts after 6 months. CONCLUSIONS: We suggest that intralesional immunotherapy with MMR vaccine is a tolerable and effective method for patients who are sensitive to pain, concerned about side effects, or have common warts. Treatment response is improved by increasing the number of injections.

An empirical model for gas phase acidity and basicity estimation.

Gas phase acidity and basicity estimation models have been developed for acidic and basic functional groups of amino acid side-chains and also for a number of small organic molecules. The acidic functional groups include aliphatic and aromatic alcohol, and aliphatic and aromatic carboxylic acid, and the basic functional groups include aliphatic, aromatic and hetero-aromatic amines, and also pyridino-, pyrazolo- and imidazolo-groupings. The models are described in terms of a linear combination of descriptors that highly influence reactivity at the reaction centres of the functional groups. In order to describe the chemical environments of the deprotonating and protonating sites, atomic descriptors such as the effective atomic electronegativity and effective atomic polarizability of the atoms in the reaction field and the electrostatic potentials at the reaction sites have been introduced. The coefficient of determination (r(2)) of each model is above 0.8, apart from the imidazole model. The models are readily applicable, ranging from simple organic molecules to proteins.

A combinatorial approach for targeted delivery using small molecules and reversible masking to bypass nonspecific uptake in vivo.

We have developed a multi-disciplinary approach combining molecular biology, delivery technology, combinatorial chemistry and reversible masking to create improved systemic, targeted delivery of plasmid DNA while avoiding nonspecific uptake in vivo. We initially used a well-characterized model targeting the asialolglycoprotein receptor in the liver. Using our bilamellar invaginated vesicle (BIV) liposomal delivery system with reversible masking, we increased expression in the liver by 76-fold, nearly equaling expression in first-pass organs using non-targeted complexes, with no expression in other organs. The same technology was then applied to efficiently target delivery to a human tumor microenvironment model. We achieved efficient, targeted delivery by attachment of specific targeting ligands to the surface of our BIV complexes in conjunction with reversible masking to bypass nonspecific tissues and organs. We identified ligands that target a human tumor microenvironment created in vitro by co-culturing primary human endothelial cells with human lung or pancreatic cancer cells. The model was confirmed by increased expression of tumor endothelial phenotypes including CD31 and vascular endothelial growth factor-A, and prolonged survival of endothelial capillary-like structures. The co-cultures were used for high-throughput screening of a specialized small molecule library to identify ligands specific for human tumor-associated endothelial cells in vitro. We identified small molecules that enhanced the transfection efficiency of tumor-associated endothelial cells, but not normal human endothelial cells or cancer cells. Intravenous (i.v.) injection of our targeted, reversibly masked complexes into mice, bearing human pancreatic tumor and endothelial cells, specifically increased transfection to this tumor microenvironment approximately 200-fold. Efficacy studies using our optimized targeted delivery of a plasmid encoding thrombospondin-1 eliminated tumors completely after five i.v. injections administered once every week.

Extract from Rhus verniciflua Stokes is capable of inhibiting the growth of human lymphoma cells.

Rhus verniciflua Stokes (RVS), used as a food additive and a traditional herbal medicine, has both antioxidant and antitumor activities which are known to be closely associated with the polyphenolic compounds that it contains. In the present study, we purified a fraction from a crude acetone extract of RVS, named RCMF (RVS chloroform-methanol fraction), and evaluated its ability to scavenge free radicals and inhibit cell growth. In addition, the active compounds responsible for the activities were identified. Results showed that RCMF contained an antioxidant potential and strongly suppressed the proliferative capability of B lymphoma cells. RCMF-mediated suppression of cell growth was verified to be apoptotic, based on the increased DNA fragmentation and low fluorescence intensity in the nuclei after propidium iodide staining, and also on the appearance of DNA laddering. Finally, EI-MS, 1H-NMR, and 13C-NMR spectra confirmed that RCMF contained flavonoid derivatives, including protocatechuic acid, fustin, fisetin, sulfuretin, and butein, suggesting that these flavonoid derivatives are the main active compounds responsible for the antioxidant and antiproliferative activities of RCMF.

Comparison of myocardial infarction with sequential ligation of the left anterior descending artery and its diagonal branch in dogs and sheep.

We report a comparison of the effects of myocardial infarction in dogs and sheep using sequential ligation of the left anterior descending artery (LAD) and its diagonal branch (DA), with hemodynamic, ultrasonographic and pathological evaluations. Five animals were used in each group. After surgical preparation, the LAD was ligated at a point approximately 40% of the distance from the apex to the base of the heart, and after one hour, the DA was ligated at the same level. Hemodynamic and ultrasonographic measurements were performed preligation, 30 minutes after LAD ligation, and 1 hour after DA ligation. As a control, two animals in each group were used for the simultaneous ligation of the LAD and the DA. Two months after the coronary ligation, the animals were evaluated as previously, and killed for postmortem examination of their hearts. All seven animals in the dog group survived the experimental procedures, while in the sheep group only animals with sequential ligation of the LAD and DA survived. Statistically significant decreases in systemic arterial blood pressure and cardiac output, and an increase in the pulmonary artery capillary wedge pressure (PACWP) were observed one hour after sequential ligation of the LAD and its DA in the sheep, while only systemic arterial pressures decreased in the dog. Ultrasonographic analyses demonstrated variable degrees of anteroseptal dyskinesia and akinesia in all sheep, but in no dogs. Data two months after coronary artery ligation showed significant increases in central venous pressure, pulmonary artery pressure, and PACWP in the sheep, but not in the dog. Left ventricular end-diastolic dimension and left ventricular end-systolic dimension in ultrasonographic studies were also increased only in the sheep. Pathologically, the well-demarcated thin-walled transmural anteroseptal infarcts with chamber enlargement were clearly seen in all specimens of sheep, and only-mild-to-moderate chamber enlargements with endocardial fibrosis were observed in the dog hearts. In conclusion, this study confirms that the dog is not a suitable model for myocardial infarction with failure by coronary artery ligation despite negligent operative mortality, when compared directly with an ovine model.

Autologous cardiomyocyte transplantation in an ovine myocardial infarction model.

BACKGROUND: To evaluate the possibility of autologous cardiomyocyte transplantation, we transplanted cultured autologous cells into an infarct region developed by coronary artery ligation in an ovine model. MATERIALS AND METHODS: A chronic heart failure model with a considerable portion of myocardial infarction was created in sheep using sequential ligation of the homonymous artery and its diagonal branch. Autologous cardiomyocytes were cultured and isolated from the right ventricular infundibulum. After a predetermined interval (one animal for two months and the other for three months), the two animals were reanesthetized and a suspension of cultured autologous vetricular cells in 0.3 ml of culture medium (1.2 x 10(7) cells) was injected into the center of three out of the four sites in the infarcted area using a tuberculin syringe. The same amount of culture medium was injected with an identical procedure into the center of the remaining site, as control. The animals were kept alive for a further month, and then sacrificed for postmortem heart examinations. Light microscopic analysis and immunohistochemical study for myoglobin were done. RESULTS AND CONCLUSIONS: On postmortem gross examination, well-demarcated thin-walled anteroseptal infarcts with chamber enlargement were clearly seen in specimens from the two animals. Microscopic analysis showed homogenous fibrosis throughout the infarcted areas. In both animals, one of the three sites of cardiomycyte injection showed an islet of cardiomyocytes in the mid-myocardium, while none were observed in the control site of either animal. A layer of cardiomyocytes was observed in subendocardial regions, as it was in the control areas. In conclusion, cardiomyocyte transplantation into the infarct regions developed by coronary artery ligation in an ovine model was achieved with only limited success. An understanding of why only 33% of cardiomyocyte-injection sites demonstrated viable cardiomyocytes, in the form of tiny cell islets, remains to be elucidated.

Altered stability of pulmonary surfactant in SP-C-deficient mice.

The surfactant protein C (SP-C) gene encodes an extremely hydrophobic, 4-kDa peptide produced by alveolar epithelial cells in the lung. To discern the role of SP-C in lung function, SP-C-deficient (-/-) mice were produced. The SP-C (-/-) mice were viable at birth and grew normally to adulthood without apparent pulmonary abnormalities. SP-C mRNA was not detected in the lungs of SP-C (-/-) mice, nor was mature SP-C protein detected by Western blot of alveolar lavage from SP-C (-/-) mice. The levels of the other surfactant proteins (A, B, D) in alveolar lavage were comparable to those in wild-type mice. Surfactant pool sizes, surfactant synthesis, and lung morphology were similar in SP-C (-/-) and SP-C (+/+) mice. Lamellar bodies were present in SP-C (-/-) type II cells, and tubular myelin was present in the alveolar lumen. Lung mechanics studies demonstrated abnormalities in lung hysteresivity (a term used to reflect the mechanical coupling between energy dissipative forces and tissue-elastic properties) at low, positive-end, expiratory pressures. The stability of captive bubbles with surfactant from the SP-C (-/-) mice was decreased significantly, indicating that SP-C plays a role in the stabilization of surfactant at low lung volumes, a condition that may accompany respiratory distress syndrome in infants and adults.

Secretion of surfactant protein C, an integral membrane protein, requires the N-terminal propeptide.

Proteolytic processing of surfactant protein C (SP-C) proprotein in multivesicular bodies of alveolar type II cells results in a 35-residue mature peptide, consisting of a transmembrane domain and a 10-residue extramembrane domain. SP-C mature peptide is stored in lamellar bodies (a lysosomal-like organelle) and secreted with surfactant phospholipids into the alveolar space. This study was designed to identify the peptide domain of SP-C required for sorting and secretion of this integral membrane peptide. Deletion analyses in transiently transfected PC12 cells and isolated mouse type II cells suggested the extramembrane domain of mature SP-C was cytosolic and sufficient for sorting to the regulated secretory pathway. Intratracheal injection of adenovirus encoding SP-C mature peptide resulted in secretion into the alveolar space of wild type mice but not SP-C (-/-) mice. SP-C secretion in null mice was restored by the addition of the N-terminal propeptide. The cytosolic domain, consisting of the N- terminal propeptide and extramembrane domain of mature SP-C peptide, supported secretion of the transmembrane domain of platelet-derived growth factor receptor. Collectively, these studies indicate that the N-terminal propeptide of SP-C is required for intracellular sorting and secretion of SP-C.

Effect of acupuncture treatment on uterine motility and cyclooxygenase-2 expression in pregnant rats.

As the pregnancy stage advances, prostaglandin (PG) concentrations increase in the uterus, being responsible for the increased uterus contractility during labor. Therefore, regulating the concentration of the PGs in the uterus is important for controlling preterm delivery. In oriental medicine traditionally, an acupuncture of LI-4 controls for the function and motility of the uterus. In this study, acupuncture treatment on the LI-4 acupoint in nonpregnant and pregnant rats was evaluated for its efficacy in the expression of COX-2 enzyme and uterus motility. Whether the rats were pregnant or not, immunohistochemical localization of the COX-2 enzyme was primarily found in the uterine endometrium with weak localization in the uterine myometrium. The level of expression in these two locations was intensified by pregnancy but reduced by the LI-4 acupuncture. The infusion of PGF(2alpha) in pregnant rats caused and increased COX-2 expression in the myometrium while it caused a decreased expression in the endometrium. The uterus motility monitored during the LI-4 acupuncture reduced to 67.0% in nonpregnant rats, and to 75.0% in pregnant rats. PGF(2alpha) infusion in pregnant rats increased uterine motility to 117.3%. The significant reduction in uterus motility in pregnant rats supports the role of LI-4 acupuncture in inhibiting the expression of COX-2 enzyme that can be used to regulate complicated preterm labor.

The effect of acupuncture on uterine contraction induced by oxytocin.

Preterm labor (PTL) is one of the main causes of fetal mortality and morbidity in obstetrical medicine. Current methods of treatment are not very effective and often have significant side effects. For this reason new methods of preventing PTL are currently being sought. In Western medicine the newest development is oxytocin antagonists. In Oriental medicine acupuncture and moxibustion are being utilized for the purpose of stopping PTL. The goals of this study were to determine if acupuncture in pregnant rats can suppress oxytocin induced uterine contractions and to compare these results with those inhibited by an oxytocin antagonist. Uterine contractions were induced by continuous infusion of exogenous oxytocin. The first fetus in one uterine horn near the ovarian end was removed and distilled water-filled catheter was inserted into that vacated amniotic sac to measure uterine contractions as intrauterine pressure changes. Two acupoints of Ho-Ku (LI-4) and San-Yin-Chiao (Sp-6) were selected for acupuncture and Kuan-Yüan (Co-4) was used for moxibustion. The oxytocin-induced uterine contractions were significantly suppressed by acupuncture on the LI-4 (p < 0.05), but not by Sp-6. Stimulation of Co-4 by moxibustion had no significant (p > 0.05) tocolytic effect. The administration of oxytocin antagonist eliminated all the uterine contractions induced by oxytocin. The application of acupuncture to re-stimulate the activity that was suppressed by the oxytocin antagonist did not produce any positive results. However, prostaglandins did cause the uterus to contract. In conclusion, acupuncture on LI-4 was found to suppress uterine contractions induced by oxytocin in the pregnant rat. If acupuncture is similarly effective in counteracting the effects of oxytocin in women, then this may an alternative medical treatment for women in preterm labor.

The role of homodimers in surfactant protein B function in vivo.

Surfactant protein B (SP-B) is detected in the airways as a sulfhydryl-dependent dimer (M(r) approximately 16,000). To test the hypothesis that formation of homodimers is critical for SP-B function, the cysteine residue reported to be involved in SP-B dimerization was mutated to serine (Cys(248) --> Ser) and the mutated protein was targeted to the distal respiratory epithelium of transgenic mice. Transgenic lines which demonstrated appropriate processing, sorting, and secretion of human SP-B monomer were crossed with SP-B +/- mice to achieve expression of human monomer in the absence of endogenous SP-B dimer (hSP-B(mon), mSP-B-/-). In two of three transgenic lines, hSP-B(mon), mSP-B-/- mice had normal lung structure, complete processing of SP-C proprotein, well formed lamellar bodies, and normal longevity. Pulmonary function studies revealed an altered hysteresis curve for hSP-B(mon), mSP-B-/- mice relative to wild type mice. Large aggregate surfactant fractions from hSP-B(mon), mSP-B-/- mice resulted in higher minimum surface tension in vitro compared with surfactant from wild type mice. Surfactant lipids supplemented with 2% hSP-B monomer resulted in slower adsorption and higher surface tension than surfactant with 2% hSP-B dimer. Taken together, these data indicate a role for SP-B dimer in surface tension reduction in the alveolus.

Ablation of a critical surfactant protein B intramolecular disulfide bond in transgenic mice.

The 79-amino acid, mature SP-B peptide contains three intramolecular disulfide bonds shared by all saposin-like proteins. This study tested the hypothesis that the disulfide bond formed between cysteine residues 35 and 46 (residues 235 and 246 of the SP-B proprotein) is essential for proper function of SP-B. To test the role of this bridge in SP-B function in vivo, a construct was generated in which cysteine residues 235 and 246 of the human SP-B proprotein were mutated to serine and cloned under the control of the 3.7-kilobase hSP-C promoter (hSP-B(C235S/C246S)). In two transgenic mouse lines, expression of the mutant peptide in the wild-type murine SP-B background was invariably lethal in the neonatal period. In four additional lines, survival was inversely related to the level of transgene expression. To test the ability of the mutant peptide to functionally replace the wild-type protein, transgenic mice were crossed into the SP-B null background. No animals that expressed hSP-B(C235S/C246S) in the murine SP-B-/- background survived the neonatal period. hSP-B(C235S/C246S) proprotein accumulated in the endoplasmic reticulum and was not processed to the mature, biologically active peptide. The results of these studies demonstrate that the intramolecular bridge between residues 235 and 246 is critical for intracellular trafficking of SP-B and suggest that overexpression of mutant SP-B in the wild-type background may be lethal.

Effects of yukmi, an herbal formula, on the liver of senescence accelerated mice (SAM) exposed to oxidative stress.

The effects of yukmi (Decoction of six plants including rehmannia), an herbal formula, were studied on liver oxidant damage induced by paraquat (PQ) administered intravenously in the senescence accelerated mice (SAM-P/8). The activities of superoxide dismutase (SOD) and catalase as two major antioxidant enzymes and lipid peroxidation levels were determined for six days. Data show that the activities of hepatic SODs and catalase were increased by oral administration of yukmi extracts following PQ pretreatment. Herbal medicine effectively blocked the PQ-induced effects on liver malondialdehyde (MDA) levels. For the histopathological changes in SAM-P/8 liver, yukmi extracts inhibited PQ-induced damage to the hepatic mitochondria and their membranes. Data suggest that yukmi extracts may be useful in protecting against oxidative damage.

Surfactant protein B (SP-B) -/- mice are rescued by restoration of SP-B expression in alveolar type II cells but not Clara cells.

Surfactant protein B (SP-B) mRNA and protein are restricted to alveolar Type II and Clara cells in the respiratory epithelium. In order to investigate the function of SP-B in these distinct cell types, transgenic mice were generated in which SP-B expression was selectively restored in Type II cells or Clara cells of SP-B -/- mice. The 4.8-kilobase murine SP-C promoter was used to generate 3 transgenic lines which expressed human SP-B in Type II cells (mSP-C/hSP-B). Likewise, the 2.3-kilobase murine CCSP promoter was used to generate two transgenic lines which expressed human SP-B in Clara cells (mCCSP/hSP-B). mSP-C/hSP-B and mCCSP/hSP-B transgenic mice were subsequently bred to SP-B +/- mice in order to selectively express SP-B in Type II cells or Clara cells of SP-B -/- mice. Selective restoration of SP-B expression in Type II cells completely rescued the neonatal lethal phenotype in SP-B -/- mice. Expression of SP-B in some, but not all Type II cells of SP-B -/- mice, allowed postnatal survival, but resulted in significantly altered lung architecture and function. Selective restoration of SP-B expression in Clara cells of SP-B -/- mice resulted in respiratory dysfunction and invariable neonatal death, related to the complete absence of mature SP-B peptide in these mice. These results indicate that expression and processing of the SP-B proprotein to the mature peptide in Type II cells is absolutely required for lung function in vivo and that SP-B expression in Clara cells cannot substitute for this function.