Histology Atlas of the Developing Mouse Respiratory System From Prenatal Day 9.0 Through Postnatal Day 30.

Respiratory diseases are one of the leading causes of death and disability around the world. Mice are commonly used as models of human respiratory disease. Phenotypic analysis of mice with spontaneous, congenital, inherited, or treatment-related respiratory tract abnormalities requires investigators to discriminate normal anatomic features of the respiratory system from those that have been altered by disease. Many publications describe individual aspects of normal respiratory tract development, primarily focusing on morphogenesis of the trachea and lung. However, a single reference providing detailed low- and high-magnification, high-resolution images of routine hematoxylin and eosin (H&E)-stained sections depicting all major structures of the entire developing murine respiratory system does not exist. The purpose of this atlas is to correct this deficiency by establishing one concise reference of high-resolution color photomicrographs from whole-slide scans of H&E-stained tissue sections. The atlas has detailed descriptions and well-annotated images of the developing mouse upper and lower respiratory tracts emphasizing embryonic days (E) 9.0 to 18.5 and major early postnatal events. The selected images illustrate the main structures and events at key developmental stages and thus should help investigators both confirm the chronological age of mouse embryos and distinguish normal morphology as well as structural (cellular and organ) abnormalities.

Development of the skin in the eastern quoll (Dasyurus viverrinus) with focus on cutaneous gas exchange in the early postnatal period.

A morphological and morphometric study of the skin development in the eastern quoll (Dasyurus viverrinus) was conducted to follow the transition from cutaneous to pulmonary gas exchange in this extremely immature marsupial species. Additionally, the development of the cardiac and respiratory system was followed, to evaluate the systemic prerequisites allowing for cutaneous respiration. The skin in the newborn D. viverrinus was very thin (36 ± 3 µm) and undifferentiated (no hair follicles, no sebaceous and perspiratory glands). Numerous superficial cutaneous capillaries were encountered, closely associated with the epidermis, allowing for gaseous exchange. The capillary volume density was highest in the neonate (0.33 ± 0.04) and decreased markedly during the first 4 days (0.06 ± 0.01). In the same time period, the skin diffusion barrier increased from 9 ± 1 µm to 44 ± 6 µm. From this age on the skin development was characterized by thickening of the different cutaneous layers, formation of hair follicles (day 55) and the occurrence of subcutaneous fat (day 19). The heart of the neonate D. viverrinus had incomplete interatrial, inter-ventricular, and aortico-pulmonary septa, allowing for the possibility that oxygenated blood from the skin mixes with that of the systemic circulation. The fast-structural changes in the systemic circulations (closing all shunts) in the early postnatal period (3 days) necessitate the transition from cutaneous to pulmonary respiration despite the immaturity of the lungs. At this time, the lung was still at the canalicular stage of lung development, but had to be mature enough to meet the respiratory needs of the growing organism. The morphometric results for the skin development of D. viverrinus suggest that cutaneous respiration is most pronounced in neonates and decreases rapidly during the first 3 days of postnatal life. After this time a functional transition of the skin from cutaneous respiration to insulation and protection of the body takes place.

EGFR controls Drosophila tracheal tube elongation by intracellular trafficking regulation.

Development is governed by a few conserved signalling pathways. Amongst them, the EGFR pathway is used reiteratively for organ and tissue formation, and when dysregulated can lead to cancer and metastasis. Given its relevance, identifying its downstream molecular machinery and understanding how it instructs cellular changes is crucial. Here we approach this issue in the respiratory system of Drosophila. We identify a new role for EGFR restricting the elongation of the tracheal Dorsal Trunk. We find that EGFR regulates the apical determinant Crb and the extracellular matrix regulator Serp, two factors previously known to control tube length. EGFR regulates the organisation of endosomes in which Crb and Serp proteins are loaded. Our results are consistent with a role of EGFR in regulating Retromer/WASH recycling routes. Furthermore, we provide new insights into Crb trafficking and recycling during organ formation. Our work connects cell signalling, trafficking mechanisms and morphogenesis and suggests that the regulation of cargo trafficking can be a general outcome of EGFR activation.

Pathophysiology, causes and genetics of paediatric and adult bronchiectasis.

Bronchiectasis has historically been considered to be irreversible dilatation of the airways, but with modern imaging techniques it has been proposed that 'irreversible' be dropped from the definition. The upper limit of normal for the ratio of airway to arterial development increases with age, and a developmental perspective is essential. Bronchiectasis (and persistent bacterial bronchitis, PBB) is a descriptive term and not a diagnosis, and should be the start not the end of the patient's diagnostic journey. PBB, characterized by airway infection and neutrophilic inflammation but without significant airway dilatation may be a precursor of bronchiectasis, and there are many commonalities in the microbiology and the pathology, which are reviewed in this article. A high index of suspicion is essential, and a history of chronic wet or productive cough for more than 4-8 weeks should prompt investigation. There are numerous underlying causes of bronchiectasis, although in many cases no cause is found. Causes include post-infectious, especially after tuberculosis, adenoviral or pertussis infection; aspiration syndromes; defects in host defence, which may solely affect the airways (cystic fibrosis, not considered in this review, and primary ciliary dyskinesia); and primary ciliary dyskinesia or be systemic, such as common variable immunodeficiency; genetic syndromes; and anatomical defects such as intraluminal airway obstruction (e.g. foreign body), intramural obstruction (e.g. complete cartilage rings) and external airway compression (e.g. by tuberculous lymph nodes). Identification of the underlying cause is important, because some of these conditions have specific treatments and others genetic implications for the family.

The anatomy of the pediatric airway: Has our knowledge changed in 120 years? A review of historic and recent investigations of the anatomy of the pediatric larynx.

BACKGROUND: There is disagreement regarding the anatomy of the pediatric airway, particularly regarding the shape of the cricoid cartilage and the location of the narrowest portion of the larynx. AIMS: The aim of this review is to clarify the origin and the science behind these differing views. METHODS: We undertook a review of published literature, University Libraries, and authoritative textbooks with key search words and phrases. RESULTS: In vivo observations suggest that the narrowest portion of the airway is more proximal than the cricoid cartilage. However, in vitro studies of autopsy specimens measured with rods or calipers, confirm that the nondistensible and circular or near circular cricoid outlet is the narrowest level. These anatomic studies confirmed the classic "funnel" shape of the pediatric larynx. In vivo studies are potentially misleading as the aryepiglottic, vestibular, and true vocal folds are in constant motion with respiration. These studies also do not consider the effects of normal sleep, inhalation agents, and comorbidities such as adenoid or tonsil hypertrophy that cause some degree of pharyngeal collapse and alter the normal movement of the laryngeal tissues. Thus, the radiologic studies suggesting that the narrowest portion of the airway is not the cricoid cartilage may be the result of an artifact depending upon which phase of respiration was imaged. CONCLUSION: In vivo studies do not take into account the motion of the highly pliable laryngeal upper airway structures (aryepiglottic, vestibular, and vocal folds). Maximal abduction of these structures with tracheal tubes or bronchoscopes always demonstrates a larger opening of the glottis compared to the outlet of the cricoid ring. Injury to the larynx depends upon ease of tracheal tube or endoscope passage past the cricoid cartilage and not passage through the readily distensible more proximal structures. The infant larynx is funnel shaped with the narrowest portion the circular or near circular cricoid cartilage confirmed by multiple in vitro autopsy specimens carried out over the past century.

The intersection of the extrinsic hedgehog and WNT/wingless signals with the intrinsic Hox code underpins branching pattern and tube shape diversity in the drosophila airways.

The tubular networks of the Drosophila respiratory system and our vasculature show distinct branching patterns and tube shapes in different body regions. These local variations are crucial for organ function and organismal fitness. Organotypic patterns and tube geometries in branched networks are typically controlled by variations of extrinsic signaling but the impact of intrinsic factors on branch patterns and shapes is not well explored. Here, we show that the intersection of extrinsic hedgehog(hh) and WNT/wingless (wg) signaling with the tube-intrinsic Hox code of distinct segments specifies the tube pattern and shape of the Drosophila airways. In the cephalic part of the airways, hh signaling induces expression of the transcription factor (TF) knirps (kni) in the anterior dorsal trunk (DTa1). kni represses the expression of another TF spalt major (salm), making DTa1 a narrow and long tube. In DTa branches of more posterior metameres, Bithorax Complex (BX-C) Hox genes autonomously divert hh signaling from inducing kni, thereby allowing DTa branches to develop as salm-dependent thick and short tubes. Moreover, the differential expression of BX-C genes is partly responsible for the anterior-to-posterior gradual increase of the DT tube diameter through regulating the expression level of Salm, a transcriptional target of WNT/wg signaling. Thus, our results highlight how tube intrinsic differential competence can diversify tube morphology without changing availabilities of extrinsic factors.

Does aerobic capacity predict the spatial position of individuals within schools in juvenile qingbo (Spinibarbus sinensis)?

Schooling behavior is an adaptive trait of important biological and ecological significance in fish species. However, the question of how aerobic capacity and environmental factors (i.e., food and water velocity) affect the spatial positioning within fish schools has received little attention. Our study measured the aerobic capacity-as indicated by standard metabolic rate (SMR), maximum metabolic rate (MMR) and aerobic scope (AS)-and swimming performance of juvenile qingbo (Spinibarbus sinensis) and filmed their schooling behavior in a swim tunnel under both a control treatment and food stimulus treatment at three water velocities (20, 30 and 40cms-1). Neither aerobic capacity nor swimming performance was related to spatial position within schools. Food stimulation did not trigger any change in the characteristics of spatial position at three water velocities. However, an intra-school positional preference was found between water velocities under the control treatment and food stimulus treatment. Individuals who preferred the rear of the school had smaller coefficients of variation in position under the two treatments, but this behavior was not correlated with any parameters for metabolic rates. Inter-school social interaction level, as indicated by total chase times, was not affected by either water velocity or food appearance. Although aerobic capacity and food stimulus did not influence the spatial position of individuals within schools, individual qingbo had spatial positional preferences within schools between different water speeds.

The role of the autonomic nervous system in control of cardiac and air-breathing responses to sustained aerobic exercise in the African sharptooth catfish Clarias gariepinus.

Clarias gariepinus is a facultative air-breathing catfish that exhibits changes in heart rate (ƒH) associated with air-breaths (AB). A transient bradycardia prior to the AB is followed by sustained tachycardia during breath-hold. This study evaluated air-breathing and cardiac responses to sustained aerobic exercise in juveniles (total length~20cm), and how exercise influenced variations in fH associated with AB. In particular, it investigated the role of adrenergic and cholinergic control in cardiac responses, and effects of pharmacological abolition of this control on air-breathing responses. Sustained exercise at 15, 30 and 45cms-1 in a swim tunnel caused significant increases in fAB and fH, from approximately 5breathsh-1 and 60heartbeatsmin-1 at the lowest speed, to over 60breathsh-1 and 100beatsmin-1 at the highest, respectively. There was a progressive decline in the degree of variation in fH, around each AB, as fAB increased with exercise intensity. Total autonomic blockade abolished all variation in fH during exercise, and around each AB, but fAB responses were the same as in untreated animals. Cardiac responses were exclusively due to modulation of inhibitory cholinergic tone, which varied from >100% at the lowest speed to <10% at the highest. Cholinergic blockade had no effect on fAB compared to untreated fish. Excitatory ß-adrenergic tone was approximately 20% and did not vary with swimming speed, but its blockade increased fAB at all speeds, compared to untreated animals. This reveals complex effects of autonomic control on air-breathing during exercise in C. gariepinus, which deserve further investigation.

Imaging Acute Airway Obstruction in Infants and Children.

Acute airway obstruction is much more common in infants and children than in adults because of their unique anatomic and physiologic features. Even in young patients with partial airway occlusion, symptoms can be severe and potentially life-threatening. Factors that predispose children to airway compromise include the orientation of their larynx, the narrow caliber of their trachea, and their weak intercostal muscles. Because the clinical manifestations of acute airway obstruction are often nonspecific, clinicians often rely on the findings at imaging to establish a diagnosis. Several key anatomic features of the pediatric airway make it particularly susceptible to respiratory distress, and the imaging recommendations for children suspected of having acute airway obstruction are presented. Although cross-sectional imaging may be helpful, the diagnosis can often be established by using radiographs alone. Radiographs of the chest and upper airway should be routinely acquired; however, for the child who is in severe distress, a single lateral radiographic view may be all that is necessary. The purpose of this article is to provide an imaging approach to acquired causes of acute airway obstruction in children, including (a) abnormalities affecting the upper portion of the airway, such as croup, acute epiglottitis, retropharyngeal infection, and foreign bodies, and (b) abnormalities affecting the lower portion of the airway, such as asthma, bronchiolitis, and foreign bodies. It is essential that the radiologist recognize key imaging findings and understand the pathophysiologic features of acute airway obstruction because in most cases, when the cause is identified, the condition responds well to prompt management.

Multi-character approach reveals a discordant pattern of phenotypic variation during ontogeny in Culex pipiens biotypes (Diptera: Culicidae).

Culex (Culex) pipiens s.l. (Diptera: Culicidae) comprises two distinct biotypes, pipiens ('rural') and molestus ('urban'), both of which are thought to have differing capacities due to different host preferences. To better understand West Nile encephalitis epidemiology and improve risk assessment, local distinction between these forms is essential. This study assesses phenotypic variation at larval and adult stages of 'urban' and 'rural' biotypes of the species by complementary use of meristic, univariate and multivariate traits analyzed by traditional and geometric morphometrics. Third- and fourth-instar larvae from a broad area of the city of Novi Sad (Serbia) were collected and reared in the laboratory. After adult eclosion, the sex of each larva was recorded based on the sex of the corresponding adult. Examination of the association between variations of larval traits revealed contrasting variations regarding pecten spines vs. siphonal size and siphonal shape in the 'rural' biotype. Siphons of larvae collected in marshes and forest ecosystems outside urban areas were found to be the largest, but possessed the smallest number of pecten spines. In addition, statistically significant female-biased sexual dimorphism was observed in siphonal size, wing size and wing shape. Finally, we propose that an integrative approach is essential in delimitation of Cx. pipiens s.l. biotypes, since their differentiation was not possible based solely on larval and adult traits. Our findings shed light on the phenotypic plasticity important for population persistence in the changing environment of these medically important taxa.

Thoracic anesthesia in the elderly.

PURPOSE OF REVIEW: The mean age of patients presenting for thoracic surgery is rising steadily, associated with an increased demand for thoracic surgical treatments by geriatric patients. With increasing age, physiologic changes and comorbidities have to be considered. Thoracic anesthesia for elderly patients requires greater specific knowledge. RECENT FINDINGS: Respiratory mechanics change progressively during aging, and the pharmacology of different drugs is also altered with increasing age. This has implications for the preoperative, intraoperative and postoperative management of elderly patients scheduled for thoracic surgery. Special focus has to be placed on preoperative evaluation, the ventilation regime and general intraoperative management. Effective postoperative pain treatment after geriatric thoracic surgery requires careful pain assessment and drug titration. SUMMARY: Considering key points of physiology and pharmacology can help to provide best possible care for the increasing number of elderly patients in thoracic surgery. Management of geriatric patients in thoracic surgery offer opportunities for anaesthetic interventions including protective ventilation, use of different anesthetics, anaesthesia monitoring, fluid management and pain therapy.

Sox2 modulates Lef-1 expression during airway submucosal gland development.

Tracheobronchial submucosal glands (SMGs) are derived from one or more multipotent glandular stem cells that coalesce to form a placode in surface airway epithelium (SAE). Wnt/ß-catenin-dependent induction of lymphoid enhancer factor (Lef-1) gene expression during placode formation is an early event required for SMG morphogenesis. We discovered that Sox2 expression is repressed as Lef-1 is induced within airway SMG placodes. Deletion of Lef-1 did not activate Sox2 expression in SMG placodes, demonstrating that Lef-1 activation does not directly inhibit Sox2 expression. Repression of Sox2 protein in SMG placodes occurred posttranscriptionally, since the activity of its endogenous promoter remained unchanged in SMG placodes. Thus we hypothesized that Sox2 transcriptionally represses Lef-1 expression in the SAE and that suppression of Sox2 in SMG placodes activates Wnt/ß-catenin-dependent induction of Lef-1 during SMG morphogenesis. Consistent with this hypothesis, transcriptional reporter assays, ChIP analyses, and DNA-protein binding studies revealed a functional Sox2 DNA binding site in the Lef-1 promoter that is required for suppressing ß-catenin-dependent transcription. In polarized primary airway epithelium, Wnt induction enhanced Lef-1 expression while also inhibiting Sox2 expression. Conditional deletion of Sox2 also enhanced Lef-1 expression in polarized primary airway epithelium, but this induction was significantly augmented by Wnt stimulation. Our findings provide the first evidence that Sox2 acts as a repressor to directly modulate Wnt-responsive transcription of the Lef-1 gene promoter. These studies support a model whereby Wnt signals and Sox2 dynamically regulate the expression of Lef-1 in airway epithelia and potentially also during SMG development.

Severity of neonatal hyperoxia determines structural and functional changes in developing mouse airway.

Wheezing is a major long-term respiratory morbidity in preterm infants with and without bronchopulmonary dysplasia. We hypothesized that mild vs. severe hyperoxic exposure in neonatal mice differentially affects airway smooth muscle hypertrophy and resultant airway reactivity. Newborn mice were exposed to 7 days of mild (40% oxygen) or severe (70% oxygen) hyperoxia vs. room air controls. Respiratory system resistance (Rrs), compliance (Crs), and airway reactivity were measured 14 days after oxygen exposure ended under ketamine/xylazine anesthesia. Baseline Rrs increased and Crs decreased in both treatment groups. Methacholine challenge dose dependently increased Rrs and decreased Crs in 40% oxygen-exposed mice, whereas Rrs and Crs responses were similar between 70% oxygen-exposed and normoxic controls. Airway smooth muscle thickness was increased in 40%- but not 70%-exposed mice, whereas collagen increased and both alveolar number and radial alveolar counts decreased after 40% and 70% oxygen. These data indicate that severity of hyperoxia may differentially affect structural and functional changes in the developing mouse airway that contribute to longer-term hyperreactivity. These findings may be important to our understanding of the complex role of neonatal supplemental oxygen therapy in postnatal development of airway responsiveness.

The neonatal lung--physiology and ventilation.

This review article focuses on neonatal respiratory physiology, mechanical ventilation of the neonate and changes induced by anesthesia and surgery. Optimal ventilation techniques for preterm and term neonates are discussed. In summary, neonates are at high risk for respiratory complications during anesthesia, which can be explained by their characteristic respiratory physiology. Especially the delicate balance between closing volume and functional residual capacity can be easily disturbed by anesthetic and surgical interventions resulting in respiratory deterioration. Ventilatory strategies should ideally include application of an 'open lung strategy' as well avoidance of inappropriately high VT and excessive oxygen administration. In critically ill and unstable neonates, for example, extremely low-birthweight infants surgery in the neonatal intensive care unit might be an appropriate alternative to the operating theater. Best respiratory management of neonates during anesthesia is a team effort that should involve a joint multidisciplinary approach of anesthetists, pediatric surgeons, cardiologists, and neonatologists to reduce complications and optimize outcomes in this vulnerable population.

Tracheole investment does not vary with body size among bumblebee (Bombus impatiens) sisters.

Body size is a key organism trait with critical implications for the physiology, life history, and ecology of organisms. Modern insects vary in body mass by over 6 orders of magnitude, but are small by comparison to many other metazoan taxa. The small size of modern insects may reflect limitations imposed by their open respiratory systems which rely, in part, on diffusion. Diffusion rates decline with distance such that, absent compensation, the capacity for larger insects to deliver oxygen to their tissues may be compromised. To compensate, larger grasshoppers, beetles, and bumblebees devote proportionally more of their body volume to the respiratory system, as demonstrated by hypermetric scaling of tracheal volume with body mass(>1). Among bumblebee sisters, total respiratory volume scaled with mass(2.6), but it is unclear at what level or levels of the tracheal system (main tracheal trunks, air sacs, tracheoles) bumblebees express this extreme hypermetry. Here we use transmission electron microscopy to examine the morphology of tracheoles in bumblebee flight muscle among sister bumblebees varying nearly four-fold in body mass. Neither tracheole density nor tracheole diameter changed with body mass. The total cross-sectional area of tracheoles was also invariant with body mass. Together, these results reveal that bumblebees do not compensate for size-related limitations on oxygen delivery by increasing investment at the level of the tracheoles.

The paediatric airway: basic principles and current developments.

Perioperative airway problems frequently result in significant morbidity and mortality in children. Therefore, proficiency in airway management is one of the most important key elements in the safe conduct of paediatric anaesthesia. This review includes important anatomical and physiological aspects of the paediatric airway, challenges encountered, and their management with commonly available resources. The importance of early recognition and treatment of anatomical or functional airway obstruction using locally adapted algorithms is highlighted. Children deemed at risk of aspiration require a controlled rapid sequence induction with sufficiently deep anaesthesia, confirmed complete muscle paralysis and intermittent ventilation prior to tracheal intubation. The benefits of a supraglottic airway device and a cuffed tracheal tube in paediatric airway management are discussed. The primary goal of mastering the paediatric airway is to ensure oxygenation and ventilation. This requires intricate knowledge, regular practice and experience.

Intra-puparial development of the black soldier-fly, Hermetia illucens.

The intra-puparial development of the black soldier-fly, Hermetia illucens (L.) (Diptera: Stratiomyidae), was studied based on 125 pupae under controlled conditions in laboratory. The 6(th) instar larvae were reared until they stopped feeding, and the prepupae were separated according to the reduction in larval length and degree of pigmentation and sclerotization of the cuticle. The pupal stage lasted eight days (192 hours). The process of pupation (larva/pupa apolysis) occurred in the first six hours, extroversion of the head and thoracic appendages took place between the ninth and 21(st) hours, and the pharate appeared 21 hours after completing pupation. After pupariation, four morphological phases of intra-puparial development were observed and described.

Foxm1 transcription factor is critical for proliferation and differentiation of Clara cells during development of conducting airways.

Respiratory epithelial cells are derived from cell progenitors in the foregut endoderm that subsequently differentiate into the distinct cell types lining the conducting and alveolar regions of the lung. To identify transcriptional mechanisms regulating differentiation and maintenance of respiratory epithelial cells, we conditionally deleted Foxm1 transcription factor from the conducting airways of the developing mouse lung. Conditional deletion of Foxm1 from Clara cells, controlled by the Scgb1a1 promoter, dramatically altered airway structure and caused peribronchial fibrosis, resulting in airway hyperreactivity in adult mice. Deletion of Foxm1 inhibited proliferation of Clara cells and disrupted the normal patterning of epithelial cell differentiation in the bronchioles, causing squamous and goblet cell metaplasia, and the loss of Clara and ciliated cells. Surprisingly, conducting airways of Foxm1-deficient mice contained highly differentiated cuboidal type II epithelial cells that are normally restricted to the alveoli. Lineage tracing studies showed that the ectopic alveolar type II cells in Foxm1-deficient airways were derived from Clara cells. Deletion of Foxm1 inhibited Sox2 and Scgb1a1, both of which are critical for differentiation and function of Clara cells. In co-transfection experiments, Foxm1 directly bound to and induced transcriptional activity of Scgb1a1 and Sox2 promoters. Foxm1 is required for differentiation and maintenance of epithelial cells lining conducting airways.

Programming of respiratory health in childhood: influence of outdoor air pollution.

PURPOSE OF REVIEW: This overview highlights recent experimental and epidemiological evidence for the programming effects of outdoor air pollution exposures during early development on lung function and chronic respiratory disorders, such as asthma and related allergic disorders. RECENT FINDINGS: Air pollutants may impact anatomy and/or physiological functioning of the lung and interrelated systems. Programming effects may result from pollutant-induced shifts in a number of molecular, cellular, and physiological states and their interacting systems. Specific key regulatory systems susceptible to programming may influence lung development and vulnerability to respiratory diseases, including both central and peripheral components of neuroendocrine pathways and autonomic nervous system (ANS) functioning which, in turn, influence the immune system. Starting in utero, environmental factors, including air pollutants, may permanently organize these systems toward trajectories of enhanced pediatric (e.g., asthma, allergy) as well as adult disease risk (e.g., chronic obstructive pulmonary disease). Evidence supports a central role of oxidative stress in the toxic effects of air pollution. Additional research suggests xenobiotic metabolism and subcellular components, such as mitochondria are targets of ambient air pollution and play a role in asthma and allergy programming. Mechanisms operating at the level of the placenta are being elucidated. Epigenetic mechanisms may be at the roots of adaptive developmental programming. SUMMARY: Optimal coordinated functioning of many complex processes and their networks of interaction are necessary for normal lung development and the maintenance of respiratory health. Outdoor air pollution may play an important role in early programming of respiratory health and is potentially amenable to intervention.

Deposition of small particles in the developing lung.

Infancy is a time of marked and rapid changes in respiratory tract development. Infants (0-1 year of age) and young children (1- 3 years of age) are a unique subpopulation with regard to therapeutic aerosols. Anatomical, physiological and emotional factors, peculiar to these age groups, present significant challenges for aerosol delivery to the respiratory tract. Most studies with inhaled corticosteroids (ICS) have administered aerosols with relatively large particles, frequently > 3 µm in mass median aerodynamic diameter (MMAD). These drugs were designed for use in adults and older children and were administered with masks which were frequently rejected by children under age 3-4 years. We review the reasons that large-particle aerosols are likely to be less effective in infants and young children. We suggest that the benefit of inhaled medications in this age group requires further evaluation to determine if better therapeutic outcomes might be achieved using smaller particles and more patient-friendly delivery systems.