Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer

Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer

Editor

Prashant Kesharwani

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Biography

Preface

Chapter 1. An Overview of the Anatomy and Physiology of the Lung

1. Introduction

2. Overview of the Anatomy of Lungs

3. Blood Supply of the Lungs

4. Overview of the Physiology of the Lungs

5. Expiration

6. Pulmonary Ventilation

7. Gas Exchange

8. Control of Respiration

9. Conclusion

Chapter 2. An Overview, Current Challenges of Drug Resistance, and Targeting Metastasis Associated With Lung Cancer

1. Introduction

2. Molecular Alterations in Lung Cancer: Opportunities for Therapy

3. Current Lung Cancer Therapies: Future of Cancer Medicine

4. Road Blocks to NSCLC Therapies: Drug Resistance and Metastasis

5. Conclusion

Chapter 3. Overexpressed Receptors and Proteins in Lung Cancer

1. Introduction

2. Overexpressed Receptors/Proteins on Lung Cancer Cell Surfaces

3. Overexpressed Receptors/Proteins Affecting Metabolism on Lung Cancer Cells

4. Conclusion

Chapter 4. Polymeric Nanoparticle-Based Drug/Gene Delivery for Lung Cancer

1. Introduction

2. Polymeric Nanoparticles

3. Inhalable Nanoparticles (NPs) for Lung Cancer

4. Lipid–Polymer Hybrid Nanoparticles

5. Active Targeting of Nanoparticles

6. Major Issues With Toxicological Aspects of Inhaled Polymeric NPs

7. Limitations in Polymeric Gene Delivery: In vivo

8. Clinical Applications and Commercialization

9. Conclusion and Future Perspectives

Chapter 5. Solid Lipid Nanoparticle-Based Drug Delivery for Lung Cancer

1. Introduction

2. Applications of SLNs in Drug- and Gene-Delivery Systems for Lung Cancer Treatment

3. SLNs for Gene Delivery

4. Combinatorial Drug Delivery via SLNs

5. Ligand-Directed SLNs

6. Stimuli-Responsive SLNs

7. Pulmonary Administration of SLNs

8. Pulmonary Devices

9. Intratracheal Instillation

10. Liquid Aerosol Suspension

11. Dry Powder Inhaler

12. Solid Lipid Microparticles

13. Toxicological Evaluations

14. Conclusions

Chapter 6. Liposome-Based Drug Delivery for Lung Cancer

1. Introduction

2. Liposomes as a Drug-Delivery System in Lung Cancer

3. Liposomes for Gene Therapy in Lung Cancer

4. Dual-Loaded Liposomes for Lung Cancer Treatment

5. Inhaled Liposome-Delivery System for Lung Cancer

6. Lung Tumor Imaging and Detection

7. Liposomes for Theranostic Applications in Lung Cancer

8. Conclusions and Future Perspectives

Chapter 7. Dendrimer-Based Nanocarriers in Lung Cancer Therapy

1. Introduction

2. Lung Cancer and Nanotechnology

3. Dendrimers as Biocompatible and Safe Delivery Systems

4. Dendrimers in the Treatment of Lung Cancer

5. Conclusion

Chapter 8. Polymeric Micelles in Management of Lung Cancer

1. Introduction

2. Biology of Lung Cancer

3. Types and Subtypes of Lung Cancer

4. Treatment of Lung Cancer

5. Challenges Facing Treatment of Lung Cancer

6. Polymeric Micelles

7. Mechanism of Formation

8. Different Types of Polymeric Micelle Systems

9. Preclinical Assessment of Polymeric Micelles for Lung Cancer Drug Delivery

10. Polymeric Micelles in Clinical Trials for Treatment of Lung Cancer

11. Conclusion

Chapter 9. Nanoemulsions as Effective Carriers for the Treatment of Lung Cancer

1. Introduction

2. Molecular, Biological, and Clinical Perspectives of Lung Cancer

3. Consideration of Nanotechnology to Overcome the Physiological Barriers in Lung Cancer Therapy

4. Consideration of Nanoemulsions in Current Pharmacotherapeutic Protocols for Cancer

5. Nanoemulsion-Based Targeted and Nontargeted Delivery To Lung Cancer

6. Clinical Aspects and Commercialization of Nanoemulsions for Lung Cancer

7. Conclusion and Future Trends

Chapter 10. Nanomedicine-Based Inhalation Treatments for Lung Cancer

1. An Overview of Pulmonary Drug Delivery in Lung Cancer Therapy

2. Inhaled Nanomedicine—An Ongoing Concept in Lung Cancer Therapy

3. Current Limitations and Future Challenges

Chapter 11. Toward the Development of a Novel Diagnostic Nano-Imaging Platform for Lung Cancer

1. Lung Cancer and Pulmonary Metastasis: Prevalence and Challenges

2. Diagnosis of LC and Pulmonary Metastasis

3. Current Challenges to Nano-Imaging Techniques

4. Conclusion and Future Prospects

Chapter 12. Hydrogel-Based Drug Delivery for Lung Cancer

1. Introduction

2. Lung Cancer

3. Hydrogel

4. Studies Regarding Hydrogel Toxicity

5. Pharmacokinetic Studies of Hydrogels

6. Conclusion and Future Perspectives

Chapter 13. Quantum Dot-Based Drug Delivery for Lung Cancer

1. Introduction

2. Nanotherapeutics-Based Treatment Approaches

3. Quantum Dots as a Drug-Delivery System

4. Toxicity Issues Related to Quantum Dots and Their Remedies

5. Applications of Quantum Dots

6. Studies Advocating the Role of Quantum Dots in Lung Cancer

7. Concluding Remarks and Future Perspectives

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1650, San Diego, CA 92101, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2019 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright

Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-12-815720-6

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: John Fedor

Acquisition Editor: Erin Hill-Parks

Editorial Project Manager: Timothy Bennett

Production Project Manager: Swapna Srinivasan

Cover Designer: Mark Rogers

Typeset by TNQ Technologies

Dedication

I would like to dedicate this book to my parents (Mr. Hariom Kesharwani and Mrs. Anguri Kesharwani), my elder sister Dr. Poonam, and my younger brother Er. Pankaj, who always encouraged me throughout this journey. Equally, the book is dedicated to the love and sacrifices of my wife Garima, my sweet daughter Yashsavi, my bhanja Adhyayan, and finally my mentor Professor N.K. Jain for believing in me and always being there for me.

Prashant Kesharwani

Contributors

Hadeer M. Abdelaziz

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Karim Amighi,     Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium

H.H. Aung,     Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia

Fatemah Bahman,     College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain

Subrat Kumar Bhattamishra,     School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

R. Narayana Charyulu,     Department of Pharmaceutics, NGSMIPS, Mangalore, India

Bappaditya Chatterjee,     Pharmaceutical Technology, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Malaysia

Hira Choudhury,     School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Manish K. Chourasia,     Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India

Pran Kishore Deb,     Faculty of Pharmacy, Philadelphia University-Jordan, Philadelphia University, Amman, Jordan

Sara Elkaissi,     College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain

Ahmed O. Elzoghby

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

May S. Freag

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

S.K. Gholami,     Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia

Bapi Gorain,     School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia

Khaled Greish,     College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain

Zahid Hussain,     Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Bandar Puncak Alam, Malaysia

Mohd Cairul Iqbal Mohd Amin,     Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan, Kuala Lumpur, Malaysia

Ankush Jain,     Smriti College of Pharmaceutical Education, Indore, India

Sanjay Jain,     Indore Institute of Pharmacy, Indore, India

Prashant Kesharwani,     Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

Sukant Khurana,     Pharmacology Department, Central Drug Research Institute, Lucknow, India

Kanchan Kohli,     Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

Thiagarajan Madheswaran,     School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

K.-K. Mak,     School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Shadab Md,     School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Vijay Mishra,     Department of Pharmaceutics, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India

Nagashekhara Molugulu,     School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Anroop B. Nair,     Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia

Utpal Nandi,     PK-PD, Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India

Manisha Pandey,     School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Lipika Ray,     CSIR-Central Drug Research Institute, Lucknow, India

Bushra Riyaz,     Department of Pharmaceutics, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India

Rémi Rosière,     Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium

Rahul Shukla,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER, Raebareli), Raebareli, India

A. Sivakumar,     Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia

Paulina Skupin-Mrugalska,     Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Poznan, Poland

Kalvatala Sudhakar,     Department of Pharmaceutics, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India

Murtaza Tambuwala,     School of Pharmacy and Pharmaceutical Sciences, Saad Centre for Pharmacy and Diabetes, Ulster University, Coleraine, United Kingdom

Sebastien Taurin,     College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain

Chitra Thakur,     Department of Pharmaceutical Sciences, Wayne State University Detroit, MI, United States

Pushpendra Kumar Tripathi,     Department of Pharmacy, RITM, Affiliated Uttar Pradesh Technical University, Lucknow, India

S.P. Venkateswaran,     Division of Pathology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia

Nathalie Wauthoz,     Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium

Biography

Dr. Prashant Kesharwani is currently working as Assistant Professor, Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India. He received his doctoral degree in Pharmaceutical Sciences from the Dr. H.S. Gour University (Sagar, India) with Prof. N.K. Jain's group. He is a recipient of several internationally acclaimed awards, namely, Ramanujan Fellowship, DST, India-2017, Excellence Research Award-2014, Young Innovator Award (Gold Medal)-2012, International Travel Award/Grant from DST (New Delhi), and INSA (CCSTDS, Chennai)-2012. He has received an ICMR Senior Research Fellowship (Ph.D.) and AICTE Junior Research Fellowship (M. Pharm.). After his doctorate, he worked as a postdoctoral fellow in Wayne State University, Detroit (Michigan, USA). Dr. Kesharwani subsequently joined the School of Pharmacy, International Medical University (Malaysia) as lecturer in Pharmaceutical Technology. Subsequently he joined the Central Drug Research Institute (CDRI), Lucknow, as Ramanujan Fellow. An overarching goal of his current research is the development of nano-engineered drug-delivery systems for cancer treatment with a prime focus on dendrimer and polymeric nanomicelle-mediated drug-delivery systems. Dr. Kesharwani is a coauthor of more than 120 publications in high-impact factor international journals and 4 international books with total citations of more than 3300 (h index   =   27 and i-10 index = 65 as per Google Scholar).

Preface

The worldwide prevalence of lung cancer is the greatest amongst the other cancers and deaths due to lung cancer are also the highest. The global number of people dying of lung cancer is expected to nearly double to three million by 2035 due to aging populations, the tobacco pandemic, and air pollution in less developed countries. The standard therapy for patients with lung cancer is usually a combination of chemotherapy, surgery, and/or radiation therapy. As most lung cancers are detected at a late and metastatic stage, systemic chemotherapy is the mainstay option for the majority of patients. However, the efficacy of the treatment of lung cancer is plagued by dose-limited side effects to other organs. In recent years, these limitations have led to the development of strategies involving nanomedicines to improve tumor targeting and decrease systemic toxicity.

Nanotechnology provide an opportunity to change the pharmacokinetic outline of drugs, reduce toxicity, and enhance the therapeutic markers by development of multifunctional nanoparticles. Nanomaterials that are used in the treatment of lung cancer include polymeric nanoparticles, solid lipid nanoparticles, liposomes, niosomes, dendrimers, micelles, nanoemulsions, and nanomedicine-based inhalation system.

This book provides an overview of different aspects of nanomedicine, which help the readers to design and develop novel drug-delivery systems and devices that take advantage of recent advances in nanomedical technologies against lung cancer. The book consists of three introductory chapters giving an overview of the anatomy and physiology of the lung, followed by a discussion on the major challenges in the lung cancer therapy and receptors overexpressed in lung cancer. Several chapters are devoted to the latest technologies and advances in nanotechnology and include practical solutions on how to design more effective nanocarriers for drug and gene delivery for treatment of lung cancer. The book also contains specific chapters on nanomedicine-based inhalation systems for lung cancer and the development of novel diagnostic nano-imaging platforms as lung cancer therapeutics.

Focusing on the design, synthesis, and application of different nanocarriers in drug delivery as lung cancer therapeutics, this book will be a valuable resource for graduates, pharmaceutical scientists, clinical researchers, and anyone working to tackle the challenges of delivering drugs in a more targeted and efficient manner against lung cancer. In totality, this book will prove to be one of the most comprehensive books available that combines both the fundamental pharmaceutical principles of nanocarriers along with the most important applications of nanotechnology in targeting drug delivery against lung cancer.

I thank all the authors for their valuable contributions. This book brings pioneers of the field and early-career scientists together, which is no doubt an indication of the commitment toward the advancement of lung cancer therapeutics, to be continued across the generations to come. Featuring contributions from field experts and researchers in industry and academia "Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer" provides state-of-the-art information on nanocarriers and their use in targeting, as well as drug delivery against lung cancer.

We hope this book will stimulate further interest in the drug-delivery field, and that the readers of this book will find it useful.

Prashant Kesharwani

Chapter 1

An Overview of the Anatomy and Physiology of the Lung

H.H. Aung ¹ , A. Sivakumar ¹ , S.K. Gholami ¹ , S.P. Venkateswaran ² , Bapi Gorain ³ , and Shadab, Md ⁴       ¹ Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia      ² Division of Pathology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia      ³ School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Selangor, Malaysia      ⁴ School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Abstract

Byproducts of cellular respiration, including carbon dioxide, must be removed from cells immediately, through the circulation and finally to the outside of the body via the respiratory system to enable continuation of life and bodily functions. Understanding of the mutagenic development of cancers has led toward the development of novel treatment approaches, however an understanding of the basic architecture of the organ and its development helps. Therefore, in this chapter, the anatomy and physiology of the respiratory system are reviewed, including the embryonic development of the respiratory system followed by gross anatomy, innervation, blood circulation, and the microscopic structure of the lung and thoracic cavity. Then, the mechanism of breathing, pulmonary ventilation, and regulation of breathing are reviewed.

Keywords

Breathing; Expiration; Lungs; Respiratory system; Trachea

Outline

1. Introduction

2. Overview of the Anatomy of Lungs

2.1 Gross Anatomy

2.2 Tracheobronchial Tree

2.3 Microscopic Structure of Trachea

2.4 Microscopic Anatomy of the Lung

2.5 Intrapulmonary Bronchus

2.6 Bronchioles

2.7 Alveolar Duct

3. Blood Supply of the Lungs

3.1 Pulmonary Arteries

3.2 Pulmonary Veins

3.3 Bronchial Arteries

3.4 Bronchial Veins

3.5 Lymphatic Drainage of the Lungs

3.6 Nerve Supply of the Lungs

4. Overview of the Physiology of the Lungs

4.1 Mechanism of Breathing

4.2 Inspiration

4.3 Boyle's Law

4.4 Physical Properties of the Lungs

4.5 Compliance

4.6 Elasticity

4.7 Surface Tension

5. Expiration

6. Pulmonary Ventilation

6.1 Lung Volumes and Capacities

6.2 Dead Space

7. Gas Exchange

7.1 Oxygen Transport in the Blood

7.2 Factors That Affect Oxygen Carriage in Blood

7.3 Transport of Carbon Dioxide in the Blood

8. Control of Respiration

8.1 Chemoreceptors

9. Conclusion

Acknowledgments

References

1. Introduction

The respiratory system and cardiovascular system work together to provide oxygen-rich blood with hormones, nutrients, and other growing factors to each cell for cellular respiration, energy, and survival. Byproducts of cellular respiration, including carbon dioxide should be removed from cells immediately, through the circulation and finally to the outside of the body via the respiratory system enable continuation of life and bodily functions [1]. Understanding of the mutagenic development of cancers has led toward the development of novel treatment approaches, however an understanding of the basic architecture of the organ and its development helps [2]. During development of the embryo, the embryonic inner germ layer first forms the lungs in the primitive gut, following invasion three buds on the right and two buds on the left act as precursors for the lobes of the lungs and main-stem bronchi. During morphogenesis of the embryo, the complex lung architecture matures and becomes organized with different types of cells in a well-controlled manner. This fluid-secreting lung organ is converted to a breathing and absorbing organ by the millions of alveolar structures during birth. As the breathing movements of the lungs start before birth, some of the amniotic fluid enters into the lungs [3].

Most common morbidity and mortality cases of premature infancy are due to congenital deformities of the pulmonary developmental program in the embryo [4], however respiratory malformation of the newborn population is also considered to be one of the important causes of infant mortality and morbidity [5]. The complex vasculature system of the lungs developed during the embryonic stage facilitates efficient gaseous exchange between air and blood to maintain transition of oxygen and carbon dioxide from the blood. In the process of blood purification, it receives deoxygenated blood from the heart to oxygenate, whereas oxygenated blood from the aorta supplies pulmonary tissues for cellular activities [6]. Thus, pulmonary vasculature is entirely different to the systemic circulation, where the proximal vasculature consists of pulmonary arteries and veins, and the peripheral vasculature forms microvessels and capillaries to form the vascular beds in the alveolar region for gaseous exchange [7].

Determination of the development of cancer to this organ is solely dependent on mutation of cells leading to the expression of tumor-specific proteins, where an understanding of the critical architecture and physiology of the lungs helps in determining the existence and stages of this disease. Thus, the anatomical differentiation of the structure of the lungs and their association with adjoining organs, elucidates the site of origin of malignancies, spreading pattern, clinical presentation, and limitations of the available treatments by surgery or radiation [2]. Therefore, the objective of this chapter is to portray detailed anatomical and physiological features of the sections of the lungs, including blood supply, lymphatic drainage, and innervations of nerves in the light of natural tumors. It has also been enriched with breathing mechanism and ventilation-related physiology to emphasize the functional role of this organ. This chapter will provide a guide to readers who wish to develop novel treatment strategies for lung cancer or to readers aiming for a comprehensive treatment for thoracic ailments.

2. Overview of the Anatomy of Lungs

2.1. Gross Anatomy

Lungs are paired organs of respiration and lie in the thoracic cavity. The right and left lungs are separated from each other by the mediastinum, where the heart, great blood vessels, bronchi, esophagus, and other organs are located. Each lung is composed of respiratory passages and alveoli. Healthy lungs are soft and light. The stroma of the lung is made up of fibrous elastic connective tissue, allowing the lungs to recoil passively during expiration [8]. The surfaces of the lungs are covered by visceral pleura and the thoracic cavity is lined by parietal pleura. The pleural cavity is a potential space between the parietal and visceral pleurae. The pleural membranes produce a serous secretion, the pleural fluid which lubricates the pleural surfaces and allows the lungs to glide over the thoracic wall during breathing.

Lungs are cone-shaped organs and the narrow superior part is the apex, which is 2.5   cm above the middle of the clavicle. The apex is covered by the cervical pleura. The broad inferior part of the lung, which lies on the ipsilateral diaphragm, is the base. The right lung is comparatively larger than the left lung because the heart blobs more to the left than to the right. Each lung has three surfaces and three borders (Fig. 1.1).

The anterior border starts from the apex passing posterior to the sternoclavicular joint. On the right lung, it descends vertically along the lateral margin of sternum and meets the inferior border at the xiphisternal joint. The anterior border of the left lung descends down to the 4th costal cartilage, and passes laterally. It is more deeply indented by the cardiac notch. It curves downwards and medially to meet the 6th costal cartilage.

Figure 1.1 Lobes of the lungs. From: https://openstax.org/details/books/anatomy-and-physiology.

The inferior border crosses the 6th rib in the midclavicular line, 8th rib in the midaxillary line, and is directed towards the spinous process of the 10th thoracic vertebra.

The posterior border extends from the posterior end of the inferior border to the apex.

Each lung is divided into lobes by the fissures. The right lung has two fissures; the horizontal and oblique fissures, and three lobes, namely the upper, middle, and lower lobes. There are two lobes, the upper and lower lobes, divided by the oblique fissure in the left lung [9]. The oblique fissure extends from the spinous process of the 2nd thoracic vertebra running a spiral course downwards following the 6th rib to meet the inferior border at the 6th costal cartilage. The horizontal fissure of the right lung extends from the oblique fissure along the 4th rib and costal cartilage anteriorly.

The costal surface rests on the ribs and intercostal spaces of the thoracic cavity. It's related to the costal pleura.

The diaphragmatic surface forms the base of the lung. The concavity of the diaphragmatic surface of the right lung is deeper than that of the left lung because of the liver [10].

The mediastinal surface is related to the middle mediastinum and contains the hilum of the lung where the structures of the root enter and emerge from the lung. The structures of the root from front to back are the pulmonary veins, the pulmonary artery, and the bronchus.

On the right lung, there are impressions formed by the superior vena cava, arch of azygos vein, inferior vena cava, heart, and the esophagus on the mediastinal surface. Similarly, there are grooves for the descending aorta, arch of aorta, and cardiac impression on the mediastinal surface of the left lung [11].

2.2. Tracheobronchial Tree

The trachea is a fibrocartilaginous tube extending from the inferior end of the larynx (cervical vertebra 6) [12]. Its wall contains C-shaped cartilages, which are incomplete posteriorly and the gap is filled by smooth muscle called the trachealis muscle. It divides into right and left main bronchi at the level of thoracic vertebra 4 (TV4) (sternal angle). Each main bronchus enters the lung through the hilum [13].

The right main bronchus is shorter, wider, and more vertical than the left main bronchus.

Each main bronchus divides into lobar bronchi (secondary bronchi) within the lung to supply the lobes of the lung. Each lobar bronchus again divides into segmental bronchi (tertiary bronchi), which supply the bronchopulmonary segments.

The bronchopulmonary segments are pyramidal in shape with their apices toward the hilum and the bases lying on the surface of the lung. They are separated from one another by connective tissue septa. Each segment has a separate arterial supply (tertiary branch of the pulmonary artery) and function. They are drained by the intersegmental parts of pulmonary veins. There are 10 segments in the right lung and 8–10 in the left lung, depending on the combining of the segments. Infections and neoplastic diseases are often localized to one or more segments. The bronchopulmonary segments are surgically resectable and conservation of lung tissue is possible if the diseased segment is removed [14].

The segmental bronchi give rise to multiple generations of conducting bronchioles which end as terminal bronchioles. The terminal bronchioles further divide into microscopic branches known as respiratory bronchioles which, in turn, divide into several alveolar ducts that lead into alveolar sacs surrounded by clusters of alveoli.

2.3. Microscopic Structure of Trachea

In the mucosa the lining epithelium is pseudo-stratified columnar ciliated pseudostratified ciliated columnar (PSCC) epithelium with goblet cells. The epithelium rests on a very thick basement membrane. The lamina propria is a relatively thin layer and composed of longitudinally arranged elastic fibers which are a substitute for muscularis mucosae. The submucosa consists of many small mixed glands (serous and mucous glands) called tracheal glands. Their ducts open into the lumen of the trachea and are most frequently found as clusters in the interspaces of cartilages. The submucosa is separated from the adventitia by tracheal cartilages. They are C-shaped hyaline cartilage which opens posteriorly. This open interval is filled with a membrane of fibroelastic tissue and smooth muscles called the trachealis muscle. The adventitia lies peripheral to the cartilage rings and is composed of blood vessels, lymphatics, and nerves which supply the tracheal wall [15].

2.4. Microscopic Anatomy of the Lung

The fundamental component of the lung is a system of branching air tubes ending in compound sacs; conducting and respiratory divisions. Conduction division consists of branches of bronchi and all terminal bronchioles. The microscopic features of the extrapulmonary bronchus are the same as those of the trachea.

2.5. Intrapulmonary Bronchus

The lining epithelium is pseudo-stratified columnar ciliated epithelium (PSCC) epithelium with goblet cells. Lamina propria is thin and encircled by smooth muscles (muscularis mucosae). Its contraction causes the folding of the mucosa. Submucosa consists of mixed sero-mucous glands which decrease in number and size as the bronchi grow smaller. There are separate, irregular cartilage plates [16]. Adventitia is composed of moderately dense connective tissue.

2.6. Bronchioles

The largest bronchiole is about 1   mm in diameter and the smallest about 0.5   mm.

Epithelium is simple columnar ciliated, and goblet cells become less common and disappear in smaller tubes. Muscularis mucosae is relatively thicker and many elastic fibers intermingle with smooth muscles. Adventitia does not include the cartilage and glands. The bronchioles and smaller ducts have no tendency to collapse because the elastic framework of the lung tissue pulls on all sides of these tubes.

Respiratory division is composed of respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli. The fibrous tissue, smooth muscles, vessels, and nerves accompany the air passages. Respiratory bronchioles have a diameter of 0.5   mm or less. Epithelium ranges from simple columnar to simple cuboidal cells. There are no goblet cells, no cartilage, and no glands. Thin supporting wall consists of fibers, a spiral network of smooth muscles and elastic fibers.

Table 1.1 summarizes the microscopic changes in the wall of trachea, bronchus, and bronchioles.

2.7. Alveolar Duct

The lining epithelium is reduced to flattened. Spirals of smooth muscles and some connective tissue are present outside the epithelium. Clusters of alveoli (alveolar sacs) open into its lumen.

Atrium: any chamber between an alveolar duct and several air sacs.

Alveolar sac: lined by simple squamous epithelium and consists of variable numbers of alveoli. There are no muscles, no cartilage, and no glands. Two to five single or compound alveolar sacs open into each atrium. Alveolus: The alveolar epithelium consists of type I and II alveolar cells.

Table 1.1

Type I—pneumocyte cells or lining flat cells which form the barrier between air space and septal walls.

Type II—pneumocyte cells which produce surfactant and which decreases the alveolar surface tension.

Alveolar and septal macrophages are present in the alveolar air spaces and septal connective tissue, respectively. Air–blood barrier: Alveolar septum which consists of a thin layer of surfactant, type I epithelial cells, and capillary endothelial cells.

3. Blood Supply of the Lungs

3.1. Pulmonary Arteries

The right and left pulmonary arteries form the pulmonary trunk at the level of the thoracic vertebra. They convey the blood for aeration and divide into secondary lobar arteries. The lobar arteries again divide into tertiary segmental arteries. The arteries and bronchi are paired in the lungs.

3.2. Pulmonary Veins

The superior and inferior pulmonary veins of each lung collect the arterial blood from the corresponding lobes to the left atrium of the heart. Pulmonary veins are intersegmental in location and run in the connective tissue septa towards the hilum.

3.3. Bronchial Arteries

The right lung has one bronchial artery and the left one has two. They are branches of the thoracic aorta and supply the oxygenated blood to the supporting tissues of the lungs.

3.4. Bronchial Veins

The blood supplied to the lungs by the bronchial arteries is drained by the bronchial veins. The remaining venous blood is drained by the pulmonary veins. The left bronchial vein drains into the accessory hemiazygos vein or left superior intercostal vein, while the right bronchial vein drains into the azygos vein.

3.5. Lymphatic Drainage of the Lungs

The superficial lymphatic plexus lies deep to the visceral pleura and drains into the bronchopulmonary lymph nodes. The deep lymphatic plexus is situated in the submucosa of the bronchi and peribronchial connective tissue. Their lymph vessels drain into the pulmonary lymph nodes and then to the bronchopulmonary nodes and tracheobronchial lymph nodes. The whole right lung drains into the tracheobronchial lymph nodes and the superior part of the left lung similarly drains into the nodes on the left side. However, many lymphatics from the lower lobe of the left lung drain to the right tracheobronchial lymph nodes. Lymph from the right tracheobronchial lymph nodes finally drains into the right lymphatic duct, while the left tracheobronchial lymph nodes terminate in the thoracic duct [8].

3.6. Nerve Supply of the Lungs

Anterior and posterior pulmonary plexuses lie in front and behind the root of lung, and are formed by the branches of the vagus nerve and sympathetic trunks [14].

4. Overview of the Physiology of the Lungs

4.1. Mechanism of Breathing

Breathing, otherwise known as ventilation, is the movement of air from outside the body into the bronchial tree and alveolar spaces, which is followed by a reversal of this process. The actions that are responsible for this movement of air are called inspiration or inhalation and expiration or exhalation [1,17].

This movement of air in and out of the lungs occurs because of pressure differences induced by changes in lung volumes. Ventilation is induced by physical properties of the lungs, including surface tension, elasticity, and their compliance [1,17].

Air movement from higher to lower pressure, between the conducting zone and the terminal bronchioles, occurs because of the pressure differences between the two ends of the airways. Air flow through the bronchioles is directly proportional to the pressure difference and inversely proportional to the frictional resistance to the flow. The pressure differences in the pulmonary system are induced by changes in the lung volumes. The surface tension, elasticity, and compliance of the lungs are physical properties that affect the functioning of the lung [17,18].

4.2. Inspiration

Atmospheric pressure is the force that moves air into the lungs. At sea level, this pressure is sufficient to support a column of mercury (Hg) about 760   millimeters high in a tube. Therefore, normal air pressure equals 760   mmHg [18,19].

Air pressure is exerted on all surfaces in contact with the air. And, as we all breathe air, the inside surfaces of the lungs are also subjected to pressure. In other words, when the muscles of respiration are at rest, the pressures on the inside of the lungs and alveoli and on the outside of the thoracic cage are about the same [18,19].

4.3. Boyle's Law

Changes in the intrapulmonary pressure occur as a result of changes in lung volume. This follows Boyle's law, which states that the pressure of a given quantity of gas is inversely proportional to its volume. An increase in the lung volume during inspiration decreases the intrapulmonary pressure to subatmospheric levels; therefore, air goes in. A decrease in the lung volume, conversely, raises the intrapulmonary pressure above that of the atmosphere, expelling air from the lungs. These changes in lung volume occur because of changes in thoracic volume.

To illustrate this, pulling back on the plunger of a syringe increases the volume inside the barrel, lowering the pressure inside. Atmospheric pressure then pushes outside air into the syringe. In contrast, pushing on the plunger of a syringe reduces the volume inside the syringe, but the pressure inside increases, forcing air out into the atmosphere. Air moves in and out of the lungs in much the same way (Fig. 1.2) [17–19].

If the pressure inside the lungs and alveoli (intraalveolar pressure) decreases, outside air is pushed into the airways by the atmospheric pressure. This is what happens during normal inspiration, and it uses the muscle fibers of the diaphragm.

Figure 1.2 Changes in the air pressure causes the air movement into and out of the lung, similar to the movement of plunger in a syringe. 

Hole's Anatomy and Physiology, thirteenth ed.

The diaphragm's muscle fibers are stimulated to contract by impulses conducted by the phrenic nerves, which are associated with the cervical plexuses. When this occurs, the diaphragm moves downward, the enlargement of the thoracic cavity occurs (Fig. 1.3), and the intraalveolar pressure falls about 2   mmHg below atmospheric pressure. In response to this decrease in the intraalveolar pressure, air is forced into the airways by atmospheric pressure [20,21].

While the diaphragm is moving downwards and contracting, the external intercostal and certain thoracic muscles may be stimulated to contract. This action raises the ribs and causes sternal elevation, increasing the size of the thoracic cavity even more. This causes a further fall in the intraalveolar pressure, and the atmospheric pressure forces more air into the airways [17–19].

Lung expansion in response to diaphragmatic movements depends on the pleural membrane movements. Any separation of the pleural membranes decreases the pressure in the intrapleural space, resisting further separation and holding the membranes together [22].

In addition, only a thin film of serous fluid separates the parietal pleura from the visceral pleura. The water molecules in this fluid greatly attract the pleural membranes and each other, helping to hold the moist surfaces of these membranes tightly together. As a result of all these factors, when the intercostal muscles move the thoracic wall upward and outward, the parietal pleura moves too, and the visceral pleural follows. This helps the lung to expand in all directions [17–19,23].

4.4. Physical Properties of the Lungs

For inspiration to occur, the lungs must be able to expand when stretched, they must have high compliance. For expiration to occur, the lungs must get smaller when this tension is released; they must have elasticity. The tendency to become smaller is also aided by surface tension forces within the alveoli [17–19].

4.5. Compliance

The lungs are very distensible—they are, in fact, about 100 times more distensible than a balloon. Another term that is used for distensibility is compliance, which is referred to as the ease with which the lungs can expand under pressure [24].

Lung compliance can be defined as the change in lung volume per change in transpulmonary pressure, expressed symbolically as ΔV/ΔP. A given transpulmonary pressure will cause greater or lesser expansion, depending on the compliance of the lungs.

Figure 1.3 Maximal inspiration (a) Shape of the thorax at the end of normal inspiration. (b)Shape of the thorax at the end of maximal inspiration, aided by contraction of the sternocleidomastoid and pectoralis minor muscles. 

Hole's Anatomy and Physiology thirteenth edition.

The compliance of the lungs is reduced by factors that produce a resistance to its distension [24]. The infiltration of the lung with connective tissue proteins, a condition called pulmonary fibrosis, similarly decreases lung compliance. Conditions that obstruct air passages, destroy lung tissue, or impede lung expansion in other ways also decrease the compliance of the lung.

4.6. Elasticity

The term elasticity refers to the tendency of any structure to return to its initial size after being distended. Because of the high content of elastin proteins in the lungs, they are very elastic and resist distension. The lungs are normally stuck to the chest wall, so they are always in a state of elastic tension. This tension increases during inspiration when the lungs are stretched, and it is reduced by elastic recoil during expiration [17–19].

4.7. Surface Tension

The forces that act to resist distension include elastic resistance and the surface tension that is exerted by the fluid in the alveoli. The lungs both secrete and absorb fluid in two antagonistic processes that normally leave only a very thin film of fluid on the alveolar surface. Fluid absorption is driven (mainly through osmosis) by the active transport of Na+, while the fluid secretion is driven by active transport of Cl − out of the alveolar epithelial cells. Certain alveolar cells (type II pneumocytes), however, synthesize a mixture of lipoproteins called surfactant, which is secreted continuously into the alveolar air spaces. This secretion reduces the alveoli's tendency to collapse, especially when lung volumes are low, and makes it easier for inspiratory efforts to inflate the alveoli [25,26].

The thin film of fluid normally present in the alveolus has a surface tension, produced because water molecules at the surface are attracted more to other water molecules than to the air. As a result, the surface water molecules are pulled tightly together by the attractive forces from underneath. This surface tension acts to collapse the alveolus, and in the process increases the pressure of air within the alveolus. As described by the Laplace law, the pressure thus created is directly proportional to the surface tension and inversely proportional to the radius of the alveolus. According to this law, the pressure in a smaller alveolus would be greater than that of a larger alveolus if the surface tension were the same in both. The greater pressure of the smaller alveolus would cause it to empty its air into the larger one. This does not normally occur because, as an alveolus decreases in size, its surface tension is decreased, while its radius is reduced.

5. Expiration

The forces that are responsible for normal resting expiration come from the elastic recoil of the lung and abdominal organs and from surface tension. The lungs contain a substantial amount of elastic tissue, which stretches as the lung expands during inspiration. When the diaphragm is lowered, the abdominal organs inferior to it are compressed. As the diaphragm and external intercostal muscles relax following inspiration, the elastic tissues of the lung cause it to recoil and return them to their original shapes [17–19].

Similarly, elastic tissues in the abdominal organs cause them to spring back into their original shape, pushing the diaphragm upward. At the same time, surface tension that develops between the moist surfaces of the alveolar lining shrinks them. Each of these factors increases the intraalveolar pressure by about 1   mmHg above atmospheric pressure, forcing air inside the lungs out through the respiratory passages. Normal resting expiration occurs passively without the contraction of muscles [17–19].

The recoil of the elastic fibers in the lungs reduces the pressure in the pleural cavity. Consequently, intrapleural pressure is about 4   mmHg less than atmospheric pressure.

A person can exhale more air than normal by contracting the expiratory (posterior internal) intercostal muscles. These muscles pull the sternum and ribs downward and inward, increasing the air pressure in the lungs, pushing more air out. Also, the muscles of the abdominal wall, including the external and internal obliques, the transversus abdominis, and the rectus abdominis, squeeze the abdominal organs inward. Thus, the abdominal wall muscles can increase the pressure in the abdominal cavity and force the diaphragm still higher against the lungs, pushing additional air out of the lungs (Fig. 1.4) [17–19].

6. Pulmonary Ventilation

6.1. Lung Volumes and Capacities

The total lung capacity in normal healthy male is 5700   mL (4200   mL in female), depending on age, distensibility of the lungs, and the presence or absence of respiratory disease. However, lungs operate at about half capacity, and the lung can never be completely deflated. The beneficial effect of incomplete deflation of the lung is that gas exchange can continue through the respiratory membrane even during maximal expiratory efforts. In addition, it reduces the work of breathing [17–19].

Changes in lung volume can be determined with a spirometer in a process called spirometry. A subject breathes in a closed system in which air is trapped within a light plastic ball floating in water. With inhalation, the ball moves up and it moves down with exhalation, which consequently moves the pen and traces a record of the breathing called a spirogram (Fig. 1.5).

Lung volume and capacities (Table 1.2) are affected by age, sex, and body size; women, for instance, have lower lung volume and capacities compared to men [27]. Vital capacity gradually declines as we age. In addition, vital capacity is higher in tall people than short people, whilst trained athletes have 30–40% higher vital capacity as opposed to untrained people. Normal lung volumes and capacities are impaired in obstructive (difficulty in emptying the lung, such as asthma) and restrictive (difficulty in filling the lungs, such as pulmonary fibrosis) disease [28]. In obstructive disease, the resistance to air flow increases due to bronchoconstriction, therefore, the vital capacity is normal, whilst expiration takes a longer time. By contrast, in restrictive lung disease, vital capacity is reduced, whereas the expiratory rate is normal.

Figure 1.4 Expiration. (a)Normal resting expiration is due to elastic recoil of the lung tissues and the abdominal organs. (b) Contraction of the abdominal wall muscles and posterior internal intercostal muscles aids maximal expiration. 

Hole's Anatomy and Physiology thirteenth edition.

Figure 1.5 A spirogram showing lung volumes and capacities in a healthy